Infliximab for pediatric patients with Crohn’s disease: A Phase 3, open-label, uncontrolled, multicenter trial in Japan

Objectives The prevalence of pediatric Crohn’s disease (CD) is increasing in Japan and other countries, and many patients are unresponsive to or do not tolerate current treatment options. This study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe CD and inadequate response to existing treatment. Study design This was an open-label, uncontrolled, multicenter Phase 3 study conducted at nine sites in Japan between April 2012 and March 2015. Pediatric patients (aged 6–17 years) with moderate-to-severe CD were treated with IFX 5 mg/kg at Weeks 0, 2, and 6, and at 8-week intervals thereafter until Week 46, with final evaluation at Week 54. IFX dose was increased to 10 mg/kg in patients who showed loss of response to IFX from Week 14 onwards. Results A total of 14 patients fulfilled eligibility criteria and were treated. Dose-escalation criteria were met by five patients who then received 10 mg/kg IFX. The remaining nine patients continued to receive an IFX dose of 5 mg/kg. IFX rapidly improved clinical symptoms and its effect was maintained for up to 54 weeks. Overall Pediatric Crohn’s Disease Activity Index (PCDAI) response rate was 85.7%, and overall PCDAI remission rate was 64.3%. Three out of five patients who increased IFX dose regained PCDAI remission by retrieval of serum IFX concentration. Adverse events and serious adverse events occurred in 100.0% and 14.3% of patients, respectively. There was no substantial difference in the safety profiles of patients taking a constant dose of 5 mg/kg and those taking an increased dose of 10 mg/kg. Conclusions These findings support the effective use of IFX in the treatment of pediatric patients with CD where other treatments have proven ineffective.


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Objectives: To assess the efficacy of TA-650 until Week 30 in pediatric patients with moderate to severe ulcerative colitis when TA-650 is administered at a dose of 5 mg/kg at Weeks 0, 2 and 6, followed by administration at 8-week intervals at Weeks 14 and 22, based on the evaluation index such as CAI score. Also to assess the safety and pharmacokinetics of TA-650. Methodology: Open label, uncontrolled multi-center study Number of patients (Planned and analyzed): Planned: Target number of patients: 20 patients, as the number of patients who received the study drug Analyzed: 21 patients registered; 21 patients in the efficacy analysis set, 21 patients in the safety analysis set; 21 patients in the pharmacokinetic analysis set Diagnosis and primary criteria for inclusion: Patients who satisfied all of the following inclusion criteria (including both inpatients and outpatients).
Patients who were diagnosed as having ulcerative colitis according to the revised draft of the Diagnostic Criteria for Ulcerative Colitis established by the Ministry of Health, Labour and Welfare (MHLW) Study Group for Specific Diseases/Intractable Inflammatory Bowel Disease (revised on February 13, 2010), and had been suffering for at least 3 months at the time of obtainment of informed consent.
(2) Patients aged not less than 6 years and not more than 17 years old (at the time of obtaining consent).
(3) Patients whose legal representative can give consent in writing and patients who can give themselves give oral or written assent for participation in this study.
(4) Patients with a CAI score of not less than 7 and a score for blood in stools of not less than 2 at the time of registration (5) Patients who had at least one of the treatment experiences listed in the following 1) to 4).
1) 6-mercaptopurine or azathioprine: Patients who had been using the drug for at least 12 weeks before the starting day of screening period, and receiving the drug at a stable dose for at least 4 weeks before the starting day of screening period.
2) Steroids (oral preparation): Patients using steroids at a stable dose of at least 1 mg/kg/day or at least 20 mg/day calculated on a prednisolone basis for at least 2 weeks before the starting day of screening period.
3) Patients who had either of the following experiences within 5 years before the starting day of screening period.
 Use of 6-mercaptopurine or azathioprine for at least 12 weeks, but having an inadequate response.  Use of 6-mercaptopurine or azathioprine, and having the experience of an adverse drug reaction that made it difficult to continue the treatment. 4) Patients who had at least one of the following experiences within 18 months before the starting day of screening period.
 Experience of an exacerbation or relapse in response to a reduction in the steroid dose, and failure of steroid withdrawal.  Use of steroid but having an inadequate response (using steroids at a dose of at least 1 mg/kg/day or at least 40 mg/day calculated on a prednisolone basis for at least 2 weeks Volume: Name of Active Ingredient: Infliximab (genetically-modified) Page: orally or for at least 1 week by intravenous injection but no therapeutic effects were obtained).  Use of steroids and experiencing an adverse drug reaction that made it difficult to continue treatment.
(6) Patients satisfying the following criteria for drug therapy used on the starting day of the screening period.
1) 6-mercaptopurine or azathioprine: Patients who had been using the drug for at least 12 weeks before the starting day of screening period, and receiving the drug at a stable dose for at least 4 weeks before the starting day of screening period, or had not used the drug for at least 4 weeks before the starting day of the screening period.
2) Steroids (oral preparations): Patients who had been using the drug at a stable dose for at least 2 weeks before the starting day of the screening period, or had not used the drug for at least 2 weeks before the starting day of screening period.
3) 5-aminosalicylate agents (oral preparations) or salazosulfapyridine agents (oral preparations): Patients who had been using the drug at a stable dose for at least 2 weeks before the starting day of the screening period, or had not used the drug for at least 2 weeks before the starting day of the screening period.
Study drug, dose and mode of administration, lot number:  Study drug: TA-650 (infliximab [genetically-modified])  Dose and mode of administration: TA-650 was administered at a dose of 5 mg/kg based on the body weight on each day of administration by intravenous drip infusion over at least a 2-hr period on the starting day of the study drug administration (Week 0) and at Weeks 2 and 6. Patients who had a clinical response measured by CAI score at Week 8 were further given the study drug at Weeks 14 and 22 in a similar manner. However, patients who had no response measured by the CAI score would not be given the study drug after Week 14.  Lot No.:110001, 120075 Control drug, dose and mode of administration, lot number: Not applicable Duration of treatment: Screening period: Period from the starting day of the CAI score evaluation to the start of the study treatment. Evaluation period: Period from the start of the study treatment to the evaluation day at Week 30; for CAI score-based non-responders and discontinued patients, period from the start of the study treatment to the end of the evaluation at 8 weeks after the last treatment. Criteria for evaluation Efficacy: (1) CAI score (2) CAI score-based remission (1) Serum infliximab concentrations (serum TA-650 concentrations) (2) Antibodies to infliximab (antibodies to TA-650, hereinafter referred to as ATI) Page: Statistical methods: (1) Efficacy Efficacy analysis set was the full analysis set (hereinafter referred to as FAS). Analysis of each endpoint other than steroid dose was performed in the same manner in the descriptions shown below.
Both of the results for which an imputation of missing data was not performed (data at each evaluation point include those at the "last" time point) and those for which an imputation (treatment failure, hereinafter referred to as TF) was applied were shown (except for summary statistics of each subscore).

1) CAI score (a) Endpoints
 CAI score and CAI score-based remission rate (b) Analysis method  Summary statistics of CAI score and CAI score change, and CAI score-based remission rate at each evaluation point were calculated.
2) Partial Mayo score (a) Endpoint  Partial Mayo score (b) Analysis method  Summary statistics of partial Mayo score and partial Mayo score change at each evaluation point were calculated.
3) Mayo score (a) Endpoints  Mayo score, Mayo score-based response rate, Mayo score-based remission rate, and rate of mucosal healing (b) Analysis method  Summary statistics of Mayo score and Mayo score change, and Mayo score-based response rate, Mayo score-based remission rate and rate of mucosal healing at each evaluation point were calculated. 4) PUCAI score (a) Endpoints  PUCAI score, PUCAI score-based remission rate, and proportion of patients who achieved a PUCAI score decrease by at least 20 points (b) Analysis method  Summary statistics of PUCAI score and PUCAI score change, PUCAI score-based remission rates, and the proportion of patients who achieved a PUCAI score decrease by at least 20 points at each evaluation point were calculated.

5) Steroid dose (a) Endpoints
 Steroid dose and rate of steroid withdrawal (b) Analysis method  Among FAS, those patients who had been using steroids (oral preparation) at the time of registration were included in the analysis set.
 Both of the results for which an imputation of missing data was not performed (data at each evaluation point include those at the "last" time point) and those for which an imputation (TF) was applied were shown.
 Summary statistics of steroid dose and rate of steroid dose change, and rate of steroid withdrawal at each evaluation point were calculated.
(2) Safety Patients in the safety analysis set were analyzed.
The incidence rates of AEs and ADRs during the evaluation period were calculated. In addition, the incidence rates of AEs by timing, infusion reactions by the number of doses, infusion reactions per one dose of the study drug, infusion reactions by ATI, and AEs by severity were calculated. Furthermore, the incidence rates of abnormal changes for the general laboratory tests, cross tabulation of each determination result for the immunoserological tests, and summary statistics for the physical examination were tabulated.
(3) Evaluation of pharmacokinetics 1) Analysis method  Summary statistics of serum infliximab concentrations at each evaluation time point were listed.
 The frequency distribution and proportions of ATI determination (negative, positive or inconclusive) were listed. In addition, the summary statistics of serum infliximab concentration by ATI determination at each evaluation time point were listed. Summary-Conclusions Efficacy results: (1) The CAI score (Mean ± SD) was 9.7 ± 2.7 at the time of registration, but decreased over time to 4.0 ± 3.2, 3.5 ± 3.5 and 3.2 ± 3.5 respectively at Weeks 2, 6 and 8. The CAI score ranged from 2.5 ± 2.3 to 3.5 ± 2.2 during the period from Week 10 to Week 30, and that at the last time point was 5.6 ± 3.8. The CAI score changes (Mean ± SD) were -5.5 ± 2.7, -6.0 ± 4.0 and -6.2 ± 3.7 at Weeks 2, 6 and 8, indicating an increase in the degree of score change with time, and ranged from -5.9 ± 3.8 to -6.9 ± 3.8 during the period from Week 10 to Week 30, and that at the last time point was -4.1 ± 4.2. In terms of both CAI score and CAI score change, the effect of the study drug in improving symptoms was observed from Week 2, and the effect lasted up to Week 30. Data on both CAI score and CAI score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(2) The CAI score-based remission rate was 60.0% (12/20) at Week 2, and increased to 80.0% (16/20) at both Weeks 6 and 8, and ranged from 64.3% to 87.5% during the period from Week 10 to Week 30. The CAI score-based remission rate at the last time point was 42.9% (9/21). In terms of CAI score-based remission rate, the study drug was observed to have the effect of bringing the clinical condition of patients to remission from Week 2, and this effect was confirmed to last up to Week 30. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(3) The partial Mayo score (Mean ± SD) was 5.6 ± 1.6 at the time of registration, and decreased over time to respectively 2.6 ± 2.3, 2.2 ± 2.0 and 1.7 ± 1.7 at Weeks 2, 6 and 8, and ranged from 1.8 ± 1.7 to 2.8 ± 1.9 during the period from Week 10 to Week 30. The partial Mayo score at the last time point was 3.7 ± 2.2. The partial Mayo score changes (Mean ± SD) at Weeks 2, 6 and 8 were respectively -2.9 ± 2.2, -3.3 ± 2.2 and -3.8 ± 1.7, indicating an increase in the degree of score change with time. The partial Mayo changes ranged from -2.6 ± 2.8 to -3.6 ± 2.5 during the period from Week 10 to Week 30, and the change at the last time point was -1.9 ± 2.7. In terms of partial Mayo score and partial Mayo score change, the effect of the study drug in improving symptoms was observed from Week 2, and the effect lasted up to Week 30. Data on partial Mayo score and partial Mayo score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(4) The Mayo score (Mean ± SD) was 7.0 ± 2.4 at the time of registration, but decreased to 4.9 ± 2.4 at Week 30. The Mayo score at the last time point was 5.0 ± 2.3.The Mayo score changes (Mean ± SD) at Week 30 and the last time point were respectively -2.6 ± 3.9 and -2.0 ± 3.9. Data on both Mayo score and Mayo score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(5) The Mayo score-based response rate and Mayo score-based remission rate at Week 30 were respectively 42.9% (3/7) and 14.3% (1/7), and at the last point were respectively 37.5% (3/8) and 12.5% (1/8). Both Mayo score-based response rate and Mayo score-based remission rate calculated based on data obtained by TF imputation were similar to those obtained before imputation. Page: (6) The PUCAI score (Mean ± SD) was 47.1 ± 15.2 at the time of registration and decreased over time to 20.3 ± 16.3, 17.3 ± 17.5 and 12.5 ± 13.5 respectively at Weeks 2, 6 and 8. The score ranged from 12.2 ± 12.0 to 19.3 ± 18.8 during the period from Week 10 to Week 30, and was 28. 8 ± 22.5 at the last time point. The PUCAI score changes (Mean ± SD) were -25.8 ± 17.5, -28.8 ± 21.1 and -33.5 ± 14.0 at Weeks 2, 6 and 8 respectively, and ranged from -26.8 ± 27.8 to -34.1 ± 17.7 during the period from Week 10 to Week 30. The score at the last time point was -18.3 ± 28.4. In terms of both PUCAI score and PUCAI score change, the effect of the study drug in improving symptoms was observed from Week 2, and lasted up to Week 30. Data on PUCAI score and PUCAI score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(7) The PUCAI score-based remission rate was 35.0% (7/20) at Week 2, and increased to 40.0% (8/20) at both Weeks 6 and 8. Afterward, the rate ranged from 28.6% to 42.9% during the period from Week 10 to Week 30, and was 19.0% (4/21) at the last time point. It was observed that the drug had the effect of leading the clinical condition of patients to remission from Week 2, and it was confirmed that the effect lasted. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation. (8) The proportion of patients who achieved a PUCAI score decrease by at least 20 points was 68.4% (13/19) at Week 2, and increased to 73.7% (14/19) and 89.5% (17/19) at Weeks 6 and 8, respectively. Afterward, the proportion ranged from 64.3% to 88.2% during the period from Week 10 to Week 30, and was 60.0% (12/20) at the last time point. The effect of the study drug to improve the score was observed from Week 2, and it was confirmed that the effect lasted thereafter. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation. (9) The rate of mucosal healing at Week 30 and the last time point were 33.3% (2/6) and 28.6% (2/7), respectively. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(10) In 12 patients who had been using steroids (oral preparations) at the time of registration, the median steroid dose was 0.20 mg/kg/day at the time of registration, but decreased to 0.19, 0.17 and 0.16 mg/kg/day respectively at Weeks 2, 6 and 8. The median steroid dose ranged from 0.04 mg/kg/day to 0.15 mg/kg/day during the period from Week 10 to Week 30, and was 0.05 mg/kg/day at the last time point. The median rates of steroid dose change were -1.63%, -25.05% and -43.91% respectively at Weeks 2, 6 and 8, and the degree of change increased over time. The median rate of steroid dose change ranged from -61.72% to -86.93% during the period from Week 10 to Week 30, and was -85.44% at the last time point. Data on both steroid dose and rate of steroid dose change obtained by TF imputation showed a similar tendency to data obtained before TF imputation, suggesting that the study drug may possibly decrease the steroid dose. (11) The rate of steroid withdrawal was 8.3% at Week 2, and increased over time to 25.0% at both Page: Weeks 6 and 8. The rate of steroid withdrawal ranged from 25.0% to 37.5% during the period from Week 10 to Week 30, and was 41.7% at the last time point. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation. Two patients achieved steroid withdrawal at Week 30, and one of these patients also achieved CAI score-based remission. (12) The patients included in the efficacy analysis set were divided into two groups, one for those aged not less than 6 years and less than 12 years, and another for those aged not less than 12 years and not more than 17 years, and efficacy of the study drug was evaluated for each group. As a result, both of the two groups included a different number of patients, but the efficacy of the study drug between the two groups was not considered significantly different.
(13) The median trough serum infliximab concentrations in CAI score-based responders were respectively 2.58, 1.54 and 1.34 μg/mL, at Weeks 14, 22 and 30 thus indicating that the serum infliximab concentration was maintained.
(14) The median CAI score changes at Week 30 in each of the 4 groups by serum infliximab concentration, i.e. less than 0.1 μg/mL, not less than 0.1 and less than 1 μg/mL, not less than 1 and less than 10 μg/mL, and not less than 10 μg/mL, were respectively -4.5 and NC (impossible to calculate), -6.0, and NC. The CAI score changes in individual patients included in the group which exhibited NC were -4 and -3 in the group of not less than 0.1 and less than 1 μg/mL , and -10 in the group of not less than 10 μg/mL. Based on these results, though some of the serum infliximab concentration groups included a small number of patients, it was observed that a higher serum infliximab concentration tended to show better efficacy.
(15) Throughout the study period, the results for ATI determination were inconclusive in 81.0% (7/21) and negative in 19.0% (4/21) in the overall population, and none of the patients exhibited positive results.
Based on the above results, it was shown that TA-650 given to pediatric patients with moderate to severe ulcerative colitis at a dose of 5 mg/kg at Weeks 0, 2 and 6 was able to improve the clinical symptoms of ulcerative colitis and achieve mucosal healing. Continuous administration at 8-week intervals at Weeks 14 and 22 was also confirmed to maintain the effect of the drug. In addition, it was suggested that administration of TA-650 might enable decreased steroid dose or steroid withdrawal.
Safety results: Safety evaluation was performed on 21 patients who received the study drug at least once and whose safety data after the start of administration of the study drug was obtained. Based on that evaluation, the following conclusions were obtained.
The system organ classes (SOCs) of AEs having the highest incidence rate were "infections and infestations" and "investigations," each having an incidence rate of 57.1% (12/21), and "gastrointestinal disorders" having an incidence rate of 52.4% (11/21). The AEs with a high incidence rate were "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21), and "nasopharyngitis" having an incidence rate of 33.3% (7/21). The SOCs of ADRs having a high incidence rate were "investigations" having an incidence rate of 57.1% (12/21), and the ADR having a high incidence rate was "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21).
(2) The incidence rates of serious AEs and serious ADRs were 14.3% (3/21) and 4.8% (1/21), respectively. "Colitis ulcerative" (recorded as "worsened ulcerative colitis" by the investigator) occurred in 2 patients, but a causal relationship of this event with the study drug was ruled out. Since serious ADR, "enterocolitis" was observed. This event was moderate and recovery occurred without any treatment.
(3) The incidence rate of AEs leading to discontinuation of the study was 4.8% (1/21), and the event was "colitis ulcerative" (recorded as "worsened ulcerative colitis" by the investigator).
No ADRs leading to discontinuation of the study were observed.
(5) The incidence rates of infusion reactions and infusion reactions (ADRs) were both 9.5% (2/21). The events were moderate and mild, each observed in one patient, but in both of the events recovered occurred on the same day that the reactions occurred. No serious infusion reactions and infusion reactions leading to discontinuation of treatment were observed. (6) The incidence rate of immunoserological test-related AEs was 57.1% (12/21), and the incidence rates of "double stranded DNA (IgM) antibody positive" and "antinuclear antibody increased" were respectively 57.1% (12/21) and 4.8% (1/21). No patients were observed to have experienced a change from negative to positive to double stranded DNA IgG antibody, which is said to be correlated with lupus-like syndrome. Furthermore, lupus-like syndrome did not occur in any patients.
(7) No events to be noted related to the study drug, such as malignancy (including hepatosplenic T-cell lymphoma which has been reported in children and young adults), demyelinating disorders, interstitial pneumonia, liver dysfunction, delayed hypersensitivity (including serum sickness-like reaction), congestive cardiac failure, serious blood disorder and rhabdomyolysis, were observed.
(8) There were 7 laboratory parameters where the incidence rate of abnormal change in general laboratory values was not less than 10%, including urine protein (increase) and urinary occult blood (increase) each having an incidence rate of 47.6% (10/21), ALT (GPT) (decrease) having an incidence rate of 33.3% (7/21), white blood cell count (decrease), ALP (decrease), γ-GTP (decrease) and BUN (decrease) each having an incidence rate of 14.3% (3/21). No changes in laboratory parameters which were clinically significant were observed. (9) The changes in summary statistics of physical examinations (systolic and diastolic blood pressure, pulse rate, and body temperature) did not show any problematic tendencies. As an AE related to physical examinations, "blood pressure decreased" occurred in 4.8% (1/21) of the patients, but a causal relationship of this event with the study drug was ruled out.
Based on the results of safety evaluation obtained for 30 weeks in this study where TA-650 was administered to pediatric patients with moderate to severe ulcerative colitis up to Week 22, it was confirmed that this study drug was mostly tolerable. In addition, similarly to the safety profiles for the approved indications including ulcerative colitis in adults, some events related to infections, infusion reactions, and immunoserological tests were observed. The frequency and severity of the events of concern related to the study drug administration had not increased significantly, and it was considered that no new events to be noted were observed.

Conclusions:
In this study, it was observed that TA-650 had the effect of improving clinical conditions and achieving mucosal healing when administered to pediatric patients with moderate to severe ulcerative colitis at a dose of 5 mg/kg at Weeks 0, 2 and 6 and at 8-week intervals thereafter. It was also suggested that the treatment with the study drug in the above-mentioned manner might allow for a decreased steroid dose or steroid withdrawal while maintaining the effect. In terms of safety of the drug, though many infections, infusion reactions and events related to immunoserological tests were observed similarly to the safety profile observed in adult patients with ulcerative colitis, the frequency of occurrence and severity of the events of concern related to the study drug administration were not significantly increased. Based on these results, TA-650 was considered effective in pediatric patients with ulcerative colitis.  Period from the starting day of the CAI score evaluation to the start of administration of the study drug. Efficacy evaluation period Period from the start of administration of the study drug to the evaluation day at Week 30; for patients who had no response measured by CAI score (CAI score-based non-responders), period from the start of administration of the study drug to the evaluation at Week 8; for discontinued patients, period from the start of administration of the study drug to the evaluation at the time of discontinuation. Safety and pharmacokinetics evaluation period (= Evaluation period) Period from the start of administration of the study drug to the evaluation day at Week 30; for CAI score-based non-responders and discontinued patients, period from the start of administration of the study drug to the evaluation 8 weeks after the last administration. Evaluation day Day when the evaluation (medical examination) necessary to determine CAI score, partial Mayo score and PUCAI score was made. CAI score-based responder Patient who had a decreased (improved) CAI score at Week 8 compared to that measured at the time of registration. CAI score-based non-responder Patient who had an unchanged or increased (worsened) CAI score at Week 8 compared to that measured at the time of registration. Evaluation period for CAI score based on Symptom Assessment Sheet Evaluation period for partial Mayo score based on Symptom Assessment Sheet The evaluation period for CAI score is the period from 7 days before the evaluation day to the day before the evaluation day; the evaluation period for Mayo score is the period from 3 days before the evaluation day to the day before the evaluation day. However, if drugs that might affect stool frequency were used, 7 days or 3 days before the evaluation day excluding the following days is used as the evaluation period for Symptom Assessment Sheet. [Days excluded from evaluation]  Days when drugs for the treatment of constipation or diarrhea were used  Days when drugs having a potent antidiarrheal effect (e.g., loperamide hydrochloride, opium alkaloids, atropine sulfate-containing preparations) were used and for 2 days after the use of the above drugs (3 days in total)  Days when drugs that might affect stool frequency (e.g., laxatives) were used as pretreatment of sigmoidoscopy  Days when colonoscopy or sigmoidoscopy was performed and for 3 days after the examination (4 days in total) CAI score A sum (0 to 29 points) of subscores for 7 clinical criteria, consisting of the number of stools per week, blood in stools (based on weekly average), investigator's global assessment of symptomatic state, abdominal pain, temperature elevation due to ulcerative colitis, extraintestinal manifestations, and laboratory findings.

Table of Contents
CAI score-based remission Cases where a CAI score was not more than 4 on the evaluation day (excluding the evaluation at the time of registration). Mayo score A sum (0 to 12 points) of 4 Mayo subscores (stool frequency, rectal bleeding, physician's global assessment, and findings of endoscopy) assessed by the investigator (subinvestigator) based on a 4-point scale of 0 to 3. Partial Mayo score A sum (0 to 9 points) of Mayo subscores for stool frequency, rectal bleeding, and physician's global assessment. Mayo score-based response Case where the Mayo score measured on the evaluation day (excluding the evaluation at the time of registration) satisfied the following two criteria. -Mayo score: A decrease by at least 30% and by at least 3 points compared to those measured at the time of registration. -Rectal bleeding subscore: A decrease by at least 1 point compared to that measured at the time of registration or a rectal bleeding subscore of not more than 1 point. Mayo score-based remission Mayo score on the evaluation day (excluding the evaluation at the time of registration) was not more than 2 points and none of the subscores were more than 1 point. PUCAI score A sum (0 to 85 points) of subscores for 6 clinical conditions, consisting of abdominal pain, rectal bleeding, stool consistency, stool frequency per 24 hours, nocturnal stool, and activity level. PUCAI score-based remission Case where PUCAI score on the evaluation day (excluding the evaluation at the time of registration) was less than 10.

Steroid withdrawal
Case where the steroid dose on the evaluation day (excluding the evaluation at the time of registration) was 0. Mucosal healing A subscore for endoscopy findings of the Mayo score on the evaluation day (excluding the evaluation at the time of registration) was not more than 1, excluding patients whose subscore for findings of endoscopy at the time of registration was 1.

Infusion reaction
AEs observed during study drug administration or within 2 hours after the end of administration Left-sided colitis Lesion limited distal to the splenic flexure Total colitis Lesion extending proximal to the splenic flexure Legal representative An individual or judicial or other body authorized to consent to the subject's participation in a clinical study on behalf of a prospective subject who is incapable of giving informed consent. Legal representative includes parents, guardian, and any equivalent individual, and must be one who can act in the subject's best interest in terms of the mutual relation between actual quality of life and mental aspects. Assent Consent obtained from pediatric patients who were not subject to legal regulations. Prior to the start of the study, the appropriateness of how the study was conducted was reviewed by each IRB for the 34 participating study sites from ethical, scientific and medical standpoints based on the investigator's brochure, protocol, written information for legal representatives and informed consent form, written information for patients and assent form, and sample CRF. As results, the conduct of the study was approved at 22 sites, and was decided to be approved after correction at the other 13 sites. The conditions for approval include partial modification of the written information for legal representatives and informed consent form, written information for patients and assent form and document about compensation to patients. All of these changes were minor and did not affect the entire aspect of the protocol. When the protocol, the investigator's brochure, written information for legal representatives and informed consent form, and written information for patients and assent form were revised during the study, the study was continued after obtaining approval from the IRBs. A list of the IRBs is provided in Appendix 16.1.3a.

Ethical Conduct of the Study
This study was conducted in accordance with ethical principles that have their origins in the Declaration of Helsinki and in compliance with "Act on Securing Quality, Efficacy, and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products and Cosmetics," "Ministry of Health and Welfare Ordinance on Good Clinical Practice (GCP)" and the protocol.
Statements regarding GCP compliance were described in the protocol and the study contract, and the sponsor visited the medical institutions regularly and confirmed that the study was actually conducted in compliance with GCP. Safety information obtained during the study was immediately reported to investigators who made arrangements for a safe study. In preparation and handling of CRFs and submission of data to the regulatory authority, patient identification codes not linkable to the identity of the patients were used to ensure confidentiality of information of the patients.
Throughout the study period, no significant violation of GCP was reported from the medical institutions, and it was confirmed that this study was conducted ethically while ensuring safety of the patients.

Patient Information and Consent
Prior to the start of the study, the investigator (subinvestigator) provided legal representatives and candidate patients with the IRB-approved written information for legal representatives and informed consent forms, and written information for patients and assents form respectively, and fully explained the contents of the study. Supplemental explanations by a study collaborator were also allowed. The investigator (subinvestigator) tried to provide the explanations using language that was as simple as possible in a way that legal representatives and patients could easily understand, and sufficiently answer the questions from legal representatives and patients. After confirming that the legal representative and patient had fully understood the contents of the study, the investigator (subinvestigator) obtained written informed consent from each legal representative and written assent (consent obtained from pediatric patients who were not subject to legal regulations), if possible from each patient of their own free will.
On the written informed consent form, the investigator (subinvestigator) who provided an explanation and the legal representative signed and sealed or placed their signatures, and the dates respectively. On the written assent form, the investigator (subinvestigator) who provided an explanation and the patient signed and sealed or placed their signature and the dates respectively. In the case where a study collaborator provided supplemental explanation, the relevant study collaborator also signed and sealed, or placed their signature, and the date. In addition, the investigator (subinvestigator) confirmed that the relationship between a legal representative and a patient was described on the written consent form signed by the legal representative. Before the start of administration of the study drug, consent was obtained from all of the patients by means of a written assent form.
Before patients participated in this study, the investigator (subinvestigator) issued a written information and consent form, and written information and assent form, both signed/sealed or signed and dated, to the legal representatives and patients, while the original copies of the consent form and assent form were properly stored in accordance with the rules of the relevant medical institution.
The date when informed consent was obtained and the version numbers of the written information and informed consent form used for explanation were recorded in the CRF.
When new important information which might affect the consent from legal representatives or the assent from patients were obtained, the investigator immediately judged the necessity for revision of the written information and consent form and the written information and assent form based on the obtained information. When revision of the written information and consent form and the written information and assent form was judged to be necessary, the investigator immediately revised the written information and consent form and the written information and assent form and submitted the revised documents to the sponsor, while obtaining approval from the IRB again. In this case, the investigator (subinvestigator) reported the relevant information to the patients who had already participated in the study and their legal representatives orally, confirmed whether they would continue to participate in the study or not, and recorded them in the medical record. The investigator (subinvestigator) gave an explanation to the patients who had already participated in the study and their legal representatives using the IRB-reapproved written information for patients and assent form and written information for legal representatives and informed consent form respectively, and obtained assent and written consent for continuous participation in the study from the patients and legal representatives respectively of their own free will. Similar to obtaining of the first consent, the investigator (subinvestigator) who provided an explanation, patients and the legal representative signed and sealed, or placed their signature and the dates respectively. In the case where a study collaborator provided supplemental explanation, the relevant study collaborators also signed and sealed or placed their signature and the dates. The investigator (subinvestigator) issued written information and consent form, and written information and assent form, both signed/sealed or signed and dated, to legal representatives and patients, while the original copies of the consent form and assent form were properly stored in accordance with the rules of the relevant medical institution. The dates when informed consent was again obtained and the version numbers of the written information and informed consent form used for the explanation were recorded in the CRF.
During the study period, the written information for legal representatives and informed consent form was revised 5 times due to the obtaining of safety information that might affect the patient's consent and amendments to the Japanese package insert. The written information for patients (for those aged 13 years or older) and assent form was revised 4 times, and the written information for patients (for those aged 12 years or younger) and assent form has not been revised. At each revision, written informed consent and assent were reobtained from all of the legal representatives and patients respectively participating in the study.
The 6th version (prepared on August 6, 2014) of written information for legal representatives and informed consent form (sponsor's final version), the 5th version (prepared on August 6, 2014) of written information for patients and assent form (for those aged 13 years or older, sponsor's final version), the 1st version (prepared on December 20, 2011) of written information for patients and assent form (for those aged 12 years or younger, sponsor's final version), a list of revisions, and a list of versions for medical institutions are attached in Appendix 16.1.3b to Appendix 16.1.3i.

Investigators and Study Administrative Structure
The history of changes until the date of preparation of this report is described as regards persons in charge at the sponsor, medical experts, clinical operation team leaders, and persons in charge of audit. For other items, the history of changes until the date of submission of clinical trial completion notification (April 24, 2015) is described. Scope of services: Confirming that human rights, safety, and the welfare of the patients are protected; that the study is conducted in compliance with the latest protocol and GCP, etc.; and that the study data are accurate and complete and can be examined with study-related records including source documents Scope of services: Systematic and independent examination of work and documents related to the study to evaluate that work and records, analysis and accurate reports of data related to the study were conducted in accordance with Pharmaceutical Affairs Law, regulatory requirements including GCP ordinance, standard operating procedures and protocols.

Safety Evaluation Committee
Akira Watanabe, Professor, Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer, Tohoku University Scope of services: If any serious adverse events including infections occurred during the period of the study, the safety evaluation committee members assessed the safety information and gave the sponsor advice on the continuation, revision or discontinuation of the study.

Study Centers and Investigators
A list of participating study centers and investigators is provided in Appendix 16.1.4.
Scope of services of investigators: Investigators agree on the study protocol prepared by the sponsor, prepare and revise the written information and consent form, select candidate patients and obtain consent from them, conduct the study, provide medical care and information to patients, give guidance and supervise subinvestigators and study collaborators, provide materials and information, provide help in monitoring and audit, report deviations from or changes of the study protocol and adverse events, prepare case report forms, and store documents or records related to this study.

Introduction
The study drug TA-650 (non-proprietary name: infliximab, trade name: Remicade ® ) is an anti-human tumor necrosis factor-α (TNFα) monoclonal antibody discovered and manufactured by Centocor, Inc. (present Janssen Biotech, Inc., US) using genetic engineering techniques, and that affects various inflammatory diseases related to TNFα by neutralizing TNFα and by damaging cells expressing membrane-bound TNFα. From 1998 to August 2014, TA-650 has been approved in 105 countries, including Japan and administered to approximately 2.21 million patients. In Japan, TA-650 has been approved as a treatment for Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis vulgaris, psoriasis arthropathica, pustular psoriasis, erythrodermic psoriasis, ulcerative colitis, refractory uveoretinitis induced by Behcet's disease, and gastrointestinal-, neuro-and vascular Behcet's disease. In addition, dose increase and shortening of the dosing interval for rheumatoid arthritis and dose increase for Crohn's disease, and gastrointestinal-, neuro-and vascular Behcet's disease have been approved. Presently, the applications of partial changes in the approved items for a dose increase for Kawasaki disease and psoriasis have been submitted. TA-650 has been approved for Crohn's disease and ulcerative colitis in pediatric patients overseas.
Ulcerative colitis is a diffuse non-specific inflammatory disease of unknown etiology, primarily affecting the mucosa membrane of the large intestine where erosion and ulcers are often formed. Ulcerative colitis is a disease with lesions continuously extending proximally from the rectum proximally, up to the entire colon, and is characterized by chronic bloody mucoid stools and bloody stools. Some patients with ulcerative colitis repeat relapse and remission, and require long-term medical control due to difficulties in treatment. At present, removal of the large intestine is the only therapy to radically treat ulcerative colitis, and ulcerative colitis is a specified intractable disease. The number of patients with ulcerative colitis has been increasing, and a medical care certificate for patients with ulcerative colitis was issued to more than 110,000 patients in fiscal 2009, when this study was planned, and more than 150,000 patients had the medical care certificate for patients with ulcerative colitis in fiscal 2013. Though the number of pediatric patients experiencing onset in childhood is small compared to adult patients, it is showing a trend to increase the same as in adult patients.
Primary treatment of ulcerative colitis is drug therapy. Some patients repeat relapse and remission, resulting in difficulty in treating the disease. The Guidelines for the Treatment of Ulcerative Colitis (2010) established by the "Intractable Inflammatory Bowel Disease Study Group" of the MHLW, which was the current version when this study was planned, stated that the therapeutic plan should be established based on severity and lesion extent. Patients with mild to moderate ulcerative colitis are treated with oral preparations or intestinal injection of aminosalicylates or intestinal injection of steroids. Patients refractory to the above agents or having a severe form of ulcerative colitis are treated with oral preparations or intravenous infusion of steroids. Steroid therapy is the primary treatment for ulcerative colitis, and a good remission induction therapy if used under an adequate dosing regimen. However, steroid therapy is less effective in maintaining remission, and administering steroids without any specific goal would cause more adverse drug reactions. Immunomodulators are used on steroid-dependent or resistant patients which are refractory cases. Treatment with cyclosporine, tacrolimus and cytapheresis is used for the purpose of remission induction; and azathioprine and 6-mercaptopurine are used for the purpose of remission maintenance. However, there exist numerous cases where patients are not adequately responding to treatment with existing drugs, and are eventually referred to surgery. Against this background, TA-650 was approved for use in patients with ulcerative colitis in June 2010, and positioned as a therapeutic drug for ulcerative colitis to be used in steroid-resistant or dependent patients by the above-mentioned guideline for treatment. These problems relating to the therapy for ulcerative colitis are also observed in pediatric patients. Furthermore, pediatric ulcerative colitis is characterized by a higher likelihood of extended and/or severe lesions compared to adults. In addition, long-term administration of steroids may be likely to cause steroid-related complications such as failure to thrive and steroid dependence and therefore many patients receive active therapies such as immunomodulators.
The results of the C0168T72 study on pediatric patients with ulcerative colitis and the ACT1 and ACT2 studies in adult patients, each conducted in foreign countries suggested that efficacy, safety profile, and pharmacokinetics of TA-650 in children are similar to those in adults. Based on the results of the above studies, TA-650 was approved for treatment of ulcerative colitis in children under a dosing regimen of 5 mg/kg administration at Weeks 0, 2 and 6 followed by administration at 8-week intervals, which is the same regimen as that for adults, in the US and EU respectively in September 2011 and February in 2012.
In contrast, no domestic clinical trials of TA-650 in pediatric patients with ulcerative colitis have been conducted, and "children" is not clearly specified in the description of dosage and administration, therefore physicians may hesitate to use TA-650 on pediatric patients with ulcerative colitis who require administration of this drug. To resolve these problems, it was decided to conduct a clinical study of TA-650 in pediatric patients with ulcerative colitis to evaluate the efficacy, safety and pharmacokinetics of TA-650 when administered at a dose of 5 mg/kg at Weeks 0, 2 and 6 followed by administration at 8-week intervals at Weeks 14 and 22.
In preparing the protocol for this study, we held face-to-face consultations with the Pharmaceuticals and Medical Devices Agency on December 21, 2010. The minutes of this consultation (prepared on February 3, 2011) are attached as Appendix 16.1.13h.
In this consultation, we agreed to widely evaluate not only the pharmacokinetics but also the efficacy and safety, and to make a comprehensive judgment, since the evaluation would be performed based on the data obtained from limited number of patients in a clinical trial in pediatric patients with ulcerative colitis. In terms of evaluation indices, endoscopy causes physical and emotional suffering in patients, and also places a great burden on physicians as well as patients since pediatric patients as young as 6 to 8 years old sometimes undergo endoscopy under general anesthesia, it was therefore considered difficult to add endoscopy as an essential test item. However, since endoscopy is an important test item for evaluating the efficacy of the study drug in patients with ulcerative colitis, we agreed to perform endoscopy as much as possible in order to accumulate data. In addition, we agreed to give consideration to avoiding creating an imbalance to a certain age group among the target patient ages.

Study Objective
The purpose of this study was to evaluate efficacy of TA-650 up to Week 30 when administered to pediatric patients with moderate to severe ulcerative colitis at a dose of 5 mg/kg at Weeks 0, 2 and 6, followed by administration at 8-week intervals at Weeks 14 and 22 using the evaluation indices including CAI score. Safety and pharmacokinetics of TA-650 are also assessed.

Overall Study Design and Plan-Description
The protocol (Ver. 02.00.00000, prepared on May 22, 2013) and the list of changes in the protocol are respectively attached as Appendix 16.1.1a and Appendix 16.1.1b, and the case report form (Ver. 01.00.00000, prepared on December 20, 2011) is attached as Appendix 16.1.2. All of the medical institutions that the sponsor requested to conduct the study used the protocol and the case report form sample prepared by the sponsor, and no medical institution version of each document was prepared.

Treatment Method Studied
TA-650 was administered at a dose of 5 mg/kg based on the body weight on each day of administration by intravenous drip infusion over at least a 2-hour period. Patients were given the study drug at the initial administration (Week 0) and at Weeks 2 and 6, and the responders measured by a CAI score (CAI score-based responder) determined at Week 8 were further given the study drug at Weeks 14 and 22. However, the CAI score-based non-responders were not given the study drug after Week 14.

Type of Control and Study Configuration
Not applicable because this study was an uncontrolled study.

Method of Assignment to Treatment
Not applicable because this study was an uncontrolled study.

Sequence and Duration of Study Period
The study design is shown in Figure 9.1-1. Patients who had an unchanged or increased (worsened) CAI score at Week 8 compared to that measured at the time of registration (CAI score-based non-responders) were not given the study drug after Week 14, and completed the study after the end of evaluation of safety and pharmacokinetics at Weeks 10 and 14.
Study period: Period from the starting day of the screening period to the last day of the evaluation period.
Screening period: Period from the starting day of CAI score evaluation to the start of administration of the study drug.
Evaluation period: Period from the start of administration of the study drug to the evaluation day at Week 30. For CAI score-based non-responders and discontinued patients, the period from the start of administration of the study drug to the evaluation 8 weeks after the last administration.
[Definition of each evaluation period] Efficacy evaluation period: Period from the start of administration of the study drug to the evaluation day at Week 30. For CAI score-based non-responders, the period from the start of administration of the study drug to the evaluation at Week 8; for discontinued patients, the period from the start of administration of the study drug to the evaluation at the time of discontinuation.
Safety and pharmacokinetic evaluation period (= Evaluation period): Period from the start of administration of the study drug to the evaluation day at Week 30. For CAI score-based non-responders and discontinued patients, the period from the start of administration of the study drug to the evaluation 8 weeks after the last administration.

Study period
Screening period Efficacy/ Safety/ PK evaluation period CAI score-based responder CAI score-based non-responder CAI score-based responder: Patient who had a decreased (improved) CAI score at Week 8 compared to that measured at the time of registration CAI score-based non-responder: Patient who had an unchanged or increased (worsened) CAI score at Week 8 compared to that measured at the time of registration.

Identification of When Patients were Randomized
Not applicable because this study was an uncontrolled study.

Various Committees Established and Their Roles
Based on the results obtained by previous domestic and overseas clinical studies and post-marketing safety information for TA-650, it is known that TA-650 should be administered while giving sufficient attention to serious infections such as tuberculosis, opportunistic infection and sepsis, so it was necessary to proceed with this study by paying careful attention to the safety of patients. Consequently, the safety evaluation committee was established for the purpose of evaluating safety information obtained during the study from an objective standpoint and providing the sponsor with advice concerning continuation, change or discontinuation of the study.
The safety evaluation committee consisted of one physician who was independent of the sponsor, the medical expert and investigators (subinvestigators), and possessed expertise in infections, and the member of the committee evaluated safety information in accordance with the operating procedures for the safety evaluation committee. The operating procedures for the safety evaluation committee are attached as Appendix 16.1.13b.

Interim Analyses
Interim analyses were not planned and performed.

Discussion of Study Design, Including the Choice of Control Groups
Reasons for open label and uncontrolled: Pediatric ulcerative colitis is characterized by a higher likelihood of extended and/or more severe lesions compared to adults, a likelihood of steroid-related complications such as failure to thrive and a likelihood of having steroid dependence, so the therapy of ulcerative colitis in children aims at suppressing disease activity to improve their quality of life (hereinafter referred to as QOL) and avoiding failure to thrive. Since a study using placebo as a comparator would adversely affect the growth and development of patients to be studied in this study who have inadequate response to the existing therapies, use of placebo in this study was considered to present ethical difficulties. In addition, since the "pediatric" patients with "moderate to severe ulcerative colitis," who received the medical care certificate for ulcerative colitis in fiscal 2009, to be studied in this study included those who might be able to maintain remission by existing therapies and those with indications for surgical procedures such as failure to thrive, undernutrition, and worsened QOL specific to children, it was considered that patients actually eligible for this study would be even fewer and the number of patients accumulated for this study would be limited. Consequently, this study was designed to be conducted as an open label and uncontrolled study.

Inclusion Criteria
Patients who satisfied all of the following inclusion criteria were included in the study (including both inpatients and outpatients).
(1) Target disease: Ulcerative colitis Patients who were diagnosed as having ulcerative colitis according to the draft of the Diagnostic Criteria established by the MHLW "Study Group for Specific Diseases/Intractable Inflammatory Bowel Disease" (revised on February 13, 2010) (Attachment 1 of Appendix 16.1.1a), and had been suffering for at least 3 months at the time of consent obtainment.
(2) Patients aged not less than 6 years and not more than 17 years (at the time of consent obtainment).
(3) Patients whose legal representative would give consent in writing, and who can give oral or written assent by themselves for participation in this study. (Depending on the understanding of each patient, written assent was obtained from patients of approximately junior high school age or older. For patients of approximately less than junior high school age, written assent was obtained if possible.) (4) Patients with a CAI score of at least 7 and blood in stools score in a CAI score of at least 2 at the time of registration.
(5) Patients who satisfied at least one of the treatment experiences listed in the following 1) to 4).
1) 6-Mercaptopurine or azathioprine: Patients who had been using the drug for at least 12 weeks before the starting day of screening period, and receiving at a stable dose for at least 4 weeks before the starting day of screening period.
2) Steroids (oral preparations): Patients who had been using the drug at a stable dose of at least 1 mg/kg/day or at least 20 mg/day calculated on a prednisolone basis for at least 2 weeks before the starting day of screening period.
3) Patients who experienced either of the following within 5 years before the starting day of the screening period.
 Had used 6-mercaptopurine or azathioprine for at least 12 weeks, but had an inadequate response.
 Had used 6-mercaptopurine or azathioprine, and experienced an adverse drug reaction that made it difficult to continue the treatment.
4) Patients who experienced at least one of the following within 18 months before the starting day of screening period.
 Experienced an exacerbation or relapse of the disease in response to a reduction in the steroid dose, and failed to withdraw from steroid use.
 Had used a steroid, but had an inadequate response (No clinical response to steroids at a dose of at least 1 mg/kg/day or at least 40 mg/day calculated on a prednisolone basis for at least 2 weeks for oral preparations or at least 1 week for intravenous injection).
 Had used steroids and experienced an adverse drug reaction that made it difficult to continue the treatment.
(6) Patients who satisfied any of the following with regard to medication being used at the start of screening period.
1) 6-Mercaptopurine or azathioprine: Patients who had been using the drug for at least 12 weeks before the starting day of screening period, and receiving at a stable dose for at least 4 weeks before the starting day of screening period, or those who had not used the drug for at least 4 weeks before the starting day of screening period.
2) Steroids (oral preparations): Patients who had been using the drug at a stable dose for at least 2 weeks before the starting day of screening period, or had not used the drug for at least 2 weeks before the starting day of screening period.
3) 5-aminosalicylate agents (oral preparation) or salazosulfapyridine agents (oral preparation): Patients who had been using the drug at a stable dose for at least 2 weeks before the starting day of screening period, or had not used the drug for at least 2 weeks before the starting day of screening period.
[Rationale for Setting] (1)(4)(5) These were established since this study targeted patients with ulcerative colitis who had an inadequate response to existing therapies.
(2) Based on the objectives of this study, since the draft of revision of guideline for treatment of pediatric ulcerative colitis (2008) (Working Group for Preparation of the Guideline for Treatment of Ulcerative Colitis, Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition) states that a child is defined as a person aged less than 18 years from the viewpoint that children are in the process of growing, the upper limit of age criterion was set as not more than 17 years old. In addition, from an epidemiological viewpoint, patients with ulcerative colitis aged less than 6 years old are considered to be very rare, so the requirement for an age of not less than 6 years old was set.
(3) This criterion was set in order to conduct the clinical trial ethically.
(6) Conditions for using therapeutic drugs commonly used for treatment of ulcerative colitis were made uniform for all patients before the start of efficacy evaluation in order to appropriately evaluate the efficacy of the study drug during the study period.

Exclusion Criteria
Patients who met any of the following exclusion criteria were excluded from the study.
(1) Patients who had total colitis (lesion extending proximal to the splenic flexure) and that satisfied either (1) or (2) below: 1) Patients diagnosed as needing a colectomy at the time of registration.
2) Patients who satisfied at least 4 of the following (a) to (e) at the time of registration.
(a) At least 6 episodes of bloody diarrhea daily (b) Intense abdominal pain or rebound tenderness (c) Persistent pyrexia of not less than 37.5°C (d) Pulse rate: more than 90 beats/min (e) Hemoglobin: less than 8.5 g/dL (2) Patients who underwent surgery for ulcerative colitis within 8 weeks before registration, or those for whom surgery for ulcerative colitis was deemed necessary at the time of registration.
(3) Patients who underwent any surgical operation that required caution to prevent postoperative infections within 4 weeks before registration.
(4) Patients who had severe and symptomatic fibrotic stenosis in the large or small intestine.
(5) Patients who had evidence of intestinal stenosis or obstruction, or had intestinal stenosis or obstruction confirmed by enema X-ray, colonoscopy, or sigmoidoscopy within 6 months before registration.
[A stenosis was defined as a narrowing adjacent to which there is a dilation of the proximal intestinal tract on the edema X-ray or a narrowing that an endoscope cannot pass through.] (6) Patients with a past or current history of fistula.
(8) Patients who satisfied any of the following 1) to 4): 1) Patients with current or past dysplasia of the colonic mucosa.
3) Patients suffering from total colitis for at least 8 years.
4) Patients suffering from left-sided colitis for at least 10 years (lesion limited distal to the splenic flexure).
However, enrollment was allowed for patients who could be confirmed to have no evidence of dysplasia of the colonic mucosa or adenomatous colonic polyp by colon cancer screening (colonoscopy and biopsy) performed within 1 year before registration of patients who satisfied the above 3) or 4).
(11) Patients who had a lesion limited to the rectum only or in the colon up to 20 cm.
(12) Patients who were previously treated with infliximab or other biological products (such as anti-TNFα agents and anti-IL-6 agents).
(13) Patients who had used immunomodulators (excluding azathioprine, and 6-mercaptopurine methotrexate) such as cyclosporine, tacrolimus (excluding for external use), methotrexate, mycophenolate mofetil and mizoribine within 8 weeks before the starting day of the screening period.
(14) Patients who received cytapheresis within 4 weeks before the starting day of screening period.
(15) Patients who used any of the following drugs/therapies within 1 week before the starting day of the screening period.

1) Total parenteral nutrition
2) Total enteral nutrition [Total enteral nutrition refers to the delivery of total nutrient requirements enterally (nutrient or digest diet nutrient), instead of consumption of a normal diet, low-residue diet, or semidigest diet nutrient, which is followed according to the investigator's (sub investigator's) instructions.] (16) Patients who were on chronic use of nonsteroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) (injection/oral/suppository). However, the temporary (a maximum of 4 weeks) use for the purpose of treatment of AEs or use of low-dose aspirin for prevention of heart attack, unstable angina, or transient ischemic attack was allowed.
(17) Patients with infections: 1) Patients complicated with any serious infection (active hepatitis, pneumonia, pyelonephritis, etc.) requiring hospitalization or with a history of these infections within 6 months before registration.
2) Patients complicated with opportunistic infection (cytomegalovirus infection, systemic fungal infection, pneumocystis pneumonia, nontuberculous mycobacterial infection, etc.) or with a history of these infections within 6 months before registration.
3) Patients complicated with active tuberculosis. 4) Patients with a history or a suspected diagnosis of tuberculosis infection. However, this criterion did not apply to use of antituberculosis drugs (isoniazid [INH], in principle) from at least 3 weeks before the scheduled starting day of administration of the study drug.
[Patients corresponding to either of the following conditions are defined as patients with suspected tuberculosis infection.]  Patients with findings matching old pulmonary tuberculosis (including pleural adhesions or calcification only) by imaging examination.  Patients exposed to other patients with active tuberculosis.
 Patients who tested positive for QuantiFERON (QFT) test or T-spot.TB test.
In patients whose judgment by QFT test or T-spot.TB test was put on hold or who were tuberculin test-positive (patients suspected of being infected with tuberculosis in consideration of the effect of Bacille de Calmette et Guérin [BCG] vaccination), treatment with antitubercular drugs was not mandatory in the case where investigators (subinvestigators) judged that suspected tuberculosis infection was able to be refuted based on the results of other screening tests for tuberculosis (such as chest X-ray, chest CT scan and medical examination).
Assessment of the results of imaging examinations was performed in consultation with the specialist as needed. (18) Patients with a history of hypersensitivity to mouse-derived proteins (murine-, chimera-and humanized antibodies, etc.).
(19) Patients with a complication or history of demyelinating diseases (multiple sclerosis, etc.).
(20) Patients with a complication of congestive cardiac failure.
(21) Patients with a history or a complication of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location, or clinically significant hepatomegaly or splenomegaly.
(22) Patients with a family history of lymphoma or leukemia.
(23) Patients with malignant tumor or a history of malignant tumor within 5 years before registration.
(24) Patients with a laboratory test value corresponding to any of the following 10 test items at the time of registration. The test values measured after obtaining informed consent and within 2 weeks before registration. (27) Patients who had been inoculated with live vaccines within 3 months before the start of administration of the study drug.
(28) Patients who had difficulties in repeated blood collection during the study period.
(29) Patients who did not consent to use contraception during the period from the starting day of study drug administration to 6 months after the last treatment.
(30) Female patients who were pregnant or potentially pregnant, or lactating mothers.
(31) Patients who had participated in another clinical study and had received another study drug within 12 weeks before obtainment of informed consent.
(32) Patients who were judged to be ineligible for the study by the investigator (subinvestigator).
Note) Each period was calculated as described below.
The following examples show the minimum unit of year, month or week.
 At least one week before the starting day of the screening period means before the same day of the week during the week before the starting day of the screening period.
 One month before the starting day of the screening period means the same date during the month before the starting day of the screening period.
 One year before the starting day of screening period means the same date during the year before the starting day of screening period.
[Rationale for Setting] (1) Patients with ulcerative colitis who were systemically ill were excluded to ensure the patient's safety.
(2) Any surgical procedure for ulcerative colitis before the start of the study and during the study affects the efficacy and safety evaluation of TA-650. Therefore, patients who underwent surgery and seemed likely to need surgery were excluded.
(3) (17) This criterion was set because TA-650 may affect immune responses, and may cause increased susceptibility to infections in these patients accordingly.
(4) (5) This criterion was set because patients listed in these criteria seemed likely to need surgery or affect the efficacy evaluation in terms of the number of stools, abdominal pain, etc.
(6) This criterion was set because patients listed in this criterion seemed likely to need surgery, which may affect efficacy or safety evaluation accordingly.
(7) This criterion was set because toxic megacolon is extremely severe and an indication for surgery.
(9) This criterion was set because it was considered difficult to make an appropriate efficacy evaluation in terms of the number of stools and rectal bleeding in patients who underwent enterostomy.
(10) (11) These criteria were set because it was considered inappropriate to assess TA-650 in patients with localized lesions.
(12) This criterion was set because the safety and efficacy in this study may be biased by the previous clinical evaluation of infliximab, the identical component as the study drug, etc. and the serum TA-650 concentration and ATI may also be affected. In addition, this criterion was set because other biological products may similarly affect the evaluation of safety and efficacy.
(13) to (16) These criteria were set because it was considered that the efficacy evaluation of TA-650 would be affected.
(18) This criterion was set because a hypersensitive reaction due to TA-650 administration may occur in these patients.
(19) (20) These criteria were set because TA-650 may induce relapse or aggravation of symptoms.
(21) to (23) These criteria were set because TA-650 may affect the immune response and therefore administration of TA-650 might increase the risk of development of malignant tumors such as malignant lymphoma.
(25) This criterion was set because TA-650 administration may cause symptoms that suggest lupus-like syndrome in these patients.
(28) This criterion was set because assessment of the study drug would be difficult.
(29) (30) These criteria were set because the safety of TA-650 with regard to reproductive and developmental toxicity has not been established in humans.
(31) This criterion was set in order to conduct this study in an ethical manner. In addition, it was set because the effects of drugs which have not been well established are unpredictable in terms of their efficacy and safety.
(32) This criterion was set in order to conduct this study in a safe and ethical manner.

Removal of Patients from Therapy or Assessment
(1) Discontinuation criteria for patients If any of the following discontinuation criteria applied, treatment was discontinued.
1) Upon request from the legal representative or the patient to discontinue participation in the study.
2) When the investigator (subinvestigator) considered it inappropriate to continue the study for the relevant patient due to an exacerbation of ulcerative colitis (for example, use of prohibited concomitant drugs/therapies, excluding incision for drainage).
3) When the investigator (subinvestigator) considered it difficult to continue the study for the relevant patient due to AEs. If a lupus-like syndrome occurred, and the patient was found to be positive for double stranded DNA antibodies (double stranded DNA IgM antibody titer of ≥6 U/mL or double stranded DNA IgG antibody titer of >12 IU/mL), the study for the relevant patient was to be discontinued. 4) When the patient was found to be apparently ineligible for the study from the standpoint of safety assurance or efficacy evaluation after the start of administration of the study drug.
5) Other situations where the investigator (subinvestigator) considered it necessary to discontinue the study.
[Rationale for Setting] These criteria were set in order to conduct the study in an ethical manner and to also take the patients' safety into consideration.
(2) Procedure for discontinuation of the study When the study was discontinued during the evaluation period, the investigator (subinvestigator) took appropriate action for the relevant patient, and immediately notified the monitor of the matter. The investigator (subinvestigator) performed examinations and observations specified at the time of discontinuation and 8 weeks after the last treatment.
The investigator (subinvestigator) documented the day of discontinuation, reason for discontinuation and the details, circumstances that leading to discontinuation, and subsequent course after discontinuation in the CRF. When the study was discontinued due to AEs, the investigator (subinvestigator) documented AE terms leading to discontinuation in the discontinuation page in the CRF. The day of discontinuation was defined as the day when assessment at the time of discontinuation was performed (day when medical examination for assessment at the time of discontinuation was performed). When the assessment at the time of discontinuation was not able to be performed, the day when discontinuation was decided was referred to as the day of discontinuation.
The investigator (subinvestigator) followed patients for whom the specified observations/examinations were not able to be performed within 8 weeks after the last treatment or those who failed to visit the hospital after discontinuation by means of mail (sealed letter) or telephone etc. to obtain the information such as the reason and their subsequent courses, and documented the result in the discontinuation page in the CRF. The investigator (subinvestigator) were to collect Symptom Assessment Sheets from patients who did not visit the medical institutions as much as possible through mail or other method.
The investigator (subinvestigator) or the study collaborator collected the Symptom Assessment Sheet from patients who failed to visit the study site by means of mail etc. as much as possible.
(3) Discontinuation or suspension of the study 1) Criteria for discontinuation or suspension of the study In the following cases, the sponsor examined the appropriateness of continuing the study in the entire or a part of medical institutions.
(a) When the sponsor obtained information related to the quality, efficacy, or safety of the study drug, or other important information for proper conduct of the study.
(b) When the sponsor was advised to terminate the study by the safety evaluation committee.
(c) When any revision to the protocol became necessary, but the medical institution was not able to deal with it.
(d) When any correction to the protocol, etc. was proposed by the director of the medical institution based on the opinions of the IRB, but the sponsor was not able to accept it.
(e) When discontinuation of the study was instructed by the director of the medical institution based on the decision of the IRB of the medical institution.
(f) When the medical institution seriously or persistently violated GCP, the protocol, or the study contract.
2) Discontinuation or suspension of the entire study based on the decision of the sponsor Upon decision of discontinuation or suspension of the entire study, the sponsor was to immediately notify the director of the medical institution as well as regulatory authorities in writing of the matter and the reason for termination or suspension. Upon receipt of notification of discontinuation or suspension of the study from the sponsor, the director of the medical institution was to immediately notify the investigator and the IRB in writing of the matter and the details of the reason.
Upon receipt of notification of termination or suspension of the study from the sponsor through the director of the institution, the investigator was to immediately notify patients of the matter, and ensure appropriate treatment and other procedures for patients.
Handling of patients at discontinuation of the study should be performed according to " (2) Procedure for discontinuation of the study." 3) Discontinuation or suspension of the study at the relevant medical institution based on the decision of the investigator or the IRB If the investigator decided discontinuation or suspension of the study at that investigator's own discretion, the investigator was to immediately notify the director of the medical institution in writing of the matter and the details of the reason. The director of the institution was to immediately notify the sponsor and the IRB of the matter in writing. If the IRB decided upon termination or suspension of the study at its own discretion, it was to immediately notify the director of the medical institution of the matter in writing. The director of the institution was to immediately notify the investigator and the sponsor of the matter in writing.

4) Discontinuation of the study based on cancellation of the contract with the medical institution
If the sponsor discontinued the study because the medical institution seriously or persistently violated GCP, the protocol, or the study contract during the study period, the sponsor was to immediately report the matter to regulatory authorities. 9.4.1 Treatments

Dosage Regimen and Route of Administration of the Study Drug
TA-650 was administered at a dose of 5mg/kg based on the body weight of patient on each administration day by intravenous drip infusion over at least a 2-hr period. The study drug was administered at the initial treatment (Week 0) and Weeks 2 and 6, and CAI score-based responders based on determination of CAI score at Week 8 were further given the study drug at Weeks 14 and 22 in a similar manner. However, CAI score-based non-responders did not receive the study drug after Week 14.

Method of Preparation
The dose required for administration was calculated based on the patient's body weight (by rounding off to the whole number) on the day of administration, and diluted with approximately 250 mL of physiological saline. The dissolution of the study drug was performed before use, and treatment was started within 3 hours after dissolution. To patients whose body weight on the day of administration was less than 20 kg, the study drug was diluted with approximately 100 mL of physiological saline and administered.

Dosage Form and Content
TA-650 100 mg vial: A vial containing 100 mg of infliximab supplied as a lyophilized product. It is an injection used by dissolving in water for injection (JP grade) and diluting with physiological saline (JP grade) before use. Note: Unused drugs will be collected after completion of the study.

Manufacturer and Batch Number
TA-650 100 mg vial: 110001, 120075 (batch number) The study drug was obtained from Janssen Biotech, Inc.

Study Drug Management
The sponsor supplied the study drug to medical institutions after first concluding a clinical trial contract with the institutions. The study drug manager stored and managed the study drug according to the "Procedure for Study Drug Management" (Appendix 16.1.13a) specified by the sponsor. After completion of the study, the unused study drug, the study drug which was prescribed but returned before preparation, and empty boxes were returned to the monitor. The study drug was not used for purposes other than those specified in the protocol (such as other clinical studies, animal experiments and basic experiments).

Allocation of the Study Drug
Not applicable because this is an uncontrolled study.

Registration of Patients
Patients were registered into the study in accordance with the procedures shown in the method for registration of patients "Flow chart of study procedures (Appendix 16.1.1a, Attachment 3)" and the following descriptions. The registration date was defined as the day when eligibility confirmation was completed.
After obtaining informed consent, the investigator (subinvestigator) completed the "Contact form for informed consent obtainment (Appendix 16.1.1a, Attachment 4)" and faxed it to the sponsor.
After obtaining informed consent, the investigator (subinvestigator) confirmed the eligibility of the patient by observations and examinations, and then filled in the "Registration Form (Appendix 16.1.1a, Attachment 5)," and faxed it to the sponsor. In the case where the period from CAI score evaluation day in the screening period to the initial administration of the study drug exceeded one week, the patient was to be re-registered after re-evaluation of the CAI score. At the time of this re-evaluation, the partial Mayo score and PUCAI score were also determined, and sigmoidoscopy was to be performed as much as possible.

Selection of Doses in the Study
TA-650 was administered at a dose of 5mg/kg based on the body weight of the patient on each day of administration by intravenous drip infusion over at least a 2-hr period. The study drug was administered at the initial treatment (Week 0) and Weeks 2 and 6, and CAI score-based responders based on determination of CAI score at Week 8 were further given the study drug at Weeks 14 and 22 in a similar manner. However, CAI score-based non-responders did not receive the study drug after Week 14.
[Rationale for Setting] In Japan, administration of TA-650 at a dose of 5 mg/kg at Weeks 0, 2 and 6 followed by administration at 8-week intervals has been approved for treatment of patients with moderate to severe ulcerative colitis who had insufficient response to the existing therapies. In foreign countries, based on the results of the C0168T72 study conducted on pediatric patients with ulcerative colitis and the ACTI study conducted in adult patients, it has been suggested that the efficacy and safety profiles and pharmacokinetics of the study drug in children are similar to those in adults. Consequently, in the US and Europe, administration of TA-650 at a dose of 5 mg/kg at Weeks 0, 2 and 6 followed by administration at 8-week intervals has been approved for treatment of moderate to severe active ulcerative colitis in pediatric patients, similarly to the dosage regimen for adults. Based on this approval, it was decided to administer TA-650 at a dose of 5 mg/kg at Weeks 0, 2 and 6, followed by administration at Weeks 14 and 22.

Selection and Timing of Dose for Each Patient
All of the patients were given TA-650 at a dose of 5 mg/kg. The timing of treatment for each patient is described in 9.4.1.1 Dosage Regimen and Route of Administration of the Study Drug.

Blinding
Not applicable because this is an open label study.

Prohibited Concomitant Drugs and Therapies
Use of the drugs and therapies listed in the following (1) to (15) was prohibited throughout the screening period and the efficacy evaluation period, and use of those listed in (16) and (17) was prohibited throughout the screening period and the evaluation period.
Steroid injection was allowed for the purpose of treatment of AEs such as infusion reactions or pretreatment. However, pretreatment with steroids was allowed only after completion of the efficacy assessment.
(7) Laxatives The use of laxatives was allowed as a pretreatment for sigmoidoscopy, colonoscopy, and other tests/examinations.

(8) Antidiarrheal drugs and drugs for the treatment of diarrhea
The temporary (not more than approximately 3 consecutive days) use was allowed in an unavoidable case, but use of these drugs were prohibited during the period from 3 days before each starting day of CAI score evaluation to the evaluation day.
(9) NSAIDs (injection, oral preparation and suppository) The temporary (a maximum of 4 weeks) use for the purpose of treatment of AEs or use of low-dose aspirin for prevention of heart attack, unstable angina, or transient ischemic attack was allowed.
(10) Total parenteral nutrition (11) Total enteral nutrition Total enteral nutrition refers to the delivery of total nutrient requirements enterally (nutrient or digest diet nutrient), instead of consumption of normal diet, low-residue diet, or semidigest diet nutrient, which must be used according to the investigator's (sub investigator's) instructions.

(12) Fasting
Fasting must be used for the purpose of treatment of ulcerative colitis according to the investigator's (sub investigator's) instruction. (1) This criterion was set as administration of infliximab which is the same component as the study drug and which might result in failure to evaluate the efficacy, safety and pharmacokinetics in this study. Concomitant use of other biological products was also prohibited since it might similarly affect the evaluation of efficacy and safety of the study drug.
(2) to (6) Use of these drugs and therapies was prohibited because it was deemed difficult to appropriately assess the efficacy in the presence of these drugs or therapies. However, temporary use of ciprofloxacin or metronidazole for the purpose of treatment of AEs was allowed, taking the patient's safety into consideration. In addition, temporary use of steroid injection in patients who experienced AEs such as infusion reactions was allowed in consideration of the safety of patients.
(7), (8) Use of these drugs was prohibited because these drugs could affect the number of stools, which is a subscore of CAI score, partial Mayo score, Mayo score and PUCAI score. However, taking the actual treatment practice into consideration, temporary use of these drugs was allowed as a pretreatment for tests/examinations or in an unavoidable case.
(9) Since it has been reported that these drugs may exacerbate ulcerative colitis, use of these drugs was in principle prohibited due to the possibility of affecting the efficacy evaluation of the study drug. However, the temporary use for the purpose of treatment of AEs or use of low-dose aspirin for prevention of transient ischemic attack was allowed, taking the patient's safety into consideration.
(10) to (14)1), (15) Use of these drugs and therapies was prohibited because it was deemed difficult to appropriately assess the efficacy in the presence of these drugs or therapies.
(14)2) Use of the therapy was prohibited because potential postoperative infections were of concern and these might affect an efficacy evaluation of the study drug.
(16) Concomitant use of this therapy was prohibited because the response to vaccinations was unknown, and possibility of secondary infection with live vaccines could not be ruled out.
(17) Concomitant use of these drugs was prohibited because their effects on efficacy and safety were unknown.

Restricted Concomitant Drugs and Therapies
Medicines and therapies not included in "9.4.7.1 Prohibited Concomitant Drugs and Therapies" were permissible throughout the screening period and the evaluation period. However, use of steroids (oral preparations), azathioprine, 6-mercaptopurine, 5-aminosalicylate preparations (oral preparations) and salazosulfapyridine preparations (oral preparations) was only permitted under the following conditions.
(1) Steroids (oral preparations) Use of steroids (oral preparations) was allowed under the condition that the dose remained stable in principle throughout the screening period and the efficacy evaluation period and additional usage or a dose increase was prohibited. However, reducing the dose in an unavoidable medical situation was allowed.
After the evaluation on the starting day of study drug administration, reducing the dose was allowed when a clinical improvement in the symptoms of ulcerative colitis was observed by the investigator (subinvestigator). The steroid (oral preparations) dose should be carefully reduced within the following reduction range at a maximum, taking the clinical findings and the patient's progress into due consideration.
[Reduction in steroid (oral preparation) dose] Not less than 20 mg/day calculated on a prednisolone basis: Reduction by 10 mg/week calculated on a prednisolone basis at a maximum.
Not less than 10 mg/day and less than 20 mg/day calculated on a prednisolone basis: Reduction by 5 mg/week calculated on a prednisolone basis at a maximum.
Less than 10 mg/day calculated on prednisolone basis: Reduction by 2.5 mg/week calculated on prednisolone basis at a maximum.
If the patient experienced an exacerbation of the symptoms in response to a reduction in the dose or discontinuation of use of steroids (oral preparations), the temporary (a maximum of 4 weeks) use of the relevant steroid at a dose exceeding the dose used during the screening period was allowed to improve the symptoms. In such a case, the daily dose had to be reduced to the dose used during the screening period or lower, within 4 weeks from the dose change.
The temporary (a maximum of 4 weeks) use of steroids at a dose exceeding the dose used during the screening period was also allowed in unavoidable medical situations other than the case for treatment of the primary disease.
(2) Azathioprine, 6-mercaptopurine, 5-aminosalicylate preparations (oral preparations) and salazosulfapyridine preparations (oral preparations) Use of these drugs was allowed in principle, only when used at a stable dose throughout the screening period and the efficacy evaluation period; additional use or dose increase was prohibited. However, after the evaluation on the starting day of study drug administration, reducing the dose was allowed only when it became necessary to reduce the dose for other reasons than the primary disease (AEs or other medical reasons). In such a case, the dose should be stable throughout the efficacy evaluation period after dose reduction or should not exceed the dose used during the screening period.
[Rationale for Setting] The use of these drugs was allowed when used for a specified period at a constant dose before the start of efficacy evaluation because the use of these drugs under said conditions was considered unlikely to affect the efficacy evaluation of TA-650.
Steroid therapy is known to involve many ADRs, and to the steroid dose is preferably reduced as much as possible when clinical symptoms have improved. Consequently, it was decided to evaluate the steroid dose as one of the efficacy indices, and reduction of the dose or discontinuation of steroids (oral preparations) due to an improvement in the symptoms of the primary disease was allowed. The temporary increase in the dose was also allowed when patients experienced an exacerbation of the symptoms after dose reduction.

Precautions for Other Concomitant Drugs
(1) Vaccination Due to potential risk of secondary infection caused by live vaccination during TA-650 treatment period, a criterion to exclude patients who had received live vaccine within 3 months before the start of TA-650 administration from the study was established, and live vaccination during the evaluation period was prohibited. In the case of vaccination with any inactivated vaccine during TA-650 treatment period, vaccination was to be given in consideration of an unknown response of TA-650 to vaccination.
Based on these, a patient's history of routine/voluntary vaccination and the past history of infections preventable by vaccination were checked before registration, and the necessity of vaccination in the patient was considered.
(2) Treatment for tuberculosis prevention Patients who had a history of tuberculosis or who were suspected of having tuberculosis infection were given INH throughout the evaluation period from at least 3 weeks before the starting day of study drug administration. The dose was set at 10 to 15 mg/kg with a maximum of 300 mg/day as a guide. If the use of INH was discontinued due to ADRs etc. within 3 weeks before the start of study drug administration, the study drug was not administered to the relevant patient. If INH could not be used due to ADRs etc. after the start of study drug administration, then appropriate actions were to be taken in consultation with the specialist.
[Patients corresponding to either of the following conditions are defined as patients with suspected tuberculosis infection.]  Patients with findings matching prior pulmonary tuberculosis (including pleural adhesions or calcification only) by imaging examination.  Patients exposed to other patients with active tuberculosis.
 Patients who were positive for the QFT test or T-spot.TB test.
In patients whose judgment by the QFT test or T-spot.TB test was put on hold or who were tuberculin test-positive (patients suspected of being infected with tuberculosis in consideration of the effect of BCG vaccination), treatment with antitubercular drugs was not mandatory in the case where investigators (subinvestigators) judged that suspected tuberculosis infection could be refuted based on the results from other screening tests for tuberculosis (such as chest X-rays, chest CT scans and medical examinations).
Assessment of the results of imaging examinations was performed in consultation with the specialist as needed.

Descriptions of Concomitant Drugs and Therapies
The investigators (subinvestigators) documented the following information about the concomitant drugs and therapies used during the period from the screening period to the end of the efficacy evaluation period in the page for concomitant drugs and therapies in the CRF.
(1) Concomitant drug: name of the drug, reasons for use, reasons for dose change, daily dose, route of administration, treatment period (2) Treatment and therapies for the purpose of treatment of ulcerative colitis: treatment and therapy, date of start, date of completion Information about the following drugs did not require a description in the CRF.
 Physiological saline etc. used to dissolve injection products.
 Physiological saline and water for injection etc. used as a fluid replacement for infusion.
 Perioperative drugs used in surgery for treatment of AEs (anesthetics, infusion, physiological saline solution, disinfectants, etc.). However, information about the prohibited concomitant drugs and restricted concomitant drugs was recorded in the CRF.
The study collaborator was allowed to transcribe the data to the CRF only when the relevant data were recorded in the source documents.

Treatment Compliance
(1) Daily life guidance The investigator (subinvestigator) or the study collaborator provided legal representatives and patients with daily life guidance with attention to the following points.
1) Patients should visit the medical institution and undergo medical examination and tests on the designated days. Patients who could not visit the medical institution on the designated days should make sure to contact the investigator (subinvestigator) or the study collaborator and follow their instructions.
2) Patients should carry and show their study participation card when they visit other hospitals and departments. Patients should inform the investigator (subinvestigator) or the study collaborator of the use of any drug prescribed by a physician not involved in this study or over-the-counter (OTC) drugs purchased at a pharmacy. Patients should make sure to inform the investigator (subinvestigator) or the study collaborator in advance about use of any additional drugs and vaccinations including influenza vaccines (special attention should be paid to prohibition of concomitant use of live vaccine) during study.
3) Patients should maintain their lifestyle (especially dietary habit and health food) to the extent possible.
4) Patients should immediately inform the investigator (subinvestigator) or the study collaborator of any physical abnormality such as a sign of infection (even a slight cold) , pregnancy, or clear exacerbation of ulcerative colitis symptoms (including frequency of stools, blood in stools, abdominal pain etc.), and ask them if a visit to the hospital is necessary. 5) Patients should use contraception during the period from registration to 6 months after the last treatment.
(2) Instruction on how to complete the Symptom Assessment Sheet After obtainment of informed consent, the investigator (subinvestigator) or the study collaborator gave the Symptom Assessment Sheet to the patient or legal representative, explained how to complete the sheet and instructed them to fill out the sheet in regards to the following items every day for 7 days before the designated visit days, and make sure to bring it on the visit days.  To fill out the sheet using writing tools such as a ballpoint pen whose markings are not easily erased.

1) Items entered in the Symptom Assessment Sheet
 To change or correct the description by crossing out with double lines so that the entry prior to correction is legible.
 Not to write in the spaces for medical institution use.
 To count evidence of blood even without stools as the number of stools.
 Not to count among the number of stools, an episode where the patient had an urgent desire to evacuate a stool but could not defecate.
 In terms of tenesmus and incomplete defecation, an episode such that the patient defecated several small stools in a very short term should be counted as one defecation. This study was conducted in accordance with the following flow chart and Table 9.5-1.

Flow chart for study procedures
Preparation of CRFs As needed Prior to registration, the investigator (subinvestigator) performed the following examinations and observations to confirm the eligibility of the patients.
(1) Laboratory tests The investigator (subinvestigator) measured the following laboratory parameters within 2 weeks before registration after obtaining of informed consent. When there were multiple laboratory test values, the value obtained on the closest day to the registration day was used, except for the values obtained by the centralized laboratory tests performed at the start of administration of the study drug.
Hemoglobin, WBC count, neutrophil count*, lymphocyte count, platelet count, AST (GOT), ALT (GPT), ALP, HBs antigen, HBs antibody, HBc antibody, HIV antibody and pregnancy test (only for female patients of physiologically childbearing potential) * Neutrophil count: The total count of stab and segmented cells was used, if applicable.
(2) Tuberculosis testing The investigator (subinvestigator) performed a medical interview, chest X-ray, chest CT scan (as needed), and tuberculin skin test or QFT test (T-spot.TB test may be used) within 4 weeks before registration after obtaining informed consent and confirming the presence or absence of respiratory infection including tuberculosis. If patients underwent multiple examinations, the data obtained on the closest day to the registration day was used.
The investigator (subinvestigator) administered antituberculosis drugs (INH, in principle) to patients who were found to have a history of tuberculosis infection or were suspected of having tuberculosis infection at least 3 weeks before the starting day of study drug administration.
[Patients corresponding to either of the following conditions are defined as patients with suspected tuberculosis infection.]  Patients with findings matching old pulmonary tuberculosis (including pleural adhesions or calcification only) by imaging examination  Patients exposed to other patients with active tuberculosis  Patients who were positive for QFT test or T-spot.TB test In patients whose judgment was made by QFT test or T-spot.TB test was put on hold or who were tuberculin test-positive (patients suspected of being infected with tuberculosis in consideration of the effect of BCG vaccination), treatment with antitubercular drugs was not mandatory in the case where investigators (subinvestigators) judged that suspected tuberculosis infection could be refuted based on the results of other screening tests for tuberculosis (such as chest X-ray, chest CT scan and medical examination).
Assessment of the results of imaging examinations was performed in consultation with the specialist as needed.
(3) Vaccination The investigator (subinvestigator) checked a patient's history of routine/voluntary vaccination and the past history of infections preventable by vaccination before registration, and considered the necessity for vaccination in the patient. Check of a patient's history of vaccination and the past history of infections was performed by the registration day at the latest.
(4) Confirmation of clinical severity and whether the patient falls under the exclusion criterion (1) The investigator (subinvestigator) checked the pulse rate, hemoglobin, ESR, number of stools, overt bloody stools, number of bloody diarrhea, pyrexia (body temperature), and abdominal pain at the time of registration, and confirmed that the patient did not fall under 9.3.2 Exclusion criteria (1) and determined the clinical severity of the primary disease based on these sets of information.
(5) Colon cancer screening When the patient satisfied either of the following, the investigator (subinvestigator) was required to perform colon cancer screening (colonoscopy and biopsy) after obtaining of informed consent and obtaining consent by 4 days before the start of the screening period, and confirmed that there was no evidence of dysplasia of the colonic mucosa or adenomatous colonic polyp.
 Patients who had been suffering from total colitis for at least 8 years, and had not undergone colon cancer screening within 1 year before registration.
 Patients who had been suffering from left-sided colitis for at least 10 years, and had not undergone colon cancer screening within 1 year before registration.
A colonoscopy performed as the colon cancer screening could substitute for a sigmoidoscopy performed to determine the Mayo score.
Safety Subjective symptoms and objective findings Blood pressure, pulse rate, and body When administration of the study drug was scheduled on the evaluation day, evaluation and examinations were performed before study drug administration. a: These evaluations were not necessary when a CAI score-based non-responder discontinued the study after the evaluation at Week 8. b: Performed as far as possible. However, when it was impossible to perform this examination during the screening period (in principle, performed after registration and by the start of the study drug administration. in unavoidable cases, it was allowed to perform the examination within 2 weeks from the starting day of study drug administration and by 4 days before the start of the screening period), it was not necessary to perform the examination at Week 30 or at the time of discontinuation. c: Blood was collected twice in total, immediately before administration and 1 hour after completion of administration of TA-650. d: The permissible time range for sigmoidoscopy was set as the range from -13 to +14 days.
(Example) Observation/examination items necessary at the time of registration and until the start of study drug administration (in the case where CAI score was determined on the registration day.) * [Performed after obtaining of informed consent and by 4 days before the start of the screening period] Colonoscopy and biopsy  The study treatment was started within one week from the CAI evaluation day in the screening period. In the case where the period from CAI evaluation day in the screening period to the initial administration of the study drug exceeded one week, the patient was to be re-registered after re-evaluation of the CAI score of the relevant patient.  When there were multiple laboratory test values, the value obtained on the closest day to the registration day was used, except for the values obtained by the centralized laboratory tests performed at the start of study drug administration.  If chest X-ray, chest CT scan (as needed), tuberculin skin test, QFT test or T-spot.TB test were performed several times after obtaining consent, the data obtained on the closest day to the registration day were used.  Either tuberculin skin test or QFT test (T-spot.TB test may be used) had to be performed. The results of tuberculin skin test were judged in consideration of the effect of BCG vaccination.  Colon cancer screening was performed only for patients deemed necessary according to the exclusion criterion (8). A colonoscopy performed as colon cancer screening could substitute for sigmoidoscopy performed to assess the Mayo score. In an unavoidable case, allowed to perform the examination within 2 weeks from the starting day of study drug administration and by 4 days before the start of the screening period. Number of stools per week, blood in stools (based on weekly average)  For hemoglobin and ESR, the measurement values obtained in the medical institution during the period from 7 days before the evaluation day to the evaluation day were used.  When administration of the study drug was scheduled on the evaluation day, evaluation and examinations were performed before administration of the study drug for the relevant week.  When there were several hemoglobin and ESR data during the permissible time windows, the value obtained on the closest day to the CAI evaluation day was used.  Sigmoidoscopy in the screening period was performed in principle, after registration and by the start of the study drug administration. In an unavoidable case, it was allowed to perform the examination within 2 weeks from the starting day of study drug administration and by 4 days before the start of the evaluation period.  The permissible time range for sigmoidoscopy at Week 30 was set as between -13 days and +14 days. However, in consideration of the effect on the efficacy evaluation at Week 30, conducting sigmoidoscopy during the evaluation period for the CAI score based on Symptom Assessment Sheet was avoided as much as possible.
*5 Observations necessary for determination of PUCAI scores: The investigator obtained information from the patients about 6 subscores including abdominal pain, rectal bleeding, stool consistency of most stools, number of stools per 24 hours, nocturnal stools and activity level.
*6 Blood pressure, pulse rate and body temperature: These parameters were measured immediately before the start of administration, every 30 minutes during administration, and also every 30 minutes for 2 hours after completion of administration. When there was at least a 15-minute interval between completion of administration and the last measurement before completion of administration, measurement was also performed at the time of completion of administration.
*7 General laboratory tests: Measurement of laboratory parameters was performed at the contract laboratory.
*10 CRP: Centralized measurement was performed at the contract laboratory.
*11 Serum infliximab concentration: Blood samples were collected before administration when study drug administration was scheduled on the evaluation day. On the starting day of study drug administration and at Weeks 14 and 22, blood was collected twice in total before administration and one hour after completion of administration.

Patient Demographic Items
(1) Patient background data The investigator (subinvestigator) investigated patient background factors listed below and recorded the obtained information in the CRFs. The study collaborator was allowed to transcribe information available from source documents to the CRFs. Medical interview (interview day, findings), chest X-ray (examination day, findings), chest CT scan (examination day, findings), and tuberculin skin test (assessment day, diameter of redness, diameter of induration) or QFT test or T-spot.TB test (blood sampling day, measured value, result of assessment), and presence or absence of treatment with antitubercular drugs from at least 3 weeks before the starting day of study drug administration.

17) History of vaccination 18) Past history of infections
Timing of investigation: at the time of registration (the investigation of complications was performed at the start of administration.) *1: The value was expressed as whole numbers in principle, however if within a number range, the mean value of the maximum and minimum values was allowed to be used. *2: Regarding drugs and therapies which had previously been used for treatment of ulcerative colitis, it was recorded in the CRFs whether a patient had been a non-responder to cyclosporine, tacrolimus, and cytapheresis or not within one year before registration. Prior to CAI, partial Mayo, Mayo and PUCAI score assessment, the investigator (subinvestigator) or the study collaborator collected the Symptom Assessment Sheets from patients or legal representatives at the following evaluation time points, checked the contents of the sheets, and filled out the space for study site use. The original copy of the Symptom Assessment Sheet was retained at the medical institution, and a copy was submitted to the sponsor. Evaluation of CAI score-based non-responders was finished at Week 8. In addition, when CAI score-based non-responders discontinued the study after evaluation at Week 8, evaluation was not required at the time of discontinuation.
(1) Space filled out by patients and legal representatives The investigator (subinvestigator) or the study collaborator confirmed that there was no inadequate/incomplete descriptions in the spaces filled out by patients or legal representatives during the medical examination at registration and at Weeks 2, 6, 8, 10, 14, 18, 22, 26, and 30 or at the time of discontinuation; if there was an inadequate/incomplete description, the investigator (subinvestigator) or the study collaborator asked the relevant patient or legal representative to make an additional description. If any correction was made to the sheet filled out by patients or legal representatives, the investigator (subinvestigator) or the study collaborator checked with the relevant patient or legal representative, and affixed the seal for correction with the date.
(2) Space for study center use During the medical examination at registration and at Week 2,6,8,10,14,18,22,26,and 30 or at the time of discontinuation, if a drug for the treatment of constipation or diarrhea was used, the investigator (subinvestigator) or the study collaborator checked the relevant drug with the relevant patient or the patient's legal representative and documented the name of the drug. The investigator (subinvestigator) or the study collaborator also documented the presence/absence of pretreatment of sigmoidoscopy etc. in the space for study center use in the Symptom Assessment Sheet.
The investigator (subinvestigator) or the study collaborator assessed whether to use the data for efficacy evaluation or not based on the descriptions in the Symptom Assessment Sheet according to the following criteria, and documented the result of assessment in the space for study site use.
[Days to be excluded from assessment]*  Days when drugs for the treatment of constipation or diarrhea were used  Days when drugs having a potent antidiarrheal effect (e.g., loperamide hydrochloride, opium alkaloids, atropine sulfate-containing preparations) were used and for 2 days after use (3 days in total)  Days when drugs that might affect stool frequency (e.g., laxatives) were used as pretreatment of sigmoidoscopy  Days when colonoscopy or sigmoidoscopy was performed and for 3 days after the examination (4 days in total) *: Days to be excluded from the evaluation period for CAI score (number of stools, blood in stools [based on weekly average]), partial Mayo score (number of stools, rectal bleeding) and PUCAI score.
(3) Space for investigator (subinvestigator) The investigator (subinvestigator) confirmed that there were no inadequate descriptions in the Symptom Assessment Sheet at the time of registration, Weeks 2, 6, 8, 10, 14, 18, 22, 26 and 30, and the time of discontinuation of the study, and signed the sheet.

CAI Score
The CAI score was determined as a sum (0 to 29 points) of subscores for 7 evaluation items, including number of stools per week, blood in stools (based on weekly average), investigator's global assessment of symptomatic state, abdominal pain/cramps, temperature elevation due to ulcerative colitis, extraintestinal manifestations and laboratory tests (hemoglobin and ESR). When administration of the study drug was scheduled on the evaluation day, the predetermined examinations and observations were performed before administration of the study drug. When sigmoidoscopy was scheduled on the evaluation day, the predetermined examinations and observations were performed before conducting the sigmoidoscopy. The evaluation of CAI score-based non-responders was discontinued at Week 8. When CAI score-based non-responders discontinued the study after the evaluation at Week 8, the evaluation at the time of discontinuation was not required.
When each of the scores determined by the investigator (subinvestigator) was recorded in the source documents such as medical record etc., the study collaborator was allowed to transcribe each score in the CRF.
(1) No. of stools weekly The investigators (subinvestigators) determined the subscore based on the number of stools for 7 days before the evaluation day (the evaluation period for CAI score based on Symptom Assessment Sheet) excluding the days to be excluded from the evaluation specified in "9.5.1.3.2 Confirmation of the Contents of the Symptom Assessment Sheet," according to the following conversion table, and recorded the score thus determined in the CRF. When the evaluation period of Symptom Assessment Sheet was less than 7 days, if assessment data for at least 4 days were obtained, the score was determined by conversion according to the calculation formula (Sum of the number of stools during the evaluation period of Symptom Assessment Sheet [for N days]) ×7/N, and recorded the calculated score in the CRF.
Part referenced in the Symptom Assessment Sheet: Number of stools Score Sum of the number of stools during the evaluation period of Symptom Assessment Sheet (7 days) < 18 stools 0 ≥18 stools, ≤35 stools 1 ≥36 stools, ≤60 stools 2 ≥61 stools 3 (2) Blood in stools (based on weekly average) The investigators (subinvestigators) determined the subscore based on blood in stools during the 7 days before the evaluation day (the evaluation period for CAI score based on Symptom Assessment Sheet) excluding the days to be excluded from the evaluation specified in "9.5.1.3.2 Confirmation of the Contents of the Symptom Assessment Sheet," according to the following conversion table, and recorded the determined score in the CRF. When the evaluation period of Symptom Assessment Sheet was less than 7 days, if assessment data for at least 4 days were obtained, the score was determined according to the following conversion table, and the determined score was recorded in the CRF.
Part referenced in the Symptom Assessment Sheet: Blood in stools Score "0" throughout the evaluation period of Symptom Assessment Sheet (7 days) None 0 Other cases Small amount: Bloody mucoid stools are not apparent, but blood in stools can be macroscopically confirmed. On each evaluation day, the investigator (subinvestigator) assessed the laboratory values of ESR and hemoglobin during the period from 7 days before the evaluation day to the evaluation day according to the categories shown below, and recorded the score in the CRF. Throughout the screening period and the efficacy evaluation period, the ESR and hemoglobin were to be measured at the relevant medical institution, and the places to measure these parameters were not changed. When there were multiple values measured, the value obtained on the closest day to the CAI score evaluation day was used. When the measurement value of hemoglobin was less than 10 g/dL, the subscore for the relevant patient was determined to be 4 regardless of the measurement result of ESR. When the measurement result of ESR was not more than 50 mm/hr and the measurement result of hemoglobin was not less than 10 g/dL, the subscore was determined to be 0.

Partial Mayo Score and Mayo Score
The Mayo score consists of four subscores (stool frequency, rectal bleeding, physician's global assessment and findings of endoscopy), each of which was assessed according to a four-level rating scale (0 to 3 points), and was determined from a total of the four subscores (0 to 12 points). In addition, the sum of the subscores (0 to 9 points) for stool frequency, rectal bleeding and physician's global assessment was used as a partial Mayo score.
The investigator (subinvestigator) made an assessment based on the results of medical examination and the data in the Symptom Assessment Sheet to determine a partial Mayo score at the time of registration, at Weeks 2, 6, 8, 10, 14, 18, 22, 26 and 30, and the time of discontinuation. In addition, sigmoidoscopy was performed during the screening period (Performed in principle after registration and by the start of the study drug administration. In an unavoidable case, it was allowed to perform the examination within 2 weeks from the starting day of study drug administration and by 4 days before the start of the evaluation period.), at Week 30 and the time of discontinuation and sigmoidoscopy performed as much as possible to determine the Mayo score. The obtained assessment results were recorded in the CRF.
When administration of the study drug was scheduled on the evaluation day, the predetermined examinations and observations were performed before administration of the study drug for the relevant week. In addition, when sigmoidoscopy was scheduled on the evaluation day, the predetermined observations were performed before sigmoidoscopy. Evaluation of CAI score-based non-responders was discontinued at Week 8. In addition, when CAI score-based non-responders discontinued the study after evaluation at Week 8, an evaluation was not required at the time of discontinuation.
When each of the subscores determined by the investigator (subinvestigator) was recorded in the source documents such as medical records etc., the study collaborator was allowed to transcribe each subscore in the CRF.
(1) Stool frequency The investigators (subinvestigators) determined the subscore based on the stool frequency for 3 days before the evaluation day (the evaluation period for partial Mayo score based on the Symptom Assessment Sheet) excluding the days to be excluded from the evaluation specified in "9.5.1.3.2 Confirmation of the Contents of the Symptom Assessment Sheet" and the daily stool frequency before the development of the disease (ulcerative colitis), according to the following conversion table, and recorded the determined score in the CRF. ≥4.5 The number of stools per day documented as demographic data in the CRF was used for the number of stools per day before the development of disease (ulcerative colitis). The number of stools per day before the development of disease (ulcerative colitis) was in principle expressed as a whole number; however if the number was within a number range, the mean value of the maximum and minimum values could be used (e.g., recorded as 1.5 for "1 to 2").
(2) Rectal bleeding The investigators (subinvestigators) recorded the worst (largest) subscore for rectal bleeding among those determined for the symptoms recorded in the Symptom Assessment Sheet for 3 days before the evaluation day (the evaluation period for partial Mayo score based on Symptom Assessment Sheet) excluding the days to be excluded from the evaluation specified in "9.5.1.3.2 Confirmation of the Contents of the Symptom Assessment Sheet" in the CRF in each evaluation day. The PUCAI score was determined as a total of the subscores for each of the six evaluation items (0 to 85), including abdominal pain, rectal bleeding, stool consistency of most stools, number of stools per 24 hours, nocturnal stools and activity level. When administration of the study drug was scheduled on the evaluation day, the evaluation was performed before administration of the study drug. In addition, when sigmoidoscopy was scheduled on the evaluation day, the evaluation was performed before conducting the sigmoidoscopy. Evaluation of CAI score-based non-responders was discontinued at Week 8. In addition, when CAI score-based non-responders discontinued the study after evaluation at Week 8, an evaluation was not required at the time of discontinuation.
When each of the subscores determined by the investigator (subinvestigator) was recorded in the source documents such as medical records etc. the study collaborator was allowed to transcribe PUCAI score in the CRF.
To determine PUCAI score, six evaluation items were assessed based on the information obtained from patients by the interview according to the following rules.
 An average of the conditions or values observed for 2 days before each evaluation day, excluding the days to be excluded from the evaluation specified in "9.5.1.3.2 Confirmation of the Contents of the Symptom Assessment Sheet," was used for determination of the score.
 In the case where clinical symptoms changed rapidly, the clinical condition in the last 24 hours was taken into consideration.  "Occasional limitation of activity" means that the relevant patient can go to school or can perform an activity equivalent to going to school, but that patient's activity is limited (for example, the patient can go to school but cannot play during recess).
 "Severe restricted activity" means that the relevant patient cannot go to school or cannot perform an action equivalent to going to school. The investigator (subinvestigator) collected blood and urine samples on the starting day of study drug administration (Week 0), and at Weeks 2, 6, 8, 10, 14, 18, 22, 26 and 30, and the collected samples were delivered to the contract laboratory for measurement of the following laboratory parameters. For CAI score-based non-responders, laboratory tests were finished at Week 14. For discontinued patients, laboratory tests were performed at the time of discontinuation and 8 weeks after the last administration.
When administration of the study drug was scheduled on the examination day, collection of blood and urine samples was performed before study drug administration. Samples were collected by the contact laboratory. Test slips provided by the contract laboratory were stored by the medical institutions and the sponsor.
(2) Immunoserology The investigator (subinvestigator) collected blood samples for measurement of antinuclear antibodies and double stranded DNA antibodies (double stranded DNA IgG and double stranded DNA IgM antibodies) on the starting day of study drug administration (Week 0), and at Weeks 14 and 30. For CAI score-based non-responders, the evaluation at Week 30 was not performed since the evaluation had been finished at Week 14. For discontinued patients, measurement was also performed at the time of discontinuation and 8 weeks after the last administration.
When administration of the study drug was scheduled on the examination day, collection of blood samples was performed before study drug administration. Samples were collected and measured by the contact laboratory. Test slips provided by the contract laboratory were stored by the medical institutions and the sponsor. The amount of blood collected per each test was approximately 3 mL.
(3) Physical examination The investigator (subinvestigator) measured the blood pressure, pulse rate and body temperature immediately before the start of administration, every 30 minutes during administration, and every 30 minutes for 2 hours after the end of administration on each administration day. When there was at least a 15-minute interval between the end of administration and the latest measurement before the end of administration, measurement was also performed at the end of administration. The measurement results were recorded in the CRFs.
Case 1) When the duration of administration was 2 hr 00 min (an arrow indicates a measurement point) Case 2) When the duration of administration was 2 hr 15 min (an arrow indicates a measurement point)

Adverse Events
An adverse event (AE) is any clinically unfavorable or unintended sign (including clinically significant abnormal laboratory values), symptom, or disease that occurred during the evaluation period after study drug administration regardless of causal relationship to the study drug. Worsening of the efficacy endpoints was not considered as an AE unless the event was serious or judged to be handled as an AE by the investigator (subinvestigator).
If an AE occurred, the investigator (subinvestigator) was to provide appropriate treatment. Regardless of the causal relationship with the study drug, the AE was followed in principle, until it was normalized or resolved to the extent that it was no longer assessed as an AE. If an AE was irreversible due to organic impairment, the patient was to be followed until the symptom stabilized or became unchanged.

(1) Symptoms or diseases
The investigator (subinvestigator) checked for the presence or absence of AEs at each visit from administration of the study drug to the end of the evaluation period by medical interview and examination.
In addition, to assess the presence or absence of respiratory infections including tuberculosis, chest X-rays and chest CT scans (as appropriate) were performed by the investigator (subinvestigator) after obtaining informed consent and within 4 weeks before registration. Chest X rays and chest CT scans (as appropriate) were also performed at Weeks 14 and 30 during the evaluation period (only for CAI score-based responders) or at the time of discontinuation of the study to assess the presence or absence of abnormal findings. If any abnormal finding was observed, the disease or symptom causing the finding was handled as an AE.
(2) Objective findings 1) General laboratory test and physical examination (blood pressure, pulse rate and body temperature) An abnormal value which was judged to be clinically significant* by the investigator (subinvestigator) was handled as an AE.
*: "A clinically significant abnormality" was assessed according to the following definitions:  A case where the abnormal value was related to clinical signs or clinical symptoms. However, if these symptoms or signs had already been reported as AEs, it was not necessary to handle the relevant abnormal laboratory value as an AE.
 A case where any medical or surgical therapy for the relevant abnormal laboratory value was conducted.
 A case where the mode of administration (dose change, interventions or discontinuation) of the study drug was changed as a result of the relevant abnormal value.


In addition to the above-mentioned cases, a case where the investigator (subinvestigator) judged the relevant abnormal value as clinically significant.

2) Immunoserological tests
Levels of anti-nuclear antibody, double stranded DNA IgG antibody and double stranded DNA IgM antibody deviating from the reference range shown below were considered as "abnormal," and those applicable to the following criteria for AEs were handled as AEs. (c) Seriousness Seriousness of AEs was classified as follows: 1. Non-serious: Other than those meeting the criteria of 2 below. The causal relationship with the study drug was classified as follows.

Definitely related
There is a temporal relationship between administration of the study drug and onset of the AE, and there were no other factors except for the study drug to explain the event, or no necessity to consider the influence by other factors except the study drug.

Probably related
There is a temporal relationship between administration of the study drug and onset of the AE, and the event was less likely to be explained by other factors such as primary disease, complications, and concomitant drugs and therapies.

Possibly related
The temporal relationship between administration of the study drug and onset of the AE cannot be ruled out, and the AE can be explained by other factors such as primary disease, complications, and concomitant drugs and therapies, but the relationship with the study drug cannot completely be ruled out.

Not related
There is no temporal relationship between administration of the study drug and onset of the AE.
The AE can be reasonably explained by other factors such as the primary disease, complications, and concomitant drugs and therapies.
AEs classified as other ratings than "Not related" were handled as ADRs.
(e) Outcome The outcome of AEs was classified according to the following criteria. (f) Day of outcome The day of outcome was classified according to the following criteria.
Recovered: Day when the patient recovered. If the day of recovery is uncertain, the day when the outcome was confirmed or determined is used as the day of recovery.
Ongoing: Day when the ongoing AE was confirmed or determined.
Death: Day when the patient died. If the day of death is unclear, the day when the death was confirmed or determined is used as the day of death.
Unknown: Day when the patient died if the outcome was unknown because the patient died due to a cause other than the relevant AE. In other cases, the day when the outcome was confirmed or determined is used as the day of outcome for unknown criteria.
(g) Follow-up -The period [1] after completion of study drug administration was set as 56 days, and the presence or absence of AEs was assessed.
-The period [2] after the end of observation was set as 28 days, and the AEs that occurred during the evaluation period (the treatment period + [1]) were followed up.
-The clinical courses of the AEs followed up during the period [2] after the end of observation were recorded in the CRFs.
-When AEs had not been recovered, the day of outcome recorded in the CRF was the day of observation after the end of period [2] after the end of observation.
-ADRs that had not been recovered at the end of period [2] after the end of observation were followed up ( [3]). -If there was a reasonable cause for discontinuation of the investigation after the end of the evaluation period (after the end of period [1]), the cause was recorded in the CRFs and the follow-up was finished.

4) Entries to the CRF
If an AE was observed, the investigator (subinvestigator) recorded the following information on the AE page of the CRF, the name of the AE * , severity, seriousness, infections, day and time of onset (filled in the time of onset in the case where the AE occurred between the start of administration of the study drug and 2 hours after the end of administration), day of outcome, outcome, the treatment, and causal relationship with the study drug were recorded. If a disease name was recorded as the name of the AE, the symptoms or abnormal changes in laboratory test values associated with the disease, and abnormal findings in the chest X-ray/CT scan were not to be recorded in the AE page. Since safety evaluation for the immunoserological tests was performed separately, findings observed in the immunoserological tests were not to be recorded in the AE page.
When the outcome of an AE was assessed as other categories than "recovered" but follow-up was considered unnecessary, the rationale for judgment that follow-up was unnecessary, as well as the reason for assessment of the causal relationship with the study drug were recorded in the "comment column" for AEs. In addition, in the case where the relevant AE led to discontinuation of the study, the AE was recorded as an AE leading to discontinuation on the discontinuation page of the CRF.
The study collaborator was able to transcribe this information to the CRFs only when the information was described in the source documents such as medical records. *: "AE name" was presented according to the following rules:  The name of diagnosis is used in principle.
 If the diagnosis is uncertain, the symptoms are used.
 If several symptoms appear but are able to be represented as one diagnosis, the diagnosis is used.
 Surgical interventions are not included in AEs. If diseases or symptoms which require surgical interventions are observed, they are considered as AEs.

Other Laboratory Test Parameters
(1) TNFα, IL-6, CRP The investigator (subinvestigator) collected blood samples only on the starting day of study drug administration (Week 0) for measurement of TNFα and IL-6, and on the starting day of study drug administration (Week 0) and at Weeks 2, 6, 8, 10, 14, 18, 22, 26 and 30 and at the time of discontinuation for measurement of CRP. For CAI score-based non-responders, measurement of these parameters was finished after the measurement at Week 8. In addition, when CAI score-based non-responders discontinued the study after evaluation at Week 8, measurement of these parameters was not required at the time of discontinuation. When administration of the study drug was scheduled on the day of tests, the blood sample was collected before the study drug administration.
Blood samples for TNFα and IL-6 measurement were centrifuged, and a certain amount of serum or plasma obtained was collected and stored frozen. Samples for CRP measurement were handled in the same manner as those for general laboratory tests. Sample were collected and measured by the contract laboratory. Test slips provided by the contract laboratory were stored by the medical institution and the sponsor.
The amount of blood collected for each sampling was approximately 2 mL for TNFα and IL-6 measurement, and a total of approximately 4 mL for CRP measurement and blood biochemistry tests.

Appropriateness of Measurements
(1) Rationale for efficacy endpoints Since this study was conducted on children, it was considered difficult to perform sigmoidoscopy, which is needed in order to determine the Mayo score in all of the patients. Therefore, it was decided to assess the efficacy of the study drug using the CAI score, which is a noninvasive score used as an evaluation index in the domestic clinical study of TA-650 in adults. The CAI score is an index containing a good balance of clinical symptoms and laboratory test data, and has been frequently used as a noninvasive evaluation index. The CAI score is also reported to have a high correlation with the Mayo score (r=0.92) 1) . In addition to the CAI score, a partial Mayo score, which has been used in domestic and overseas clinical studies, was also evaluated. For patients who underwent sigmoidoscopy, the Mayo score was also evaluated. The PUCAI score, which has been used in overseas clinical studies in children, was also evaluated in this study.
In addition, the steroid dose on each evaluation day was used as an endpoint to evaluate the effect of TA-650 to reduce steroid dose in pediatric patients with ulcerative colitis.
(2) Rationale for safety endpoint As with clinical studies of TA-650 conducted to date, general laboratory tests as well as measurement of anti-nuclear antibodies and double stranded DNA IgG and IgM antibodies were performed to monitor the occurrence of lupus-like symptoms. Since patients treated with TA-650 should also be carefully monitored for AEs such as infections including tuberculosis, a chest X-ray and chest CT scan (as appropriate) were performed.

Items and Timing of Examinations and Observations
The investigator (subinvestigator) collected blood samples for measurement of the serum infliximab concentration and ATI.
The drug concentration assay facility prepared a separate study protocol (Appendix 16.1.13d) before the start of measurement, then measured the serum concentration of infliximab and ATI, and prepared a final report (Appendix 16.1.13e) for the measurement results. The person responsible for clinical pharmacological analysis prepared the pharmacokinetic analysis plan (Ver. 1.0) (prepared on January 19, 2015) (Appendix 16.1.9c) by the time the data were locked. After data were locked, pharmacokinetics of the study drug was analyzed and a pharmacokinetic analysis report (Appendix 16.1.9d) was prepared.
(1) Time points for blood collection The investigator (subinvestigator) collected blood samples on the starting day of study drug administration (Week 0) and at Weeks 2, 6, 8, 10, 14, 18, 22, 26 and 30. For CAI score-based non-responders, the blood sampling was finished at Week 14. For discontinued patients, the blood sampling was also performed at the time of discontinuation and 8 weeks after the last administration.
When administration of the study drug was scheduled on the blood sampling day, the blood sample was collected before the study drug administration. However, on the starting day of study drug administration (Week 0) and at Weeks 14 and 22, the blood was collected twice in total before administration and 1 hour after completion of administration. For CAI score-based non-responders, there was no blood collection 1 hour after completion of administration at Week 14.
(2) Blood volume: approximately 2 mL per test (3) Processing of blood samples A certain volume of serum was obtained for pharmacokinetic analysis by centrifugation of collected blood (approximately 2 mL), and stored frozen below -20°C.
The cryopreserved samples for pharmacokinetic analysis were collected from the medical institutions by the contract laboratory. The contract laboratory delivered the samples to the drug concentration assay facility in accordance with the "operating procedures for shipment of samples" specified separately.
(4) Entries in the CRF The investigator (subinvestigator) recorded the date and time of blood collection in the CRF.

[Rationale for Setting]
In reference to overseas ACT1 and ACT2 studies and domestic clinical studies in patients with ulcerative colitis, the sampling time points which were needed to study pharmacokinetics of TA-650 when administered at a dose of 5 mg/kg at Weeks 0, 2 and 6 followed by administration at Weeks 14 and 22 were set.

Data Quality Assurance
In order to maintain the quality and reliability of the present study, the sponsor performed "quality control of the study" in accordance with GCP standard operating procedures (SOP) of Mitsubishi Tanabe Pharma Corporation and "quality assurance of the study" in accordance with GCP audit SOP of Mitsubishi Tanabe Pharma Corporation. The medical institutions and investigators cooperated in quality control and quality assurance of the study implemented by the sponsor.
In quality control of the study, the monitors had direct access as appropriate to confirm that the present study was conducted in compliance with the study-related operating procedures of the medical institution, the current protocol and GCP. The monitors also confirmed that it was possible to verify that the descriptions in the CRFs reported from the investigator (subinvestigator) were accurate and complete, by referring to study-related records such as source documents. The monitoring procedures (Appendix 16.1.13e) specifying the monitoring procedures in details was prepared and monitoring was performed in accordance with the procedures.
In order to ensure that the study was conducted in compliance with the protocol and GCP, the auditor conducted audits in compliance with GCP audit SOP and confirmed that the quality of the study was appropriately controlled. (c) Patients without any available efficacy data in the evaluation period.
(2) Safety Analysis Set Safety analysis set does not include the following patients.
(a) A patient who had received no study drug in the evaluation period.
(b) A patient without any available safety data after the start of study drug administration in the evaluation period. (

3) Pharmacokinetic Analysis Set
Pharmacokinetic analysis set was defined as described below, but handling of each case was decided in accordance with the arrangements made by the clinical conference.
Among the patients who had received at least one dose of the study drug, the population of patients from whom serum infliximab concentration or ATI data was obtained once or more times after administration of the study drug was used as the pharmacokinetic analysis set.

Data Handling
Obtained data were handled as described below. When it was required to consider data handling with respect to the items not stipulated in this section, rules for data handling and data handling were decided in accordance with the procedures stipulated in the sponsor's GCP SOP. Detailed procedures are described in the statistical analysis plan (Appendix 16.1.9a).

Missing Values
(1) In the case of a missing examination or the case where measurement was impossible due to problems with test samples, the relevant item was treated as a missing value.
(2) If the dose of the study drug was <75% of the dose specified for each administration day, data for efficacy evaluation obtained from the relevant administration to the next administration of the study drug was treated as missing data.
(3) In the case of violations involving prohibited concomitant drugs and therapies, all of the data obtained from the relevant patient is handled in accordance with the arrangements made by the clinical conference and is not treated as missing data. In the tabulation of data by measurement time point, data falling within the permitted time range for the day of evaluation were selected, and imputation of the missing data by data outside the permitted range was not performed. The permitted time ranges were set as ±6 days for Weeks 2, 6 and 8, ±7 days for Week 10 and the range from -13days to +14days after Week 14.
For the efficacy evaluation (excluding other laboratory parameters), evaluation performed after study drug administration in the study drug administration week was not selected as the data for the relevant week. When multiple data existed within the permitted time range, data was selected in accordance with the following rules:  Evaluation performed on the closest day to the baseline day should be selected.
 When there are two evaluations having the same time lag before and after the baseline day, the evaluation before the baseline should be selected (2) CAI score-based responders Case of patient who completed the treatment: Last evaluation obtained within the permitted time range for Week 30 was selected.
(3) Discontinued patient (CAI score-based non-responders and responders) Discontinued case: The permitted time range for data at last time point was specified as listed below.
Last administration of study drug Permitted time range (day) Week 0 Last evaluation performed within 20 days from the initial administration is selected.
Week 2 Last evaluation performed within 48 days from the initial administration is selected Week 6 Last evaluation performed within 112 days from the initial administration is selected.
Week 14 Last evaluation performed within 168 days from the initial administration is selected.
Week 22 Last evaluation performed within 224 days from the initial administration is selected.

Treatment Failure
For patients who met the following conditions (defined as "treatment failure"), the CAI score, partial Mayo score, Mayo score and PUCAI score determined at the time of registration were used for evaluation after the time point where the relevant patient met the conditions, regardless of the actual scores in terms of the efficacy endpoints and steroid dose. In addition, for imputation (TF) of data on the remission rate based on each score (CAI, Mayo and PUCAI), the Mayo score-based response rate, the rate of mucosal healing and the rate of patients who achieved a PUCAI score decrease by at least 20 points, the above mentioned patients were respectively handled as "failure to achieve remission," "failure to achieve response," "failure to achieve mucosal healing" and "failure to achieve a decrease by at least 20 points,". For imputation of steroid dose data, the actual steroid dose was substituted by the steroid dose at Week 0, and in terms of steroid withdrawal, the relevant patients were handled as a "failure to achieve steroid withdrawal" Treatment failure (1) Patients who underwent colectomy or enterostomy (2) Patients who discontinued the study due to exacerbation of the primary disease or inadequate response to the study drug (3) Patients who experienced the start of administration or increase in a dose of the following drugs due to exacerbation of the primary disease, etc.
 Steroids (oral preparations, injection, enema, suppository)  Azathioprine, 6-mercaptopurine  Salazosulfapyridine preparations (oral preparation, suppository)  5-aminosalicylate acid preparations (oral preparations, enema) In imputation of the data related to these treatment failures, the Last Observation Carried Forward (hereinafter referred to as LOCF) approach was applied first, where existing values which were obtained at the evaluation point immediately before the missing time point were used, and then TF imputation of the evaluation results obtained after the relevant time point was performed.
Whether a patient would be handled as a treatment failure or not was decided in accordance with the judgment made by the clinical conference.

Handling of Data on Each Score
(1) CAI score Any missing data of CAI subscores at each time point were imputed with the last observed values (CAI subscore) (LOCF), and the LOCF data represented the subscore at the relevant time point, and were used for determination of CAI score at the relevant time point.
For discontinued patients and CAI score-based non-responders, the subscores at time points with no assessment data after discontinuation for the former and after Week 8 for the latter, were imputed in the same way, and the CAI score was determined.
(2) Partial Mayo score Any missing data of the 3 partial Mayo subscores (stool frequency, rectal bleeding, physician's global assessment) at each time point were imputed within the last observed value (LOCF), and the LOCF data represented the subscore at the relevant time point, and was used for determination of the partial Mayo score at the relevant time point.
For discontinued patients and CAI score-based non-responders, the 3 subscores at the time points with no assessment data after discontinuation for the former and after Week 8 for the latter, were imputed in the same way, and the partial Mayo score was determined.
(3) Mayo score The Mayo score was determined for patients who had undergone assessment of the findings of endoscopy subscores in the screening period. When findings of endoscopy at Week 30 were missing, these data were imputed with the evaluation at the time of discontinuation (LOCF), and the LOCF data were treated as the subscore at Week 30 and used to determine the Mayo score at Week 30.
In the case where the evaluation had not been performed at Week 30 or at the time of discontinuation, the Mayo scores were not determined due to lack of data to be used for imputation.
(4) PUCAI score Any missing data of PUCAI subscores at each time point were imputed with the last observed values (PUCAI subscore) (LOCF), and the LOCF data represented the subscore at the relevant time point, and was used for determination of the PUCAI score at the relevant time point. For discontinued patients and CAI score-based non-responders, the subscores at the time points with no assessment data after discontinuation for the former and after Week 8 for the latter, were imputed in the same way, and the PUCAI score was determined.
(5) Remission based on each score (CAI, Mayo, PUCAI) In terms of remission based on each score (CAI, Mayo, PUCAI), patients were evaluated on whether the patient achieved or failed to achieve remission based on each score (CAI, Mayo, PUCAI) determined in accordance with the above (1), (3) or (4), unless all of the subscores were missing at each time point.
When all of the subscores were missing, the relevant patient was assessed as having failed to achieve remission.
For discontinued patients and CAI score-based non-responders, data of the remission rates based on each score (CAI, Mayo, PUCAI) after discontinuation for the former and after Week 8 for the latter were imputed with failure to achieve remission.
(6) Mayo score-based response, mucosal healing In terms of Mayo score-based response, patients were judged as whether having achieved or failed to achieve remission based on the Mayo score determined in accordance with the above (3), unless all of the subscores were missing at the relevant time point. For mucosal healing, patients were evaluated on whether having achieved or failed to achieve mucosal healing based on the subscore of findings of endoscopy determined in accordance with the above (3). In the case where the determination of subscores of findings of endoscopy had not been performed at Week 30 or at the time of discontinuation, judgment was not performed due to lack of data to be used for imputation.
For discontinued patients, the data on Mayo score-based response and mucosal healing at the time points with no assessment data after discontinuation were respectively imputed with failure to achieve remission based on Mayo score and failure to achieve mucosal healing.
(7) PUCAI score decrease by at least 20 points In terms of a PUCAI score decrease by at least 20 points, patients were evaluated on whether they achieved or failed to achieve a PUCAI score decrease by at least 20 points based on the PUCAI score determined in accordance with the above (4), unless all of the subscores were missing at the relevant time point.
When all of the subscores were missing, the relevant patient was assessed as a failure to achieve a PUCAI score decrease by at least 20 points. For discontinued patients and CAI score-based non-responders, data on a PUCAI score decrease by at least 20 points at the time point with no assessment data after discontinuation for the former and after Week 8 for the latter, was imputed as non-applicable.

Handling of Data on Steroid Dose
(1) Steroid dose The steroid dose at the time points after discontinuation for discontinued patients or at the time points after Week 8 for CAI score-based non-responders was imputed with the last observed value (steroid dose) (LOCF).
(2) Steroid withdrawal In terms of steroid withdrawal at each time point, patients were assessed on whether steroid withdrawal was achieved or not based on the steroid dose calculated in accordance with the above (1).
For discontinued patients and CAI score-based non-responders, data on steroid withdrawal at the time point with no assessment data after discontinuation for the former and after Week 8 for the latter were imputed with failure to achieve steroid withdrawal.

Handling of Safety Evaluation Data
(1) Permitted time range for time lag at evaluation time point In tabulation of data for each measurement point, data which fell within the permitted time range for the day of evaluation were selected, and no imputation of the missing data by data outside the permitted range was performed. The permitted time ranges were set as ±6 days for Weeks 2, 6 and 8, ±7 days for Week 10 and the range from -13days to +14days after Week 14.
For safety evaluation (including the endpoint [CRP] of other laboratory test), in the study drug administration week excluding the starting day of study drug administration (Week 0), evaluation performed after study drug administration was selected as the data for the relevant week. When multiple data existed within the permitted time range, data were selected in accordance with the following rules:  Evaluation performed on the closest day to the baseline day should be selected.
 When there are two evaluations with the same time lag before and after the baseline day, the evaluation after the baseline should be selected.
 When there are several evaluations on a single measurement day, evaluation of a label for the specified timing should be selected.  Handling of the results of ATI determination after administration of Remicade ® was decided by the PK/PD/PGx Data Handling Assessment. Since it is clear that treatment with Remicade ® would affect the ATI assessment, the results of ATI determination at the time point after administration of Remicade ® (8 weeks after the last administration) for the relevant patients (Patient ID Code: TA-650UC-003-01, TA-650UC-022-02) was not included in the analysis, and treated as a missing value. ATI determination for the relevant patient was performed using the data obtained at the time points other than that where a missing value was obtained according to the ATI determination flow chart (Figure 13 (2) Handling of measurement values less than the limit of quantitation When the result of measurement of serum infliximab concentration was less than the limit of quantitation (limit of quantitation: 0.1 μg/mL), the relevant result was treated as 0 μg/mL in the calculation, and represented as "BLQ."

Efficacy Evaluation
The following analyses were performed in the efficacy analysis set.

CAI Score
(1) Endpoints  CAI score, CAI score-based remission (2) Analysis method  Both of the results for which no imputation of missing data was performed (each evaluation point includes the "last" time point) and those for which TF imputation was applied were shown (Summary statistics of each subscore were excluded).
 Summary statistics of CAI score and CAI score change and the rate of CAI score-based remission at each evaluation point were calculated.

Partial Mayo Score
(1) Endpoint  Partial Mayo score (2) Analysis method  Both of the results for which no imputation of missing data was performed (each evaluation point includes the "last" time point) and those for which TF imputation was applied were shown (Summary statistics of each subscore were excluded).
 Summary statistics of partial Mayo score and partial Mayo score change at each evaluation point were calculated.

Mayo Score
(1) Endpoints  Mayo score, Mayo score-based response, Mayo score-based remission, and mucosal healing (2) Analysis method  Both of the results for which no imputation of missing data was performed (each evaluation point includes the "last" time point) and those for which TF imputation was applied were shown (Summary statistics of each subscore were excluded).
 Summary statistics of the Mayo score and Mayo score change and the rate of Mayo score-based response, the rate of Mayo score-based remission and the rate of mucosal healing at each evaluation point were calculated.

PUCAI Score
(1) Endpoints  PUCAI score, PUCAI score-based remission, PUCAI score decrease by at least 20 points (2) Analysis method  Both of the results for which no imputation of missing data was performed (each evaluation point includes the "last" time point) and those for which TF imputation was applied were shown (Summary statistics of each subscore were excluded).
 Summary statistics of PUCAI score and PUCAI score change, and the rate of PUCAI score-based remission and the proportion of patients who achieved a PUCAI score decrease by at least 20 points at each evaluation point were calculated.

Steroid Dose
(1) Endpoints  Steroid dose, steroid withdrawal (2) Analysis method  Among FAS, patients who had been using steroids (oral preparations) at the time of registration were included in the analysis set.


Both of the results for which no imputation of missing data was performed (each evaluation point includes the "last" time point) and those for which TF imputation was applied were shown.
 Summary statistics of steroid dose and the rate of steroid dose change, and the rate of steroid withdrawal at each evaluation point were calculated.

Safety Evaluation
The following analyses were performed in the safety analysis set. Names of symptoms of AEs were coded using the Medical Dictionary for Regulatory Activities/ Japanese edition (MedDRA/J ver. 17.1).

Safety Data Summary
(1) Endpoints AEs, AEs (SOC is other than investigations), ADRs, ADRs (SOC is other than investigations), serious AEs, serious ADRs, AEs leading to discontinuation, AEs by severity, AEs by time point, ADRs leading to discontinuation, infections, infections (ADRs), serious infections, serious infections (ADRs), infections leading to discontinuation of treatment, infusion reaction, infusion reaction (ADRs), serious infusion reaction, infusion reaction leading to discontinuation of administration, AEs (immunoserological tests), general laboratory tests, physical examinations.
(2) Analysis method The number of patients who experienced an event and the incidence rate (%) of the event are shown for each endpoint.
(2) Analysis method For each endpoint, the number of patients who experienced an event, incidence rate (%), and the number of events are listed by the overall events, System Organ Class (SOC) according to MedDRA/J, and SOC/preferred term (PT). SOCs were represented in ascending internationally agreed order, and PTs were represented in descending order for the number of patients who experienced the event, and ascending order for the PT code.

AEs (Immunoserological Tests)
For AEs (immunoserological tests), the number of patients who experienced the event, incidence rate (%) and the number of events are listed by "antinuclear antibody increased," "double stranded DNA (IgG) antibody positive" and "double stranded DNA (IgM) antibody positive."

1) Incidence rate of infusion reactions by number of doses
The number of patients who experienced an event and the incidence rate (%) by number of doses is represented.

2) Incidence rate of infusion reactions per one dose
The overall number of doses (total number of doses in all patients), the number of events (the number of doses where any infusion reactions were observed) and the incidence rate of infusion reaction per one dose (the percentage of the number of events with respect to the overall number of doses) is represented.

3) Incidence rate of infusion reactions by ATI determination
The number of patients who experienced an event and the incidence rate (%) by ATI determination (negative, positive, inconclusive) is represented.

AEs, ADRs, infections and infections (ADRs)
(2) Analysis method For each endpoint (other than immunoserological tests), the number of patients who experienced an event and the incidence rate (%) are listed by severity (mild, moderate and severe) as well as by overall events, SOC according to MedDRA/J, and SOC/ PT. For each endpoint (SOC is other than Investigations), the number of patients who experienced the event and the incidence rate (%) are listed by the following classification categories:

AEs by Timing of Occurrence
Classification categories for timing of occurrence: between the starting day of study drug administration (Week 0) and before administration at Week 14, between after administration at Week 14 and before administration at Week 22, between after administration at Week 22 and evaluation day at Week 30.
AEs which occurred on the day of study drug administration excluding those that clearly occurred after administration of the study drug such as infusion reactions, were tabulated as AEs which occurred before administration of the study drug.

Immunoserological Tests
(1) Endpoints "Antinuclear antibody increased," "double stranded DNA (IgG) antibody positive" and "double stranded DNA (IgM) antibody positive," (2) Analysis method For each endpoint, the cross tabulation between each determination (negative, positive) and the time points at Weeks 0 (the starting day of administration), 14 and 30 and all of the time points after administration was performed.

General Laboratory Tests
(1) Endpoints Hematology, blood biochemistry and urinalysis (qualitative) (2) Analysis method For each laboratory parameter, the number of patients who experienced an abnormal change and incidence rate (%) of abnormal change are listed by abnormal increase and abnormal decrease. In addition, for hematology and blood biochemistry, summary statistics of laboratory test values (n, Median, Q1, Q3, Min and Max) at each evaluation point were calculated. Summary statistics were calculated based on the measurement results obtained from all of the patients, and not calculated by the age or sex of the patients.
For urinalysis (qualitative), the frequency distribution of urinalysis results in each of the assessment categories at each evaluation point is listed.
For urinalysis (qualitative, other than urobilinogen), frequency distribution of each judgment, "normal" and "abnormal" at each evaluation time point (only Weeks 8, 14, 22 and 30) is listed. For urinalysis (urobilinogen), the frequency distribution of each judgment "low," "normal" and "high," at each evaluation time point (only Weeks 8, 14, 22 and 30) is listed.
Since reference ranges of laboratory parameters for children vary depending on age and sex, the reference ranges of laboratory parameters were established by selecting reference values by sex and age (the age at informed consent obtainment is used) in reference to "New Pocket Guide of Laboratory Test Reference Values for Children" 2) . Since no reference ranges for differential count of WBC are listed in this material, abnormal changes were not assessed for this parameter.
Since it was judged that the reference ranges for urinalysis (qualitative) in adults can also be used in children without any clinical problems, the reference values (for adults) provided from the contract laboratory were used to assess abnormal changes.

Physical Examination
(1) Endpoints Systolic and diastolic blood pressure, pulse rate, and body temperature

Other Evaluations
The following items were analyzed in the efficacy analysis set.

Evaluation of Pharmacokinetics
The following analyses were performed to examine the pharmacokinetics of TA-650 in the pharmacokinetic analysis set. Detailed analysis method is described in the pharmacokinetic analysis plan. The pharmacokinetic analysis plan was locked immediately after determination of the handling of pharmacokinetic-related data after the clinical conference. Ulcerative colitis is designated as a specific disease, and a medical care certificate for patients with a specific disease was issued to approximately 110,000 patients in fiscal 2011 when this study was planned. Among these patients, the number of "pediatric" patients with "moderate to severe" ulcerative colitis, the target of this clinical study, is estimated to be approximately 1200. Since these patients included those who might be able to maintain remission by existing therapies and those with indications for surgical procedures such as failure to thrive, undernutrition, and worsened QOL specific to children, it was considered that patients actually eligible for the study would be even fewer, and the number of patients accumulated for this study was limited. Consequently, the target number of patients was set as 20 patients in terms of feasibility. In face-to-face advice from the Pharmaceuticals and Medical Devices Agency regarding this study, it had been recommended to examine the efficacy, safety and pharmacokinetics of the study drug comprehensively since the study would be conducted on a limited number of patients and it would be difficult to establish a certain achievement criteria for evaluation of efficacy and safety, and also recommended to give consideration so as not to create an imbalance to a certain age group among the target patient ages ranging from 6 years to 17 years, included both childhood (6 to 11 years old) and young adults (12 to 17 years old). Therefore, it was decided to accumulate a certain number of patients in both age groups.
Conducting this study on 20 patients was considered to allow for both efficacy and the safety evaluation as described below. Pharmacokinetic evaluation was conducted in the collected number of patients.

Efficacy
In the domestic clinical study of TA-650 in adult patients with ulcerative colitis, the CAI score-based remission rate at Week 8 (patients having a CAI score of not less than 7 and a score for blood in stools of not less than 2 at the time of registration among FAS) was 38.5% (30/78). To replicate this result in 20 patients, a 95%CI for this result would be as follows:  95%CI of CAI score-based remission rate (38.5%): 20.7% -59.9%.

Safety
One of the ADRs of TA-650 to be noted was assumed to be infections. In domestic clinical studies in adult patients with ulcerative colitis, the incidence rate of infections (ADRs) was 18.3% (19/104). Assuming that the incidence rate of infections in adults is the same as that in children, an infection would be detected in one patient out of the target number of patients (20 patients) at a probability of 98.2%, and therefore the selected number of patients would allow for evaluation of the risk of infections of the study drug.

Revision of the Protocol
The study protocol has been revised twice since the start of this study. In the first revision, the principal changes were the duration of the follow-up of AEs, treatment to expression of malignancy and clarification of the procedure for reporting pregnancy and correction of erroneous descriptions. The principal change in the second revision was the addition of the procedure for tuberculosis testing. The study protocol (Ver. 02.00.00000, prepared on May 22, 2013) is attached in Appendix 16.1.1a, and the list of changes is attached in Appendix 16.1.1b.

Revision of Analysis Plans
The statistical analysis plan and the pharmacokinetic analysis plan were fixed respectively on December 15, 2014 (ver. 3.0) and January 19, 2015 (Ver. 1.0) before the database was fixed, and both plans are described in "9.7.1 Statistical and Analytical Plans."

Disposition of Patients
The disposition of patients in this study is shown in Figure 10.1-1, and the reasons for discontinuation are shown in Table 10.1-1.
In this study, informed consent was obtained from legal representatives of patients. Informed consent from legal representatives was obtained from 30 patients, and among these patients, 21 patients were registered and started to receive the study drug. Since one patient discontinued the study before CAI score evaluation at Week 8, 20 patients underwent CAI score evaluation at Week 8. Among the patients who underwent CAI score evaluation at Week 8, 18 patients were CAI score-based responders. Among these responders, 14 patients completed the study period, and 4 discontinued the study during the study period. The reasons for discontinuation were an occurrence of an AE in one patient, insufficient response to the study drug in one patient, and worsened primary disease in 2 patients. Two CAI score-based non-responders were observed, and both of them completed the evaluation at Week 14.

Protocol Deviations
Protocol deviations were categorized into the following 5 groups.
A: Patients who did not satisfy the inclusion criteria but were enrolled in the study B: Patients who met any of the discontinuation criteria during the study period but did not discontinue the treatment

Data Sets Analyzed
Handling of the data obtained from 21 patients treated with the study drug was decided at the clinical conference held on December 15, 2014. The minutes of the clinical conference are provided in Appendix 16.1.13g. The data obtained from all of the patients treated with the study drug were used as the data set.
The efficacy analysis set was defined as the FAS excluding patients with a disease other than the target disease, patients who had never received the study drug during the evaluation period, and patients from whom no efficacy data were obtained during the evaluation period, and all of 21 patients who received the study drug were included in the efficacy analysis set. The pharmacokinetic analysis set included 21 patients from whom data for serum infliximab concentration or ATI were obtained at least once after administration among the patients who had received the study drug at least once. Table 11.2-1 shows the characteristics of patients who were included in the efficacy analysis set (FAS).

Demographic and Other Baseline Characteristics
The proportions of male and female pediatric patients were respectively 52.4% (11/21) and 47.6% (10/21), showing similar proportions between male and female patients. The median age at the time of obtainment of consent was 14.0 years and as many as 81.0% (17/21) fell within the range from 12 to 17 years, and the median height and median body weight were respectively 158.0 cm and 45.40 kg. The median BMI was 17.78 kg/m 2 , and 61.9% (13/21) of patients fell within the range of less than 18.5 kg/m 2 . The median duration of disease was 2.10 years, and approximately 80% of the patients had experienced the disease for less than 3 years. In terms of extent of disease, 95.2% (20/21) patients had total colitis, and the most common clinical severity and clinical course were moderate and the relapse-remitting type respectively, each observed in 76.2% (16/21) of patients. In terms of drugs/therapies which had been used for treatment of ulcerative colitis, whether patients were non-responders to cyclosporine, tacrolimus or cytapheresis or not was assessed, and 9.5% (2.21) of patients were non-responders to cytapheresis, while no non-responders to cyclosporine or tacrolimus were found. In addition, no patients had experienced ulcerative colitis-related segmental resection or treatment, or surgical procedures (excluding intestinal resection).
In terms of resistance to existing therapies, 81.0% (17/21) did not respond to steroids (past or at the time of registration), and among these patients, patients who did not respond to steroids (failure of steroid withdrawal) accounted for the largest portion of 76.2% (16/21), while no patients who did not respond to steroids (severe) and no patients who were intolerant to steroids (past) were found. In addition, 47.6% (10/21) of patients did not respond to 6-mercaptopurine or azathioprine (past or at registration), while patients who were intolerant to 6-mercaptopurine or azathioprine (past) were only 4.8% (1/21), showing that few patients fell into this category.
In terms of concomitant drugs for the treatment of ulcerative colitis, aminosalicylates (oral preparations) were most commonly used in 90.5% (19/21) of patients, while steroids (oral preparations) and immunomodulators (azathioprine or 6-mercaptopurine) were respectively used in 57.1% (12/21) and 42.9% (9/21) of patients.  *1: For at least 12 weeks before the starting day of the screening period, a patient had received 6-mercaptopurine or azathioprine, and had received at a stable dose for at least 4 weeks before the starting day of the screening period, but had an inadequate response. *2: Within 5 years before the starting day of the screening period, a patient had received 6-mercaptopurine or azathioprine for at least 12 weeks but had an inadequate response. *3: Patients who were categorized into either of those who did not respond to 6-mercaptopurine or azathioprine (past) or (at the time of registration). *4: Within 5 years before the starting day of the screening period, a patient had received 6-mercaptopurine or azathioprine, and experienced an adverse drug reaction that made it difficult to continue treatment. *5: For at least 2 weeks before the starting day of the screening period, a patient had received steroids at a dose of at least 1 mg/kg/day or 20 mg/day calculated on a prednisolone basis, but had an inadequate response. *6: Within 18 months before the starting day of the screening period, a patient had experienced an exacerbation or relapse of the primary disease in response to a reduction in the steroid dose, and had difficulty in steroid withdraw． *7: Within 18 months before the starting day of the screening period, a patient had used a steroid, but had an inadequate response to oral or intravenous steroid at a dose of at least 1 mg/kg/day or at least 40 mg/day calculated on prednisolone basis for at least 2 weeks for the former or at least 1 week for the latter). *8: Patients who were categorized into either of those who did not respond to steroids (at the time of registration), those who did not respond to steroids (failure of steroid withdrawal) (past or at the time of registration), or those who did not respond to steroids (severe) (past or at the time of registration). *9: Within 18 months before the starting day of the screening period, a patient had used steroids and experienced an adverse drug reaction that made it difficult to continue treatment.
The baseline data of individual endpoints (FAS) are shown in Table 11.2-2.
The CAI score (Mean ± SD) at the time of registration was 9.7 ± 2.7 points, and patients having a CAI score of 7 to 8 points, 9 to 10 points and not less than 11 points were respectively 42.9% (9/21), 28.6% (6/21) and 28.6% (6/21).The partial Mayo score (Mean ± SD) was 5.6 ± 1.6 points, and patients having a partial Mayo score of 4 to 6 points accounted for the largest percentage at 57.1% (12/21). The Mayo score (Mean ± SD) determined only in 8 patients who were able to undergo sigmoidoscopy was 7.0 ± 2.4, and moderate (Mayo score ranging from 6 to 10 points) and severe (Mayo score ranging from 11 to 12 points) conditions assessed based on the Mayo score were observed respectively in 50.0% (4/8) and 12.5% (1/8) patients. The PUCAI score (Mean ± SD) was 47.1 ± 15.2 points, and patients having a PUCAI score between 31 and 60 accounted for the largest percentage at 66.7% (14/21).
At the time of registration, 57.1% (12/21) of patients were using steroids, and all of these patients received steroids at a dose of not more than 1 mg/kg/day calculated on prednisolone basis. The median CRP was 0.20 mg/dL.

Measurements of Treatment Compliance
The treatment compliance of individual patients is provided in Appendix 16.2.8f.
In the patient with patient ID code of TA-650UC-022-01, calculation of a dose of the study drug at Week 6 was incorrect due to a wrong conversion base for body weight, and 220 mg (97.78% of the specified dose) of the study drug was administered. However, since not less than 75% of the specified dose was administered to the patient, it was judged that this deviation would not cause any problems in evaluation of efficacy and pharmacokinetics of the study drug.
In the patient with a patient ID code of TA-650UC-025-01, the duration of administration of the study drug at the starting day of study drug administration (Week 0) was 1 hour 52 minutes, which was shorter than the duration specified in the protocol (at least 2 hours). However, since the total amount of the specified dose was administered, it was judged that this deviation would not cause any problems in evaluation of efficacy of the study drug. In addition, no AEs were observed in this patient on the day of administration, therefore it was judged that this deviation would not cause any problems in evaluation of safety.
In the patient with patient ID code of TA-650UC-013-01, the day of study drug administration at Week 6 fell outside the permissible time range for study drug administration (Week 6: ±3 days) specified in the protocol. The study drug was administered 6 days after the specified day and the deviation from the specified day was not large, therefore it was judged that this deviation would not cause any problems in evaluation of efficacy.

Analysis of Efficacy
The results of tabulation based on the data employed at each evaluation point were provided for each efficacy endpoint. In case data to be obtained by evaluation at Week 30 is missing due to discontinued patients and CAI score-based non-responders, the results of tabulation based on LOCF data obtained by using the values observed at the last evaluation point immediately before the missing point were provided as the value for the last time point.
When the data at each time point until Week 30 were missing, the results of tabulation after imputation were also provided. The data at a missing evaluation time point were first imputed by the LOCF approach using the values observed at the last evaluation point immediately before the missing point. Subsequently, for the evaluation points after the time point where the relevant patient met the conditions of TF, missing data were imputed with the data satisfying the rules for TF (see 9.7.1.2.2.5 Treatment Failure). Five patients met the conditions of TF, and all of these patients fell under the category of "Patients who discontinued the study due to exacerbation of the primary disease or inadequate response to the study drug," and one out of the five patients also fell under the category of "Patients who experienced the start of administration or increase in a dose of steroids (oral preparations, injection, enema, and suppository) due to exacerbation of the primary disease, etc.," Detailed information about the patients of TF is described in the minutes of clinical conference (see Appendix 16.1.13g for details).

CAI Score
The CAI score is an activity index to evaluate disease activity, which is calculated as the sum (0 to 29 points) of subscores for 7 clinical conditions, consisting of the number of stools per week, blood in stools (based on weekly average), investigator's global assessment of the symptomatic state, abdominal pain/cramps, temperature elevation due to ulcerative colitis, extraintestinal manifestations, and laboratory findings (hemoglobin or ESR), and a higher score indicates greater disease activity. In addition, a difference calculated by subtracting the CAI score at the time of registration from the CAI score on each evaluation day was defined as a CAI score change.
Summary statistics of the CAI score and CAI score change at each evaluation point are shown in Table  11.4-1, and the time course of CAI score is shown graphically in Figure 11.4-1. Summary statistics and the time course based on data obtained by TF imputation are also respectively shown in Table 11.4-2 and Figure 11.4-2.
The CAI score (Mean ± SD) was 9.7 ± 2.7 at the time of registration and then decreased respectively over time to: 4.0 ± 3.2, 3.5 ± 3.5 and 3.2 ± 3.5 at Weeks 2, 6 and 8. Subsequently, the CAI score ranged from 2.5 ± 2.3 to 3.5 ± 2.2 during the period from Week 10 to Week 30, and was 5.6 ± 3.8 at the last time point. The CAI score changes (Mean ± SD) were -5.5 ± 2.7, -6.0 ± 4.0 and -6.2 ± 3.7 at Weeks 2, 6 and 8 respectively, indicating an increase in the degree of score change with time, and the score changes ranged from -5.9 ± 3.8 to -6.9 ± 3.8 during the period from Week 10 to Week 30, and were -4.1 ± 4.2 at the last time point. Both the CAI score and CAI score change showed the effect of the study drug in improving symptoms from Week 2, and the effect was maintained up to Week 30.
When using the data obtained by TF imputation, the CAI scores (Mean ± SD) at Weeks 2, 6 and 8 were 4.5 ± 3.9, 4.0 ± 4.3 and 3.8 ± 4.3 respectively, indicating a decreasing tendency, and the CAI score ranged from 4.1 ± 4.6 to 5.8 ± 4.1 during the period from Week 10 to Week 30. The CAI score changes (Mean ± SD) (TF) were -5.2 ± 2.9, -5.7 ± 4.2 and -5.9 ± 3.8 at Weeks 2, 6 and 8 respectively, indicating an increase in the degree of score change, and ranged from -3.9 ± 4.3 to -5.5 ± 4.4 during the period from Week 10 to Week 30. Both the CAI score and CAI score change showed similar tendencies to the data obtained before TF imputation.    The CAI score-based remission was defined as the case where a CAI score was not more than 4 on the evaluation day excluding the evaluation at the time of registration. The CAI score-based remission rates at each evaluation point are shown in Table 11.4-3. The CAI score-based remission rates calculated based on the data obtained by TF imputation are shown in Table 11.4-4.
The CAI score-based remission rate was 60.0% (12/20) at Week 2, and was increased to 80.0% (16/20) at both Weeks 6 and 8. Afterwards, the CAI score-based remission rate ranged from 64.3% to 87.5% during the period from Week 10 to Week 30, and was 42.9% (9/21) at the last time point. Based on the results of CAI score-based remission rate, the administration of TA-650 was observed to render the effect of leading at least 60% of the patients to achieve remission from Week 2, and the effect of the drug was confirmed to last up to Week 30.
When TF imputation was performed, the CAI score-based remission rates were 57.1% (12/21) at Week 2, and 76.2% (16/21) at both Weeks 6 and 8, and then ranged from 42.9% to 66.7% during the period from Week 10 to Week 30. The data obtained by TF imputation was confirmed to show a similar tendency to the data obtained before TF in that administerring the drug had the effect of leading patients to remission from Week 2 and the effect lasted.   The partial Mayo score is an activity index to evaluate disease activity, which is calculated as the sum (0 to 9 points) of subscores for 3 clinical conditions, consisting of stool frequency, rectal bleeding and physician's global assessment, and a higher score indicates greater disease activity. In addition, a difference calculated by subtracting the partial Mayo score at the time of registration from a partial Mayo score on each evaluation day was defined as a partial Mayo score change.
Summary statistics of partial Mayo score and partial Mayo score change at each evaluation point were shown in Table 11.4-5. Summary statistics of partial Mayo score and partial Mayo score change based on data obtained by TF imputation were shown in Table 11.4-6.
The partial Mayo score (Mean ± SD) was 5.6 ± 1.6 at the time of registration and decreased over time respectively to: 2.6 ± 2.3, 2.2 ± 2.0 and 1.7 ± 1.7 at Weeks 2, 6 and 8. Subsequently, the score ranged from 1.8 ± 1.7 to 2.8 ± 1.9 during the period from Week 10 to Week 30, and was 3.7 ± 2.2 at the last time point. The partial Mayo score changes (Mean ± SD) at Weeks 2, 6 and 8 were respectively -2.9 ± 2.2, -3.3 ± 2.2 and -3.8 ± 1.7, indicating an increase in degree of score change with time. The partial Mayo score change ranged from -2.6 ± 2.8 to -3.6 ± 2.5 during the period from Week 10 to Week 30, and was -1.9 ± 2.7 at the last time point. As shown above, both the partial Mayo score and partial Mayo score change showed the effect of the study drug in improving symptoms from Week 2, and the effect lasted up to Week 30.
When using the data obtained by TF imputation, the partial Mayo scores (Mean ± SD) at Weeks 2, 6 and 8 were respectively 2.9 ± 2.6, 2.5 ± 2.3 and 2.0 ± 2.1, indicating a decreasing tendency, and the partial Mayo score ranged from 2.6 ± 2.3 to 3.6 ± 2.2 during the period from Week 10 to Week 30. The partial Mayo score changes (Mean ± SD) were -2.7 ± 2.2, -3.1 ± 2.3 and -3.6 ± 1.9 respectively at Weeks 2, 6 and 8, indicating an increase in the degree of score change, and ranged from -2.0 ± 2.5 to -3.0 ± 2.5 during the period from Week 10 to Week 30. Both the partial Mayo score and partial Mayo score change showed similar tendencies to the data obtained before TF imputation in that the effect of the study drug to improve symptoms was observed from Week 2 and the effect lasted up to Week 30.

Mayo Score
The Mayo score is an activity index to evaluate disease activity, which is calculated as the sum (0 to 12 points) of subscores for 4 clinical conditions, consisting of those for the partial Mayo score and findings of endoscopy. Since this clinical study was conducted in pediatric patients taking into consideration the burden of the examination on patients, sigmoidoscopy performed to determine a Mayo score was not included as an essential test item, but it was decided to perform this examination whenever possible. It was also decided that a Mayo score would not be determined when the endoscopic examination was able to be performed only at one time point among the time of registration, Week 30 and the day of discontinuation, since it was impossible to compare Mayo scores between before and after administration of the study drug. Due to this, only 8 patients were assessed based on the Mayo score. In addition, a difference calculated by subtracting the Mayo score at the time of registration from a Mayo score on each evaluation day was defined as a Mayo score change.
Summary statistics of Mayo score and Mayo score change at each evaluation point were shown in Table 11.4-7. Summary statistics of the Mayo score and Mayo score change based on the data obtained by TF imputation were shown in Table 11.4-8.
The Mayo score (Mean ± SD) was 7.0 ± 2.4 at the time of registration and at week 30 had decreased to 4.9 ± 2.4. The Mayo score at the last time point was 5.0 ± 2.3. The Mayo score changes (Mean ± SD) at Week 30 and the last time point were respectively -2.6 ± 3.9 and -2.0 ± 3.9.
When TF imputation was performed, the Mayo score (Mean ± SD) at Week 30 was 4.8 ± 2.3, indicating a similar tendency to that obtained before TF imputation. In addition, the Mayo score change (Mean ± SD) at Week 30 based on the data obtained by TF imputation was -2.3 ± 3.7. Both the Mayo score and Mayo score change based on the data obtained by TF imputation showed a similar tendency to that obtained before TF imputation.   Mayo score-based response was defined as the case which satisfied both of the conditions, "a Mayo score was decreased by at least 30% and by at least 3 points compared to that measured at the time of registration" and "a rectal bleeding subscore was decreased by at least 1 point compared to that measured at the time of registration or the rectal bleeding subscore was not more than 1 point" at each evaluation point. Mayo score-based remission was defined as the case where a Mayo score on each evaluation day excluding the evaluation at the time of registration was not more than 2 points and all of the 4 subscores were not more than 1 point.
The Mayo score-based response rates and Mayo score-based remission rates are shown respectively in Table 11.4-9 and Table 11.4-10. The Mayo score-based response rates and Mayo score-based remission rates based on the data obtained by TF imputation are shown respectively in Table 11.4-11 and Table  11.4-12.
The Mayo score-based response rate and Mayo score-based remission rate at Week 30 based on the data obtained by TF imputation were respectively 37.5% (3/8) and 12.5% (1/8), indicating similar values to those obtained before TF imputation.

PUCAI Score
The PUCAI score is an activity index for pediatric ulcerative colitis, which is calculated as the sum (0 to 85 points) of subscores for 6 clinical conditions, consisting of abdominal pain, rectal bleeding, stool consistency, stool frequency per 24 hours, nocturnal stool, and activity level. Similar to other scores, a higher PUCAI score indicates greater disease activity. In addition, a difference calculated by subtracting the PUCAI score at the time of registration from a PUCAI score on each evaluation day was defined as the PUCAI score change.
Summary statistics of PUCAI score and PUCAI score change at each evaluation point are shown in Table 11.4-13. Summary statistics of PUCAI score and PUCAI score change based on the data obtained by TF imputation are shown in Table 11.4-14.
The PUCAI score (Mean ± SD) was 47.1 ± 15.2 at the time of registration and decreased over time to 20.3 ± 16.3, 17.3 ± 17.5 and 12.5 ± 13.5 respectively at Weeks 2, 6 and 8. The PUCAI scores ranged from 12.2 ± 12.0 to 19.3 ± 18.8 during the period from Week 10 to Week 30, and were 28.8 ± 22.5 at the last time point. The PUCAI score changes (Mean ± SD) at Weeks 2, 6 and 8 were respectively -25.8 ± 17.5, -28.8 ± 21.1 and -33.5 ± 14.0. The PUCAI score changes ranged from -26.8 ± 27.8 to -34.1 ± 17.7 during the period from Week 10 to Week 30, and were -18.3 ± 28.4 at the last time point. Both the PUCAI score and PUCAI score change showed the effect of the study drug in improving symptoms from Week 2, and the effect lasted up to Week 30.
When using the data obtained by TF imputation, the PUCAI scores (Mean ± SD) decreased to 22.6 ± 19.3, 19.8 ± 20.6 and 15.2 ± 18.2 respectively at Weeks 2, 6 and 8, and ranged from 19.3 ± 20.5 to 27.6 ± 21.9 during the period from Week 10 to Week 30. The PUCAI score changes (Mean ± SD) based on the data obtained by TF imputation were -24.5 ± 18.0, -27.4 ± 21.5 and -31.9 ± 15.4 at respectively Weeks 2, 6 and 8, indicating an increase in the degree of score change, and ranged from -19.5 ± 25.8 to -27.9 ± 19.9 during the period from Week 10 to Week 30. Both the PUCAI score and PUCAI score change based on the data obtained by TF imputation showed a tendency similar to the data before TF imputation in that the effect of the study drug in improving symptoms was observed from Week 2 and the effect lasted up to Week 30.    The PUCAI score-based remission was defined as the case where the PUCAI score on each evaluation day excluding the evaluation at the time of registration was less than 10. The PUCAI score-based remission rates are shown in Table 11.4-15, and those rates based on the data obtained by TF imputation are shown in Table 11.4-16.
The PUCAI score-based remission rate was 35.0% (7/20) at Week 2 and increased to 40.0% (8/20) at both Weeks 6 and 8. Subsequently, the PUCAI score-based remission rates ranged from 28.6% to 42.9% during the period from Week 10 to Week 30, and were 19.0% (4/21) at the last time point. The study drug was confirmed to render the effect of leading patients to remission from Week 2 and the effect lasted.
When using the data obtained by TF imputation, the PUCAI score-based remission rates were 33.3% (7/21), 38.1% (8/21) and 38.1% (8/21) respectively at Weeks 2, 6 and 8, and ranged from 19.0% to 33.3% during the period from Week 10 to Week 30. The results of the evaluation using the data obtained by TF imputation showed a similar tendency to the results obtained before TF imputation in that the effect of the study drug was observed from Week 2 and the effect lasted. A decrease in PUCAI score by at least 20 points is a clinically significant change 3) , and the proportions of patients who achieved a decrease in PUCAI score by at least 20 points are shown in Table 11.4-17, and the proportions of patients who achieved a decrease in PUCAI score by at least 20 points based on the data obtained by TF imputation are shown in Table 11.4-18. The patients having less than 20 points of PUCAI score at the time of registration were excluded from this tabulation.
The proportion of patients who achieved a PUCAI score decrease by at least 20 points was 68.4% (13/19) at Week 2, and increased to 73.7% (14/19) and 89.5% (17/19) respectively at Weeks 6 and 8. Subsequently, the proportion of patients ranged from 64.3% to 88.2% during the period from Week 10 to Week 30, and was 60.0% (12/20) at the last time point. The effect in improving the symptoms was observed from Week 2 and the effect was confirmed to last afterwards.
When using the data obtained by TF imputation, the proportions of patients who achieved a PUCAI score decrease by at least 20 points were 65.0% (13/20), 70.0% (14/20) and 85.0% (17/20) respectively at Weeks 2, 6 and 8, and ranged from 45.0% to 75.0% during the period from Week 10 to Week 30. The time course of the proportion of patients was similar to that based on the data obtained by TF imputation. Mucosal healing was defined as the case where the subscore for findings of endoscopy of Mayo score on each evaluation day excluding the evaluation at the time of registration was not more than 1. In addition, among the patients who underwent sigmoidoscopy at the time of registration and either Week 30 or the day of discontinuation, patients in whom the subscore for findings of endoscopy at the time of registration was not more than 1 were excluded from this tabulation.
The rates of patients who achieved mucosal healing are shown in Table 11.4-19, and those based on the data obtained by TF imputation are shown in Table 11.4-20.
The rates of patients who achieved mucosal healing at Week 30 and the last time point were respectively 33.3% (2/6) and 28.6% (2/7).
When using the data obtained by TF imputation, the rate of patients who achieved mucosal healing at Week 30 was 28.6% (2/7), indicating a similar tendency to that before TF imputation.

Steroid Dose
The steroid dose (oral preparation, injection) in 12 patients who had been receiving steroids (oral preparations) at the time of registration was investigated. The steroid dose should be stable for at least 2 weeks before the starting day of the screening period, and initiation of steroid treatment or an increase in steroid dose were prohibited. After the starting day of study drug administration, when a clinical improvement in the symptoms of ulcerative colitis was confirmed by the investigator (subinvestigator), a decrease in steroid dose was allowed and performed in accordance with the rules specified in the protocol. A steroid dose at each evaluation week was calculated by dividing the mean value of steroid doses, calculated on prednisolone basis, administered during the period from 6 days before the CAI score evaluation day for the relevant week to the previous day of the evaluation day by body weight measured in the relevant week.
The steroid doses (oral preparations, injection) at each evaluation time point are shown in Table 11.4-21, and those based on the data obtained by TF imputation are shown in Table 11.4-22.
The median steroid dose was 0.20 mg/kg/day at the time of registration, and was decreased to 0.19 mg/kg/day, 0.17 mg/kg/day and 0.16 mg/kg/day respectively at Weeks 2, 6 and 8. The median steroid dose ranged from 0.04 mg/kg/day to 0.15 mg/kg/day during the period from Week 10 to Week 30, and was 0.05 mg/kg/day at the last time point.
When using the data obtained by TF imputation, the median steroid doses were 0.19 mg/kg/day, 0.17 mg/kg/day and 0.16 mg/kg/day respectively at Weeks 2, 6 and 8, and ranged from 0.05 mg/kg/day to 0.15 mg/kg/day during the period from Week 10 to Week 30, indicating the similar time course of steroid dose to that obtained before TF imputation.  The rate of steroid dose change was defined as the percentage of steroid dose change calculated by subtracting a steroid dose at each evaluation day from the steroid dose at the time of registration. Summary statistics of the rate of steroid dose change are shown in Table 11.4-23, and summary statistics of the rate of steroid dose change calculated using the data obtained by TF imputation are shown in Table  11.4-24.
The median rates of steroid dose change at Weeks 2, 6 and 8 were respectively -1.63, -25.05 and -43.91%, indicating an increase in degree of change with time. The median rate of steroid dose change ranged from -61.72% to -86.93%, and was -85.44% at the last time point.
When using the data obtained by TF imputation, the rates of steroid dose change were -1.63%, -25.05% and -43.91% respectively at Weeks 2, 6 and 8, and ranged from -45.01% to -79.31% during the period from Week 10 to Week 30, indicating that the time course of the rate of steroid dose change based on the data obtained by TF imputation was similar to that obtained before TF imputation. The results suggest that administration of TA-650 might enable steroid dose reduction.  Among 12 patients who had been receiving steroid (oral preparations) at the time of registration, the case where the steroid dose on each evaluation day became 0 was defined as steroid withdrawal. The rates of steroid withdrawal at each evaluation time point are shown in Table 11.4-25, and those calculated based on the data obtained by TF imputation are shown in Table 11.4-26.
The rate of steroid withdrawal was 8.3% at Week 2, and increased to 25.0% at both Weeks 6 and 8. The rate of steroid withdrawal ranged from 25.0% to 37.5% during the period from Week 10 to Week 30, and was 41.7% at the last time point.
When using the data obtained by TF imputation, the rate of steroid withdrawal was 8.3% at Week 2, and increased to 25.0% at both Weeks 6 and 8, and ranged from 16.7% to 25.0% during the period from Week 10 to Week 30, indicating that the time course of the rate of steroid withdrawal based on the data obtained by TF imputation was similar to that obtained before TF imputation.
At week 30, 2 patients achieved steroid withdrawal, and one of these 2 patients also achieved CAI score-based remission. In addition, another patient who did not achieve CAI score-based remission at Week 30 achieved CAI score-based remission at many time points other than Week 30.

Other Laboratory Test Parameters
Laboratory values for CRP (mg/dL) are shown in Table 11.4-27.
The median CRP was 0.2 mg/dL at the time of registration, and was maintained to be 0.00 mg/dL at all time points after Week 2.

Adjustments for Covariates
Not applicable because this study was an uncontrolled study.

Handling of Dropouts, or Missing Data
Handling of dropouts or missing data was performed in accordance with the predefined "9.7.1.2 Data handling,"

Interim Analyses and Data Monitoring
No interim analysis was planned in this study.

Multicenter Studies
This study was conducted utilizing a multicenter design, and all of 17 institutions had patients included in the FAS. The number of patients by participating medical institutions is shown in Table 11.4-28. Since the number of patients per institution was small, ranging from 1 to 2, in this study, the treatment-by-center interaction was not investigated.

Multiple Comparison/Multiplicity
Since no test was performed in this study, no problems related to multiple comparison/multiplicity occurred.

Use of an "Efficacy Subset" of Patients
No analysis using the efficacy subset of patients was conducted in this study.

Active-control Studies Intended to Show Equivalence
Not applicable because this study was an uncontrolled study.

Examination of Subgroups
Since the efficacy analysis set included as few as 21 patients in this study, no statistical study of subgroups was conducted. However, patients included in the efficacy analysis set were divided into 2 groups, one including patients aged from 6 years to less than 12 years, and the other including those aged from 12 years to 17 years, and the median CAI scores, median partial Mayo scores and median PUCAI scores at Weeks 0 (at the time of registration) and 8, and changes in each scores and the rates of CAI score-based remission and PUCAI score-based remission at Week 8 are shown in Table 11.4-29.
The numbers of patients in the group of those aged from 6 years to less than 12 years (hereinafter referred to as the younger group) and the group of those aged from 12 years to 17 years (hereinafter referred to as the older group) were respectively significantly different at 4 and 17 patients, but the CAI scores, partial Mayo scores and PUCAI scores observed at Week 0 in both of the groups were almost similar. Though the numbers of patients in both group were different, in terms of each of the scores and changes in each score, and the rates of CAI score based remission and PUCAI score-based remission at Week 8, the efficacy of the drug was not considered largely different between these groups.

Tabulation of Individual Response Data
The efficacy evaluation data at each evaluation time point for individual patients are provided in Appendix 16.2.6.

Serum Infliximab Concentration
The time course of serum infliximab concentration measured at each time point is shown in Table  11.4-30. Each patient was given the study drug at a dose of 5 mg/kg at Weeks 0 (the starting day of study drug administration), 2 and 6. Subsequently, each patient was judged whether the patient was a responder or a non-responder based on the CAI score obtained at Week 8, and only CAI score-based responders were given the study drug at a dose of 5 mg/kg at Weeks 14 and 22. In addition, since CAI score-based non-responders would be allowed to use the prohibited concomitant drugs and therapies after the end of evaluation at Week 8, only the data obtained by Week 8 were included in the tabulation for all of the patients (the overall population).
The median serum infliximab concentrations 1 hour after completion of administration at Week 0 in the overall population and CAI score-based responders were respectively 97.17μg/mL and 96.35 μg/mL and those in individual patients of CAI score-based non-responders (2 patients) were respectively 106.65μg/mL and 124.05 μg/mL. The median serum infliximab concentrations at Week 8 in the overall population and the CAI score-based responders were both 25.64 μg/mL, and those in individual patients of CAI score-based non-responders (2 patients) were respectively 13.74μg/mL and 28.09 μg/mL. The median trough serum infliximab concentration in CAI score-based responders at Weeks 14, 22 and 30 was respectively 2.58 μg/mL, 1.54 μg/mL, and 1.34 μg/mL, indicating that the serum infliximab concentration was maintained. Furthermore, the serum infliximab concentrations in CAI score-based responders obtained 1 hour after completion of administration at Weeks 0, 14 and 22 were respectively 96.35 μg/mL, 95.91 μg/mL, and 102.78 μg/mL, indicating that there was not a large difference in these concentrations. Taking into consideration these results, the study drug was not considered likely to accumulate in pediatric patients by multiple administrations of the study drug. In contrast, the serum infliximab concentrations at Week 14 in individual CAI score-based non-responders (2 patients) were respectively 0.26 μg/mL and 1.74 μg/mL which were lower than the median serum infliximab concentration at Week 14 in CAI-score-based responders. The proportions of patients having a serum infliximab concentration below the limit of quantitation (0.1μg/mL) at each time point are shown in Table 11.4-31. After study drug administration, only 5.6% (1/18), 6.7% (1/15), 7.1% (1/14) and 28.6% (4/14) of the CAI score-based responders had a serum infliximab concentration respectively below the limit of quantitation before administration at Week 14, before administration at Week 22, at Week 26 and Week 30, and a serum infliximab concentration not less than the limit of quantitation was maintained in most of the patients. In addition, no CAI score-based non-responders had a serum infliximab concentration below the limit of quantitation after the study drug administration. Week

Relationship between Serum Infliximab Concentration and Efficacy Endpoints
The serum infliximab concentrations at Week 8 in patients who achieved/failed to achieve CAI score-based remission are shown in Table 11.4-32. The median serum infliximab concentrations in patients who achieved CAI score-based remission and patients who failed to achieve CAI score-based remission in the overall population were respectively 24.42 μg/mL and 26.87 μg/mL. In addition, the serum infliximab concentrations at Week 30 in patients who achieved/failed to achieve CAI score-based remission are shown in Table 11.4-33. The median serum infliximab concentrations in patients who achieved CAI score-based remission and patients who failed to achieve CAI score-based remission were respectively 1.20 μg/mL and 1.48 μg/mL. These results showed that there were no significant differences in the median serum infliximab concentrations between patients who achieved CAI score-based remission and those who failed to achieve CAI score-based remission, and since only a small number of patients were included in this study, a clear relationship could not be obtained between the efficacy of the study drug and a serum infliximab concentration.  The CAI score changes by the serum infliximab concentration (μg/mL) at Weeks 8 and 30 are shown respectively in Table 11.4-34 and Table 11.4-35. In the evaluation of the median CAI score change at Week 8, the relationship between a serum infliximab concentration and CAI score change was not clear since all patients had a serum infliximab concentration of not less than 10 μg/mL. The median CAI score changes at Week 30 in patients having a serum infliximab concentration of less than 0.1 μg/mL, not less than 0.1 μg/mL and less than 1 μg/mL, not less than 1 μg/mL and less than 10 μg/mL, and not less than 10 μg/mL were respectively -4.5, NC (unable to be calculated), 6.0 and NC. The CAI score changes in individual patients included in the groups exhibiting NC were -4 and -3 for patients with a serum infliximab concentration of not less than 0.1 μg/mL and less than 1 μg/mL, and -10 for those with a serum concentration of not less than 10 μg/mL. Based on these results, though some subgroups by serum infliximab concentration included few patients, the tendency was observed for patients having a higher serum infliximab concentration to show a larger CAI score change.

Drug-Drug and Drug-Disease Interactions
Drug-drug and drug-disease interactions were not investigated in this study.

By-Patient Display
Data for individual patients in this study are provided in Appendix 16.2.4

Efficacy Conclusions
(1) The CAI score (Mean ± SD) was 9.7 ± 2.7 at the time of registration, but decreased over time to 4.0 ± 3.2, 3.5 ± 3.5 and 3.2 ± 3.5 respectively at Weeks 2, 6 and 8. The CAI score ranged from 2.5 ± 2.3 to 3.5 ± 2.2 during the period from Week 10 to Week 30, and that at the last time point was 5.6 ± 3.8. The CAI score changes (Mean ± SD) were -5.5 ± 2.7, -6.0 ± 4.0 and -6.2 ± 3.7 respectively at Weeks 2, 6 and 8, indicating an increase in the degree of score change with time, and ranged from -5.9 ± 3.8 to -6.9 ± 3.8 during the period from Week 10 to Week 30, and that at the last time point was -4.1 ± 4.2. In terms of both CAI score and CAI score change, the effect of the study drug in improving symptoms was observed from Week 2, and the effect lasted up to Week 30. Data on both CAI score and CAI score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(2) The CAI score-based remission rate was 60.0% (12/20) at Week 2, and increased to 80.0% (16/20) at both Weeks 6 and 8, and ranged from 64.3% to 87.5% during the period from Week 10 to Week 30. The CAI score-based remission rate at the last time point was 42.9% (9/21). In terms of CAI score-based remission rate, the study drug was observed to have the effect of bringing the clinical condition of patients to remission from Week 2, and this effect was observed up to Week 30. Data obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(3) The partial Mayo score (Mean ± SD) was 5.6 ± 1.6 at the time of registration and decreased over time to 2.6 ± 2.3, 2.2 ± 2.0 and 1.7 ± 1.7 respectively at Weeks 2, 6 and 8, and ranged from 1.8 ± 1.7 to 2.8 ± 1.9 during the period from Week 10 to Week 30. The partial Mayo score at the last time point was 3.7 ± 2.2. The partial Mayo changes (Mean ± SD) at Weeks 2, 6 and 8 were respectively -2.9 ± 2.2, -3.3 ± 2.2 and -3.8 ± 1.7, indicating an increase in the degree of score change with time. The partial Mayo changes ranged from -2.6 ± 2.8 to -3.6 ± 2.5 during the period from Week 10 to Week 30, and the change at the last time point was -1.9 ± 2.7. In terms of partial Mayo score and partial Mayo score change, the effect of the study drug in improving symptoms was observed from Week 2, and the effect lasted up to Week 30. Data on partial Mayo score and partial Mayo score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(4) The Mayo score (Mean ± SD) was 7.0 ± 2.4 at the time of registration, but decreased to 4.9 ± 2.4 at Week 30. The Mayo score at the last time point was 5.0 ± 2.3.The Mayo score changes (Mean ± SD) at Week 30 and the last time point were respectively -2.6 ± 3.9 and -2.0 ± 3.9. Data on both the Mayo score and Mayo score change obtained by TF imputation showed a similar tendency to data obtained before TF imputation.
(5) The Mayo score-based response rate and Mayo score-based remission rate at Week 30 were respectively 42.9% (3/7) and 14.3% (1/7), and those at the last point were respectively 37.5% (3/8) and 12.5% (1/8). Both the Mayo score-based response rate and Mayo score-based remission rate calculated based on the data obtained by TF imputation were similar to those obtained before imputation. Week 30, and one of these patients also achieved CAI score-based remission. (12) The patients included in the efficacy analysis set were divided into two groups, one for those aged not less than 6 years and less than 12 years, and the other for those aged not less than 12 years and not more than 17 years, and the efficacy of the study drug was evaluated for each group. As a result, both of the two groups included a different number of patients, but the efficacy of the study drug between the two groups was not considered significantly different.
(13) The median trough serum infliximab concentrations in CAI score-based responders were respectively 2.58, 1.54 and 1.34 μg/mL at Weeks 14, 22 and 30 indicating maintenance of the serum infliximab concentration.
(14) The median CAI score changes at Week 30 in each of the 4 groups by serum infliximab concentration, i.e. less than 0.1 μg/mL, not less than 0.1 and less than 1 μg/mL, not less than 1 and less than 10 μg/mL, and not less than 10 μg/mL, were respectively -4.5, NC (impossible to calculate), -6.0, and NC. The CAI score changes in individual patients included in the group which exhibited NC were -4 and -3 in the group of not less than 0.1 and less than 1 μg/mL, and -10 in the group of not less than 10 μg/mL. Based on these results, though some of the serum infliximab concentration groups included a small number of patients, a higher serum infliximab concentration was observed to show a trend toward better efficacy.

Extent of Exposure
The safety analysis set included 21 patients who were given the study drug at least once and for whom safety data after the start of study drug administration were obtained.
Distribution of duration of the safety evaluation period is shown in Table 12.1-1. The mean duration of the safety evaluation period was 176.7 days, with the minimum of 61 days and the maximum of 239 days. The frequency distribution of the total number of doses is shown in Table 12.1-2. The mean number of doses was 4.3 times, and the minimum number of dose was one time in one patient. Most of the patients were given the study drug 5 times, which is the maximum number of doses.

Brief Summary of Adverse Events
The incidence rates of AEs in the safety analysis population is presented in Table 12.2-1.
The incidence rates of AEs and ADRs were respectively 95.2% (20/21) and 71.4% (15/21). The incidence rates of serious AEs and serious ADRs were respectively 14.3% (3/21) and 4.8% (1/21). The incidence rate of AEs leading to discontinuation of the study was 4.8% (1/21), but no ADRs leading to discontinuation were observed. The incidence rates of infections and infections (ADRs) were respectively 61.9% (13/21) and 23.8% (5/21). Among infections, the incidence rates of serious infections and serious infections (ADRs) were both 4.8% (1/21). No infections leading to discontinuation of treatment were observed. The incidence rates of infusion reactions and infusion reactions (ADRs) were both 9.5% (2/21). No serious infusion reactions and infusion reactions leading to discontinuation of treatment were observed.

Display of Adverse Events
Names of AEs were presented using the lowest level terms (LLT) in accordance with the ICH Medical Dictionary for Regulatory Activities Terminology/Japanese edition (MedDRA/J ver. 17.1). AEs were tabulated using preferred terms (PT) and classified according to the system organ class (SOC).
The lists of AEs and ADRs are shown respectively in Table 12    The AEs and ADRs observed during the evaluation period are respectively listed in Table and Table  12.2-3. The SOCs of AEs which occurred in at least 20% of the patients included "infections and infestations" and "investigations" both having an incidence rate of 57.1% (12/21), and "gastrointestinal disorders" having an incidence rate of 52.4% (11/21). The AEs which occurred in at least 5% of the patients included "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21), "nasopharyngitis" having an incidence rate of 33.3% (7/21), "upper respiratory tract infection," "enteritis infectious," "iron deficiency anaemia," "colitis ulcerative" (recorded as "worsened ulcerative colitis" by the investigator), "nausea," "vomiting" and "acne" each having an incidence rate of 9.5% (2/21).
The SOCs of ADRs which occurred in at least 20% of the patients included "investigations" having an incidence rate of 57.1% (12/21). The ADRs which occurred in at least 5% of the patients included "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21) and "nasopharyngitis" having an incidence rate of 9.5% (2/21). Among both AEs and ADRs observed, "double stranded DNA antibody positive" and "nasopharyngitis" had a high incidence rates.

AEs and ADRs by Severity (Other Than Immunoserological Tests)
The AEs and ADRs (other than immunoserological tests) are listed respectively by severity in Table  14.3-1 and Table 14.3-2.
Severity of AEs was judged by the investigator (subinvestigator). AEs were classified as mild (no interference with patient's activities of daily living), moderate (some interfere with patient's activities of daily living due to the event) and severe (the patient cannot perform daily living activities due to the event) in terms of the effect of the relevant event on daily life of patients.
The incidence rates of AEs by severity were 61.9% (13/21) for mild, 23.8% (5/21) for moderate, and 4.8% (1/21) for severe. The severe AE was "colitis ulcerative" which was judged to be a worsened primary disease, and a causal relationship of this event with the study drug was ruled out. The incidence rates of ADRs by severity was 23.8% (5/21) for mild and 19.0% (4/21) for moderate, and no severe ADRs were observed.

AEs and ADRs by Evaluation Time Point
The incidence rate of AEs (SOC is other than investigations) and ADRs (SOC is other than investigations) are shown in Table 12.2-4 by evaluation time point.
The incidence rates of AEs and ADRs which occurred during the period "from the start of study drug administration (Week 0) until before administration at Week 14" was respectively 76.2% (16/21) and 28.6% (6/21), and among these, the incidence rates of infections and infections (ADRs) was respectively 42.9% (9/21) and 9.5% (2/21). The incidence rates of AEs and ADRs during the period "from the start of study drug administration (Week 0) until before administration at Week 14" was higher compared to those observed during the periods "from administration as Week 14 until before administration at Week 22" and "from administration at Week 22 until the evaluation day at Week 30," In contrast, the incidence rates of AEs and ADRs which occurred during the period "from administration at Week 22 until the evaluation day at Week 30" were respectively 35.7% and 0.0%, which were equivalent to or well below the incidence rates of AEs and ADRs which occurred during the period "from administration at Week 14 until before administration respectively at Week 22," 31.3% and 18.8%, indicating no increase in the incidence rates of AEs or ADRs associated with an increase in the number of doses. The incidence rates of infections and infections (ADRs) by evaluation time point showed a similar tendency to that observed for AEs and ADRs, and no increase in an incidence rate due to repeated dose was observed. No deaths occurred throughout the evaluation period.

Other Serious Adverse Events
As other serious adverse events, "colitis ulcerative," which was a worsened primary disease, and "enterocolitis" were observed respectively in 2 patients and one patient. A list of serious AEs by patient is shown in Appendix 16.2.7b.

Other Significant Adverse Events
In this study, infections leading to discontinuation of treatment and infusion reactions leading to discontinuation of treatment were defined as significant adverse events in the protocol. Infections are defined as adverse events which were judged as infections by the investigator (subinvestigator), and infusion reactions were defined as adverse events which occurred during administration of the study drug or within 2 hours after the end of administration. No significant adverse events occurred throughout the evaluation period.

Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse Events
No deaths occurred throughout the evaluation period. The narratives of other serious AEs are shown in Table 14.3-5.

Analysis and Discussion of Deaths, Other Serious Adverse Events and Other
Significant Adverse Events

Deaths
No deaths occurred throughout the evaluation period.

Other Serious Adverse Events
Serious AEs and serious ADRs are listed respectively in Table 12.3-1 and Table 12.3-2.
Throughout the evaluation period, serious AEs were observed in 14.3% (3/21) of patients. Detailed information about serious AEs is described below.
One patient who experienced "colitis ulcerative" was a male aged 13 years, and at the evaluation at Week 10, after receiving the study drug 3 times, abdominal pain, increased stool frequency and blood in stool were observed. On the next day of the evaluation, the relevant patient was admitted to the hospital and underwent endoscopy. Since the endoscopic findings showed a relapse of ulcerative colitis, this patient discontinued participation in the study. This discontinuation was judged due to an occurrence of an adverse event "colitis ulcerative" (described as "worsened ulcerative colitis" by the investigator). Subsequently, the symptoms were improved by receiving prednisolone treatment and cytapheresis and the patient was discharged from the hospital. The severity of this event was moderate. This event was the worsened primary disease, and a causal relationship of this event with the study drug was ruled out.
Another patient who experienced "colitis ulcerative" was a female aged 17 years, and judged as a CAI score-based non-responder at evaluation at Week 8. At the evaluation at Week 10 after receiving the study drug 3 times, increased stool frequency, mushy stools and pyrexia (38.0°C) were observed. Though the patient received an increased dose of prednisolone and cytapheresis, the symptoms were exacerbated. The patient was therefore admitted to the hospital to receive a combination of steroid pulse therapy and antibiotics 15 days after the evaluation at Week 10. However, since the symptoms were not improved even after the relevant therapy, the patient started to receive tacrolimus orally. As a result of colonoscopy, diffuse deep ulcer and pseudopolyposis were found, and persistent blood in stool, frequent diarrhea and increased nocturnal abdominal pain were observed. The relevant patient discontinued receiving all oral preparations, and after being transferred to another hospital, underwent surgery (subtotal removal of the large intestine and ileostomy). Subsequently, since the symptoms were improved, the patient was discharged from the hospital. The severity of this event was severe. This event was the worsened primary disease, and a causal relationship of this event with the study drug was ruled out.
The patient who experienced "enterocolitis" was a male aged 14 years, and a slight increase in CRP was observed in this patient in the evaluation at Week 18, after receiving the study drug 4 times. Subsequently, the patient had pyrexia (39.0°C), vomiting and increased stool frequency which resulted in awakening for defecation during sleeping. The patient was therefore admitted to the hospital 4 days after the evaluation at Week 18. Adenoviral enteritis was most suspected but results from test did not allow diagnosing the patient as having adenoviral infection. After admission to the hospital, the patient underwent only the intake of fluid replacement and water, achieved remission during the natural course of the disease without any drug therapy, and the patient was discharged from the hospital. The severity of this event was moderate. Since the relationship between the study drug and onset of the AE cannot be ruled out, the causal relationship of this event with the study drug was judged as "possibly related." The outcomes of all of these events were recovery.

Other Significant Adverse Events
In this study, infections leading to discontinuation of treatment and infusion reactions (adverse events which occurred during administration of the study drug or within 2 hours after the end of administration) leading to discontinuation of treatment were defined as significant adverse events in the protocol. In this section, in addition to these events, AEs leading to discontinuation of study, infections and infusion reactions are discussed.

AEs Leading to Discontinuation
A list of AEs leading to discontinuation of the study in the overall population is shown in Table 12.3-3. AEs leading to discontinuation of the study were identified based on judgment by the investigator (subinvestigator).
As an AE leading to discontinuation, "colitis ulcerative," which was a worsened primary disease, was observed in 4.8% (1/21) of patients. The detailed information about this event is described in Section 12.3.3.2.
Throughout the evaluation period, no ADRs leading to discontinuation were observed.

Infections
Infections and infections (ADRs) are respectively listed in Table 12.3-4 and Table 12.3-5. Infections were identified based on judgment by the investigator (subinvestigator).
The incidence rate of infections throughout the evaluation period was 61.9% (13/21). The SOC of infections which occurred in at least 20% of the patients was "infections and infestations," having an incidence rate of 57.1% (12/21). Infections which occurred in at least 5% of the patients included "nasopharyngitis" having an incidence rate of 33.3% (7/21), "upper respiratory tract infection" and "enteritis infectious" each having an incidence rate of 9.5% (2/21).
The SOC of infections (ADRs) which occurred most frequently was "infections and infestations" having an incidence rate of 19.0% (4/21). The infection (ADRs) which occurred in at least 5% of the patients was "nasopharyngitis" having an incidence rate of 9.5% (2/21).
The serious infections and serious infections (ADRs) are respectively listed in Table 14.3-3 and Table  14.3-4.
"Enterocolitis" was observed as both serious infections and a serious infection (ADR) in 4.8% (1/21) of patients. The detailed information about this event is described in Section 12.3.3.2.
Throughout the evaluation period, no infections leading to discontinuation of treatment were observed.

Infusion Reaction
Infusion reactions and infusion reactions (ADRs) are respectively listed in Table 12.3-6 and Table  12.3-7. Infusion reactions were defined as adverse events which occurred during administration of the study drug or within 2 hours after completion of administration.
The incidence rates of infusion reactions and infusion reactions (ADRs) were both 9.5% (2/21), and the incidence rates of "nausea" and "injection site pain" were both 4.8% (1/21). The severity of "nausea" and "injection site pain" was respectively judged as moderate and mild. Recovery from both of these events occurred during the day of onset. In addition, no serious infusion reactions and infusion reactions leading to discontinuation of treatment were observed.  The incidence rates of infusion reactions by the number of doses is shown in Table 12.3-8.
Infusion reactions were not observed after the first and second administrations, but occurred after the third administration and onward. The incidence rates of infusion reactions and infusion reactions (ADRs) was both 5.0% (1/20) after the third administration and were both 6.3% (1/16) after the fourth administration, and neither of these events occurred after the fifth administration.
Based on the above results, a tendency for the incidence rate of infusion reactions to increase along with repeated administration of the study drug was not observed.  The incidence rates of infusion reactions per dose are shown in Table 12.3-9.
The incidence rates of infusion reactions per dose and infusion reactions (ADRs) per dose were both 2.2% (2/91). The incidence rates of infusion reactions by results from ATI determination (negative, positive, inconclusive) are shown in Table 12.3-10.
Infusion reactions and infusion reactions (ADRs) were observed only in patients who were inconclusive for ATI determination, and the incidence rates for both ware 11.8% (2/17).

.1 Immunoserological Tests
A list of AEs (immunoserological tests) in the overall population is shown in Table 12.3-11. For anti-nuclear antibody, an event where an antibody titer was worsened by 3 ranks or more compared to the previous measurement value was treated as an adverse event. For double stranded DNA IgM antibody and double stranded DNA IgG antibody, an event where the determination result changed from negative to positive or from positive to positive (worsening) was treated as an adverse event. A determination result for double stranded DNA IgG antibody titer exceeding 12 IU/mL and that for double stranded DNA IgM antibody titer of not less than 6 U/mL were judged as positive.
The incidence rate of AEs (immunoserological tests) was 57.1% (12/21), and the incidence rates of "double stranded DNA (IgM) antibody positive" and "antinuclear antibody increased" were respectively 57.1% (12/21) and 4.8% (1/21). No patients experienced a change from negative to positive to double stranded DNA IgG antibody, which is said to be correlated with lupus-like syndrome. In addition, lupus-like syndrome was not observed in any patients including those experienced these AEs (immunoserological tests). Other than the above-mentioned event, malignant tumor (including hepatosplenic T-cell lymphoma which has been observed in children and young adults), tuberculosis, demyelinating disease, interstitial pneumonia, delayed type hypersensitivity (including serum sickness-like reaction), congestive heart failure, serious blood disorder and phabdomyolysis, which are the events to be noted when using TA-650, were not observed. Throughout the evaluation period, pregnancies among female pediatric patients or spouses (partners) of male pediatric patients were not reported.

List of Individual Laboratory Measurements by Patient and Each Abnormal Laboratory Value
Lists of laboratory values (general laboratory tests and immunoserological tests) by patient are provided in Appendix 16.2.8a to Appendix 16.2.8e.

Laboratory Values throughout the Study Period
The incidence rates of abnormal changes in laboratory values are shown in Table 14.3-6. In addition, summary statistics of hematology and blood biochemistry at each evaluation point are shown in Table  14.3-7, and frequency distribution of urinalysis (qualitative) results is shown in Table 14. 3-8. Since reference ranges for laboratory parameters in children vary depending on age and sex, the reference ranges for laboratory parameters were established by using reference values based on patient's sex and age (the age at informed consent obtainment is used) in reference to the "New Pocket Guide of Laboratory Test Reference Values for Children" 2) . For a differential count of WBC, for which no reference ranges are listed in this material, abnormal changes were not assessed. Since it was judged that the reference ranges for urinalysis (qualitative) in adults can also be used in children without any clinical problems, the reference values (for adults) provided from the contract laboratory were used to assess abnormal changes.
Summary statistics of each laboratory parameter at each evaluation point were not calculated by age or sex of patients, but were calculated using the measurement values from the overall population.
For general laboratory tests excluding urinalysis, abnormal changes defined below were assessed for each laboratory parameter.
-Laboratory value at Week 0 was within the reference range (including limits), and one or more values after treatment worsened beyond the reference range (not including limits) with a percent change from the laboratory value at Week 0 of at least 25%.
-Laboratory value at Week 0 deviated from the reference range, and one or more values after treatment worsened toward the same direction with a percent change from the laboratory value at Week 0 of at least 25%.
-Laboratory value at Week 0 deviated from the reference range, and one or more values after treatment worsened beyond the opposite limit of the reference range.
-Laboratory value at Week 0 was missing, and one or more values after treatment deviated from the reference range.
For urinalysis, abnormal changes defined below were assessed for each laboratory parameter.
-Laboratory value at Week 0 was within the reference range (including limits), and one or more values after treatment worsened beyond the reference range (not including limits) with a change of at least one rank.
-Laboratory value at Week 0 deviated from the reference range, and one or more values after treatment worsened toward the same direction with a change from laboratory value at Week 0 of at least one rank.
-Laboratory value at Week 0 deviated from the reference range, and one or more values after treatment worsened beyond the opposite limit of the reference range.
-Laboratory value at Week 0 was missing, and one or more values after treatment deviated from the reference range.
The laboratory parameters with an incidence rate of abnormal changes of at least 10% included urine protein (increased) and occult blood in urine (increased) each having an incidence rate of 47.6% (10/21), ALT (GPT) (increased) having an incidence rate of 33.3% (7/21), white blood cell count (decreased), ALP (decreased), γ-GTP (decreased), and BUN (decreased) each having an incidence rate of 14.3% (3/21). Among the 7 parameters, for 5 laboratory parameters other than urinalysis (urine protein and occult blood in urine), median measurement values obtained at the starting day of study drug administration (Week 0) and at evaluation points thereafter were compared. For ALT (GPT), the median measurement value was 10.0 U/L at Week 0, and ranged between 9.0 U/L and 12.0 U/L after Week 2. For white blood cell count, the median measurement value was 8600.0/μL at Week 0, and ranged between 5800.0/μL and 7300.0/μL after Week 2. For ALP, the median measurement value was 382.0 U/L at Week 0, and ranged between 394.5 U/L and 545.0 U/L after Week 2. For γ-GTP, the median measurement value was 13.0 U/L at Week 0, and ranged between 10.5 U/L and 15.5 U/L after Week 2. For BUN, the median measurement value was 9.0 mg/dL at Week 0, and ranged between11.0 mg/dL and 13.0 mg/dL after Week 2. All of the median measurement values for these 5 test parameters fell within the ranges between the minimum and the maximum of reference values for children aged from 10 to 17 years and the range of ages in which the patients participating in this study were included. In addition, no AEs related to hematology and blood biochemistry were observed.
For urinalysis (urine protein and occult blood in urine), no significant changes in distribution were observed, but as an adverse event related to urinalysis, "Protein urine present" was observed in 4.8% (1/21) of the patients. Since the relevant patient was in menstruation at the time of the laboratory test, the investigator (subinvestigator) judged that this event was caused by menstruation, and a causal relationship of this event with the study drug was ruled out.
As described above, no changes which may cause clinical problems were observed in the above mentioned 7 laboratory parameters having an incidence rate of abnormal change of at least 10%.

Individual Patient Changes
Lists of laboratory values by patient are provided in Appendix 16.2.8a to Appendix 16.2.8e, and Appendix 16.2.8g.

Individual Clinically Significant Abnormalities
Among the abnormal changes in the laboratory values of general laboratory tests, no serious events or events leading to discontinuation of the study were observed. Determination of physical examination (systolic and diastolic blood pressure, pulse rate, and body temperature) was performed immediately before the start of administration, every 30 minutes during administration, and every 30 minutes for 2 hours after the end of administration on each administration day. When there was at least a 15-minute interval between the end of administration and the latest measurement before the end of administration, measurement was also performed at the end of administration.

Vital
Time course of summary statistics of physical examination parameters are shown in Table 14.3-9. A list of measurement values of physical examination by patient is provided in Appendix 16.2.8f.
Mean measurement values for each physical examination parameter assessed for treatment with the study drug were as follows. Systolic blood pressure was between 99.6 to 111.3 mmHg, diastolic blood pressure was between 53.2 to 63.1 mmHg, pulse rate was between 75.6 to 88.3 beats/min, and the body temperature was between 36.45 to 37.06°C. Among all of the parameters, no significant changes were observed compared to the mean values measured before administration at Week 0.
Throughout the evaluation period, as events related to physical examinations, 'Blood pressure decreased' were observed in 4.8% (1/21) of patients. This event was judged before administration of the study drug on the examination day and a causal relationship of this event with the study drug was ruled out.

Immunoserological Tests
The distribution of determination results of immunoserological tests (anti-nuclear antibody, double stranded DNA IgG antibody and double stranded DNA IgM antibody) at each evaluation time point is shown in Table 12.5-1. A list of laboratory values of immunoserological tests by patient and a list of AEs related to immunoserological tests by patient are shown respectively in Appendix 16.2.8e and Appendix 16.2.7a.

Anti-Nuclear Antibody
The distribution of patients who tested negative/positive for anti-nuclear antibody at each evaluation time point by negative/positive result at the starting day of study drug administration (Week 0) is shown in Table 12.5-1.
Among 9 patients who tested negative at Week 0, 2 patients tested positive at either of the time points after administration.

Double stranded DNA Antibody
The distribution of patients who tested negative/positive for double stranded DNA antibodies (IgG antibody and IgM antibody) at each evaluation time point by negative/positive result at the starting day of study drug administration (Week 0) is shown in Table 12.5-1.
Among patients who tested negative for double stranded DNA IgG antibody at Week 0, no patients tested positive at either of the time points after administration. Among 20 patients who tested negative for double stranded DNA IgM antibody at Week 0, 11 patients tested positive at either of the time points after administration.

Safety Conclusions
Safety evaluation was performed on 21 patients who received the study drug at least once and from whom safety data after the start of administration of the study drug were obtained. Based on the evaluation, the following conclusions were obtained.
(1) The incidence rates of AEs and ADRs were respectively 95.2% (20/21) and 71.4% (15/21). The system organ classes (SOCs) of AEs having the highest incidence rate were "infections and infestations" and "investigations" each having an incidence rate of 57.1% (12/21), and "gastrointestinal disorders" with an incidence rate of 52.4% (11/21). The AEs with a high incidence rate were "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21) and "nasopharyngitis" having an incidence rate of 33.3% (7/21). The SOCs of ADRs having a high incidence rate was "investigations" having an incidence rate of 57.1% (12/21), and the ADR having a high incidence rate was "double stranded DNA antibody positive" having an incidence rate of 57.1% (12/21).
(2) The incidence rates of serious AEs and serious ADRs were respectively 14.3% (3/21) and 4.8% (1/21). The event "colitis ulcerative" (recorded as "worsened ulcerative colitis" by the investigator) occurred in 2 patients, but a causal relationship of this event with the study drug was ruled out. As a serious ADR, "enterocolitis" was observed. This event was moderate and recovery occurred without any treatment.
(3) The incidence rate of AEs leading to discontinuation of the study was 4.8% (1/21), and the event was "colitis ulcerative" (recorded as "worsened ulcerative colitis" by the investigator). No ADRs leading to discontinuation of the study were observed.
The events were moderate and mild, each observed in one patient, but recovery of both events was achieved on the same day they occurred. No serious infusion reactions and infusion reactions leading to discontinuation of treatment were observed.
(6) The incidence rate of immunoserological test-related AEs was 57.1% (12/21), and the incidence rates of "double stranded DNA (IgM) antibody positive" and "antinuclear antibody increased" were respectively 57.1% (12/21) and 4.8% (1/21). No patients were observed who experienced a change from negative to positive to double stranded DNA IgG antibody, which is said to be correlated with lupus-like syndrome. Furthermore, lupus-like syndrome did not occur in any patients.
(7) No events to be noted related to the study drug such as malignancy (including hepatosplenic T-cell lymphoma which has been reported in children and young adults), demyelinating disorders, interstitial pneumonia, liver dysfunction, delayed hypersensitivity (including serum sickness-like reaction), congestive cardiac failure, serious blood disorder and rhabdomyolysis, were observed.
(8) There were 7 laboratory parameters where the incidence rate of abnormal change in general laboratory values was not less than 10%, including urine protein (increase) and urinary occult blood (increase) each having an incidence rate of 47.6% (10/21), ALT (GPT) (decrease) having an incidence rate of 33.3% (7/21), white blood cell count (decrease), ALP (decrease), γ-GTP (decrease) and BUN (decrease) each having an incidence rate of 14.3% (3/21). No changes in laboratory parameters which would cause clinical problems were observed. (9) The changes in summary statistics of physical examinations (systolic and diastolic blood pressure, pulse rate, and body temperature) did not show any problematic tendencies. As an AE related to physical examinations, "Decreased blood pressure" occurred in 4.8% (1/21) of patients, but a causal relationship of this event with the study drug was ruled out.
Based on the results from the evaluation of safety of the study drug for 30 weeks when administered to pediatric patients with moderate to severe ulcerative colitis up to Week 22, it was confirmed that this study drug was mostly tolerable. In addition, similarly to the safety profiles for the approved indications including ulcerative colitis in adults, some events related to infections, infusion reactions, and immunoserological tests were observed. There was no significant increase in the frequency and severity of the events of concern related to the study drug administration, and no new events to be noted were observed.

Discussion and Overall Conclusions
Ulcerative colitis is a diffuse nonspecific inflammatory disease of unknown etiology primarily affecting the mucosa membrane of the large intestine where erosion and ulcers are often formed, and the number of patients with ulcerative colitis has been increasing. The number of pediatric patients with onset in childhood is smaller than that of adult patients but has continued to increase similarly to adult patients. Primary treatment of ulcerative colitis is drug therapy, but there exist numerous cases where patients are not adequately responding to treatment with existing drugs and are eventually referred for surgery. Furthermore, pediatric ulcerative colitis is characterized by a higher likelihood of extended and/or severer lesions compared to adults, and steroid-related complications such as failure to thrive and steroid dependence caused by long-term treatment with steroids, and these characteristics become a problem in steroid therapy. Against this background, TA-650 was approved for use in patients with ulcerative colitis in Japan in June 2010, and was ranked as a therapeutic drug for ulcerative colitis to be used in steroid-dependent or resistant patients. However, no domestic clinical trials of TA-650 in pediatric patients with ulcerative colitis have been conducted, and "children" is not clearly specified in the description of dosage and administration, therefore physicians may hesitate to use TA-650 in pediatric patients with ulcerative colitis, who require administration of this drug, and this becomes a problem. In foreign countries, a Phase III study (Study No. C0168T72) was conducted on patients aged 6 to 17 years. As a result of this study, the efficacy and safety of TA-650 was confirmed when administered at a dose of 5 mg/kg at Weeks 0, 2 and 6, followed by administration at 8-week intervals, and TA-650 has been approved in Europe and US. Therefore a domestic clinical study of TA-650 in pediatric patients with ulcerative colitis was conducted to evaluate the efficacy, safety and pharmacokinetics of TA-650 when administered at a dose of 5 mg/kg at Weeks 0, 2 and 6 followed by administration at 8-week intervals at Weeks 14 and 22.
In this study, 21 patients received the study drug. The CAI score started to decrease from Week 2, and decreased over time at Weeks 6 and 8, and the decreased CAI score continued to be observed after Week 10 and afterward. In addition, decreases in partial Mayo score and PUCAI score with time until Week 8 and decreased scores after Week 10 were observed. In terms of CAI score-based remission, at least a half of the patients were judged to achieve remission at Week 2, and it was confirmed that this high remission rate was maintained until Week 30. In terms of PUCAI score-based remission, though the PUCAI score-based remission rate was not as high as the CAI score-based remission rate, some patients were judged to achieve remission at Week 2, and it was confirmed that the remission was maintained until Week 30. In addition, since it has been reported that a decrease in PUCAI score by at least 20 points is clinically significant, the proportion of patients who achieved a decrease in PUCAI score by at least 20 points was also evaluated. As a result, at least a half of the patients achieved a decrease in PUCAI score by at least 20 points at Week 2, and it was confirmed that this effect was maintained until Week 30. Based on the above results, it was suggested that TA-650 had the effect of improving the symptoms or achieving remission, within an early period after administration of Week 2, and the effect was maintained by continuous treatment with the study drug.
Sigmoidoscopy is necessary to determine a Mayo score, but sigmoidoscopy is a highly invasive examination for patients, therefore this examination was only to be performed in this study where possible. Only 8 patients were able to be evaluated by the Mayo score, which was less than a half of the patients receiving the study drug, but a decrease in the Mayo score was observed at Week 30. In addition, some patients achieved Mayo score-based response and Mayo score-based remission. Furthermore, it was observed that 2 patients achieved mucosal healing at Week 30, suggesting that TA-650 had the effect of mucosal healing.
Use of steroids causes failure to thrive, a significant problem specific to children in addition to the ADRs which have been reported for adults. In the guideline for treatment of pediatric ulcerative colitis among the Guidelines for the Treatment of Ulcerative Colitis/Crohn's Disease (the version revised in 2014), it is described that steroids should not be used for the purpose of remission maintenance as steroids may cause failure to thrive, but the guideline also reports there are patients who failed to achieve steroid withdrawal due to exacerbation or relapse of symptoms associated with a reduction of steroid dose. In this study, 76.2% (16/21) of patients, more than a half, were judged as those who failed to achieve steroid withdrawal at the time of registration. In 12 patients who had been using steroids (oral preparations) at the time of registration, the steroid dose decrease began from Week 2, and continued to decrease over time at Weeks 6 and 8. The reduced steroid dose was also observed after Week 10. Two patients achieved steroid withdrawal at Week 30, and one of these patients achieved CAI score-based remission. Based on the above results, it was suggested that continuous treatment with TA-650 would enable reduction of steroid dose or steroid withdrawal.
The trough serum infliximab concentration in CAI score-based responders indicated maintenance of serum infliximab concentration, and the serum infliximab concentration 1 hour after completion of administration in CAI score-based responders was not largely different from the trough concentration, therefore multiple doses of TA-650 were not considered to cause accumulation of the drug. In addition, CAI score changes by serum infliximab concentration at Week 30 showed a tendency for the study drug to prove more effective the higher the serum infliximab concentration was, though some subgroups contained a small number of patients by serum infliximab concentration.
In terms of safety, the incidence rates of AEs and ADRs were respectively 95.2% (20/21) and 71.4% (15/21). The SOCs of AEs with a particularly high incidence rate were "infections and infestations" and "investigations." The only serious AE other than "colitis ulcerative," (a worsened primary disease) that was observed, was "enterocolitis." This event was judged as an infection, but it did not lead to discontinuation of the study because the relevant patient recovered without any treatment. In contrast, the AE leading to discontinuation was "colitis ulcerative" which occurred in 1 patient, and no ADRs leading to discontinuation were observed, and therefore TA-650 was considered mostly tolerable. In addition, no events to be noted related to the study drug, such as malignancy (including hepatosplenic T-cell lymphoma which has been reported in children and young adults), demyelinating disorders, interstitial pneumonia, liver dysfunction, delayed hypersensitivity (including serum sickness-like reaction), congestive cardiac failure, serious blood disorder and rhabdomyolysis, were observed. Based on the above results, no significant differences from the safety profiles reported for the approved indications including ulcerative colitis in adults were observed, and the frequency and severity of the events which were of concern when the study drug was administered were not increased significantly, and no new events to be noted were observed.
As described above, administration of TA-650 to pediatric patients with ulcerative colitis at a dose of 5 mg/kg at Weeks 0, 2 and 6 demonstrated the effect of improving symptoms of ulcerative colitis. Furthermore, continuous administration of the drug at 8-week intervals at Weeks 14 and 22 was shown to maintain the therapeutic effect of the study drug and also suggested there was a mucosal healing effect and that the study drug might lead to a reduction of steroid dose or steroid withdrawal. In terms of safety,

Demographic Data
Not applicable.

Efficacy Data
Not applicable.     This event was observed in a non-responder who completed study drug administration on September 28. This event is considered to be worsened ulcerative colitis, the primary disease, and it is judged that there was no causal relationship of this event with the study drug. During the maintenance therapy with Remicade ® , the patient's case was complicated by transient enteritis associated with pyrexia and increased CRP, and the enteritis was relieved without any change of antibiotics or therapeutic drugs for ulcerative colitis. Based on the clinical course, adenoviral enteritis was largely suspected, but it was impossible to diagnose the patient as having an adenoviral infection from the feces and pharynx examinations. After the onset on March 31, the peak in symptoms of enteritis was observed on April 3, and tendency to decreased stool frequency and reduced body temperature was observed when the patient visited the hospital on April 4. However, since the patient experienced awakening for defecation during sleep, the patient was admitted to the hospital to control the symptoms. After admission, the patient achieved remission during the natural course of the disease, and was discharged from the hospital on April 9. Considering the course of the disease, enteritis due to some infection was mostly suspected. The patient achieved remission without antibiotic therapy. This event was considered to possibly occur without administration of the study drug, but it cannot be ruled out that the onset of the event might be related to the study drug. However, since the remission of the event did not require a dose decrease or discontinuation of the study drug or an immunomodulator (azathioprine), there are considered no problems to continue to use of the study drug as the therapeutic drug for the primary disease. Visited the hospital as an outpatient. The patient was admitted to the hospital due to possible complication of enteritis. Intake of fluid replacement and water, and followed up. 04/06/2014 Negative for adenovirus (feces, pharynx). Negative for CD toxin. Negative in fecal culture test. 04/07/2014 Decreased CRP. Stool frequency was decreased to 12 times, and tendency for improvement of symptoms was observed. No blood in stools. 04/08/2014 Stool frequency was 8 times. No blood in stools. 04/09/2014 Due to improvement of general condition, the patient was discharged from the hospital. 04/14/2014 Stool frequency was 8 times. No blood in stools. The condition of the patient was stable, but number of stools was high. 04/28/2014 Stool frequency was 6 times. No blood in stools. Diarrhea but sometimes formed stools.

Displays of Adverse Events
Administration of the study drug at Week 22. 05/21/2014 Stool frequency was 3 to 4 times. No blood in stool and abdominal pain. Diarrhea. The general condition was stable, and the laboratory values were improved, therefore recovery from the AE was judged.
<Causal relationship with the study drug> Cannot be ruled out.
* Age at the time of onset of the serious AE.       Week 0 H

Other CRFs Submitted
Not applicable.