Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: A randomized, placebo-controlled trial

Objective Use of growth hormone is associated with side effects, including insulin resistance. The objective of this study was to determine whether tesamorelin, a stabilized growth hormone-releasing hormone analogue, would alter insulin sensitivity or control of diabetes. Design A 12-week randomized, placebo-controlled study of 53 patients with type 2 diabetes. Three treatment groups: placebo, 1 and 2 mg tesamorelin. Measurements Fasting glucose, glucose and insulin from oral glucose tolerance test, glycosylated hemoglobin (HbA1c), home blood glucose, insulin-like growth factor-1, and lipids. Main outcome measure Relative insulin response following oral ingestion of glucose. Results No significant differences were observed between groups in relative insulin response over the 12-week treatment period. At Week 12, fasting glucose, HbA1c and overall diabetes control were not significantly different between groups. In addition, relevant modifications in diabetes medications were similar between groups. Total cholesterol (-0.3±0.6 mmol/L) and non-HDL cholesterol (-0.3±0.5 mmol/L) significantly decreased from baseline to Week 12 in the tesamorelin 2 mg group (p<0.05 vs. placebo). No patient discontinued the study due to loss of diabetes control. Conclusions Treatment of type 2 diabetic patients with tesamorelin for 12 weeks did not alter insulin response or glycemic control. Trial registration ClinicalTrials.gov NCT01264497.


Introduction
The somatotropic axis regulates many essential physiologic functions. Although growth hormone (GH) was originally recognized for its primary role in effecting growth in stature, its importance in preserving anabolism and its involvement in tissue repair during adulthood have recently been more fully documented. The aging process, however, is associated with a blunting of basal and stimulated GH secretion 1-8 . This early and progressive decrease in spontaneous GH secretion is associated with a decrease in blood levels of insulin-like growth factor 1 (IGF-1), the principal effector and marker of GH anabolic actions [9][10][11] . Experimental attempts to restore complete functionality of the somatotropic axis in aged patients have included the administration of exogenous recombinant human growth hormone (rhGH) and analogues of growth hormone releasing factor (GRF). Administration of rhGH to these patients, however, has been associated with a variety of adverse effects including hyperglycemia, insulin resistance, fluid retention, carpal tunnel syndrome, and gynecomastia [12][13][14][15] . These adverse effects have been shown to be more frequent in patients with the highest IGF-1 levels 15 . Importantly, the IGF-1 negative feedback on GH secretion is inoperative during treatment with exogenous rhGH, and exogenous rhGH is unable to mimic the physiologic, pulsatile rate of endogenous GH secretion 16 . While GRF is able to preserve the physiologic pulsatile pattern of GH secretion, rapid hydrolysis of natural GRF by dipeptidyl-amino peptidase in serum limits its efficacy as a treatment modality. Administration of a GRF analogue has been associated with enhanced insulin sensitivity in males 17 , in contrast to the insulin resistance observed with the administration of rhGH.
TH9507, a GRF analogue being developed by Theratechnologies Inc., includes the natural 44 amino acid sequence of human GRF (hGRF), on which a hexenoyl moiety (a C6 chain with a double bond on position 3) has been anchored on Tyr 1 at the N-terminus part of the molecule. The presence of this hydrophobic side chain is believed to provide steric hindrance that prevents or delays the coupling of dipeptidyl-amino peptidase to TH9507, resulting in enhanced stability in serum. In fact, the plasma half-life of TH9507 was estimated to be 8 hours (in vitro) in comparison to hGRF, which was degraded in minutes 18 . In a Phase 1b study TH9507 increased IGF-1 levels in healthy older men to levels typically observed in young adults 19 . Since TH9507 has the natural sequence of GRF and is relatively resistant to degradation by peptidases in serum, it combines three key features for optimal efficacy and safety in aged patients: specificity on GH secretion; induction of GH secretion in a pulsatile, physiologic manner; and a powerful effect on IGF-1 secretion. These characteristics are expected to translate into clear clinical benefits in a number of targeted therapeutic indications.

Rationale
The clinical development program for TH9507 includes its use in patients who could benefit from enhancement of anabolic effects, including patients with COPD, hip fractures, and other age-related disorders associated with somatopause. As noted, different changes in insulin sensitivity have been observed with rhGH and GRF analogue administration. It is anticipated that a number of patients to be enrolled in future trials of TH9507 will have glucose intolerance and/or overt diabetes. Therefore, the purpose of this study is to investigate the safety of daily administration of TH9507 in patients with type 2 diabetes mellitus, in particular, the potential for effects on insulin sensitivity and diabetic control.

Study Objectives
The primary objective will be to evaluate the safety of two doses of TH9507 administered over 12 weeks by daily subcutaneous injections in patients with stable type 2 diabetes.

Overall Study Design
This is a randomized, double-blind, placebo-controlled, parallel group, multicenter study of two doses of TH9507 (1 mg and 2 mg) administered daily by subcutaneous injection for 12 weeks.
After screening and a 14-day lead-in period, subjects will be randomized by insulin use (see Section 4.1.6) to one of three treatment groups. Subjects will be evaluated after 1, 4, 8, and 12 weeks of treatment and at a follow-up visit at Week 16.
The study schematic is presented in Figure 3.1-1.

Discussion of Design
This study will incorporate a two-week lead-in period prior to randomization for the purpose of establishing and characterizing daily dietary patterns and daily blood glucose measurements prior to the randomization visit. Further, the lead-in period will provide patients with the opportunity to become accustomed to required study procedures such as the completion of a diary to monitor diet, exercise, blood glucose, and hypoglycemic episodes. The duration of 12 weeks of treatment is adequate to discern important changes in glycosylated hemoglobin (HbA 1c ).

Patient Population
A total of approximately 45 patients with stable type 2 diabetes on stable diabetes treatment regimen (receiving oral hypoglycemics with or without insulin) will be enrolled into the study. Fifteen (15) subjects will be randomized to each treatment group to ensure that approximately 13 subjects per group complete the study. After 33 patients have been randomized based on insulin use (insulin use or non-insulin use), enrollment may be halted for that group but continued in the other group.

Interruption or Discontinuation of Treatment
Before interrupting or discontinuing study drug, the investigator must contact the sponsor or designee (except in the case of an emergency) to discuss the proposed reason. It will be documented whether or not each subject completed the clinical study. If any subject's study treatment or observations were discontinued, the reason will be recorded. Reasons that a subject may discontinue participation in this clinical study may be one or more of the following: Each vial will be reconstituted with 1.1 mL of sterile water for injection (provided by the sponsor). One mL of each preparation is then taken out of each vial using a 3-mL syringe. The total volume will be 2 mL. The preparation is then injected subcutaneously.
The lyophilized vials will be kept at -20C at the investigational sites. The supplies of study drug dispensed to the subjects will be kept refrigerated between 2ºC and 8ºC at the subject's home for daily reconstitution and use.
Subjects will self-inject 2 mL of study drug subcutaneously (using 1 mL each from vial A and vial B) at rotating sites every morning at 9:00AM ± 3 hour, (i.e., between 6AM and noon). The subject may elect to have a family member or a health professional administer the study drug.
The study drug may be administered in either one or two subcutaneous injections at each dosing time at one or two sites. The study drug will be administered at the General Clinical Research Centers (GCRCs) at Visits 3, 4, 5, and 6.
Medication labels will comply with the regulatory requirements.

Treatment Assignment
Patients will be assigned to treatment groups in a randomized fashion. Drugs will be numbered in such a way that patients at each investigational site will receive the treatment sequentially as they qualified to be randomized at Visit 3. The patient randomization number will be the lowest available treatment number.

Blinding
There will be three sets of sealed envelopes containing the randomization codes that will be generated by an external consultant. One set will be provided to the packaging supplier, another will be provided to the investigator, and another will be kept at PharmaResearch Corporation.

9
The randomized code will be broken ONLY in case of an emergency. If possible, the investigator must contact the Sponsor or designee before unblinding the code to discuss the event leading to potential unblinding such as a possibly drug-related serious adverse event.
Randomization data are kept strictly confidential, accessible only to authorized persons, until the time of unblinding. At the conclusion of the trial, the occurrence of any emergency code breaks will be verified after return of all code break reports and unused drug supplies to Theratechnologies. Only when the study has been completed, the data file verified, and the protocol violations determined, will the drug codes be broken and made available for data analysis.
[For details of the emergency procedure for unblinding of individual patients in cases of emergency see section 6.2.]

Concomitant Therapy
Oral or parenteral glucocorticoids will not be permitted during the study. Hormone replacement therapy for female subjects will be allowed. All other concomitant drugs should be maintained at constant dose during the study, if possible. Concomitant drugs will be recorded in the Case Report Forms.
Dose adjustments for insulin and/or oral hypoglycemics during the conduct of the trial will be at the discretion of the investigators.

Treatment Compliance
Compliance will be checked by counting the number of empty vials returned at each visit.

Visit Schedule and Assessments
The schedule of assessments is presented in Appendix 1.

Visit Schedule
Visits 1 and 2 are conducted prior to the baseline/randomization Visit 3, which is designated as Week 0.
-Review inclusion and exclusion criteria.
-Obtain medical history.
-Obtain body weight.
-Calculate body mass index.
-Perform funduscopy with dilation by optometrist or ophthalmologist (may be performed during the lead-in period) and examine for evidence of diabetic retinopathy (microaneurysms will not exclude the patient from participating in the study). -Obtain blood for clinical laboratory screening tests (hematology, blood chemistry, lipid profile, and urinalysis-subjects with minimal proteinuria [<2+] may continue with screening). -Obtain blood for glycosylated hemoglobin (HbA 1c ) and insulin antibodies.
-Schedule mammography (for females) and prostate examination/PSA (for males) if not done within six months of screening. -Collect 24-hour urine for albumin (may be performed during the lead-in period).
-Review inclusion and exclusion criteria.
-Obtain body weight.
-Dispense diary (to monitor home blood glucose measurement, hypoglycemic episodes, study drug administration, adjustments in oral hypoglycemic agents and/or insulin dosage, diet, and exercise) and provide instructions regarding completion of the diary.
-Dispense home glucose meter with instructions.
-Dispense boxes of strips and lancets.
-Instruct the subject to withhold oral sulfonylurea, insulin, and other insulin secretagogues but he/she may take oral non-sulfonylurea hypoglycemic medication (if oral insulin sensitizer) in the morning of Visit 3. -Instruct the subject to collect urine the day before the scheduled visit (starting at 6AM) until the morning (6AM) of the clinic visit.
-Obtain body weight.
-Review/dispense diary. Subjects should be at least 90% compliant with the diary and diet in order to continue participation in the study. -Replenish boxes of strips and lancets, if necessary -Download home glucose readings from 14-day lead-in period.
-Instruct the subjects to call the clinic for any home blood glucose value that is 250 mg/dL. -Dietician interview and assessmentcaloric intake assessment, skin thickness (Harpenden), waist/hip measurements, and body fat mass (Lange). -Collect 24-hour urine for creatinine and nitrogen.
-Obtain blood for insulin and glucose levels every 30 minutes during OGTT.
-Assign randomized study treatment to subject.
-Administer first dose of blinded study drug in clinic at approximately noon.  -Obtain blood for laboratory tests (hematology; blood chemistry; lipid profile) -Collect urine for urinalysis.
-Download home glucose readings for the period since Visit 7.

Safety Assessments
This is a study to assess the safety of 12 weeks of daily administration of TH9507. Safety assessments will include the monitoring and recording of all adverse events and any serious adverse events; the sequential assessment of hematology, blood chemistry, and urinalysis parameters; the monthly monitoring of HbA 1c , periodic assessments of lipid profiles, including HDL, LDL, total cholesterol, and triglycerides; monitoring for antibodies to TH9507 before and after 12 weeks of treatment; and periodic measurements of blood pressure, as well as performance of physical examinations including screening testing for diabetic sensory neuropathy. This study will seek to assess any clinically meaningful changes in insulin sensitivity through use of sequential periodic oral glucose tolerance tests with paired insulin and glucose levels to determine insulin:glucose ratios.

Adverse Events
Information regarding adverse events will be collected and recorded on the Adverse Events case report form. An adverse event is any undesirable sign symptom or medical condition occurring after the subject is enrolled in the study, whether considered drug-related or not. Medical conditions/diseases present before starting study drug are only considered adverse events if they worsened after starting study drug. Study drug includes any drug(s) under evaluation in the study, including reference drug(s), placebo, or any other drug required by the protocol.
Adverse events, whether volunteered by the subject, discovered during general questioning by the investigator, or detected through physical examination, laboratory tests or other means will be recorded on the Adverse Event case report form and followed carefully until they resolve.
Abnormal laboratory values or test results should not generally be considered adverse events, unless they induce clinical signs or symptoms or require therapeutic intervention, when they should be recorded on the Adverse Events case report form using an appropriate diagnostic description.
As far as possible, each adverse event will also be described by: -its duration (start and end dates), -the severity grade (mild, moderate, severe), -its relationship to the study drug (suspected / not suspected), -the action(s) taken Examples of the severity grade, relationship to study drug and actions taken, as presented in the case report form are provided in section 6.3: Instruction for completing Adverse Event case report forms.

Serious adverse events
Information regarding serious adverse events will be collected and recorded on the Serious Adverse Event (SAE) Report Form. A serious adverse event is defined as any untoward medical occurrence that occurs at any dose and: -results in death, -is life-threatening, -requires inpatient hospitalization or prolongation of existing hospitalization, -results in persistent or significant disability / incapacity, or -is a congenital anomaly/birth defect in the offspring of a subject who received study drug.
Important medical events that may not be immediately life-threatening or result in death or hospitalization may be considered an SAE when, based upon appropriate medical judgement, they may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in the definition above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
Any serious adverse event occurring after a subject has signed the informed consent form and until four (4) weeks after the stopping study drug must be reported by the investigator to Theratechnologies or designee within 24 hours of learning of its occurrence, even if not seeming to be drug-related. Follow-up information about a previously reported serious adverse event must also be reported to Theratechnologies or designee within 24 hours of receiving it. The investigator should send the completed Serious Adverse Event Report Form by fax to the local representative responsible (see Section 6.1: Instructions for rapid notification of serious adverse events).

Laboratory Evaluations
Approved laboratories will be used for all assays of TH9507 antibody, IGF-1, IGFBP-1, IGFBP-3, glucose, insulin, insulin antibody, hematology analytes, blood chemistry analytes, and urinalysis. Names, addresses and information concerning sample collections and shipment will be provided separately.

24-Hour Quantitative Urine Tests
Albumin, creatinine, nitrogen, and total urine volume

Special Tests
HbA 1c , insulin and TH9507 antibodies

Oral Glucose Tolerance Test (OGTT) with paired glucose and insulin levels
Blood glucose and insulin will be measured at 0 minutes (prior to ingestion of glucose), 30 minutes, 1, 1.5, 2, 2.5, and 3 hours. For these determinations, oral sulfonylureas, insulin, and other insulin secretagogues must be withheld on the morning of the OGTT. Insulin sensitizers need not be withheld at such times.

Home Blood Glucose
Home blood glucose will be obtained 4 times per day (before breakfast, lunch, and dinner, and at bedtime) using a standard blood glucose meter. The glucose values will be downloaded into a computerized recall system. Subjects will be instructed to record the glucose values in their diaries and to call the clinic for any glucose value that is 250 mg/dL.. Subjects will be instructed to maintain a consistent meal schedule throughout the study.

Vital Signs
Respiration rate, pulse rate and sitting blood pressure after 5 minutes of rest.

Physical examination
Information about the physical examination must be present in the source documentation at the study site. Significant findings that are present prior to the start of the study drug must be included in the Relevant Medical History case report from or Current Medical Conditions case report form. Significant findings made after the start of the study drug which meet the definition of an AE must be recorded in the Adverse Event case report form.
The examination of the following will be performed: eyes, ears, nose and throat; heart; peripheral vasculature; lungs; muskuloskeletal system, abdomen, neurologic function (with testing for diabetic sensory neuropathy), endocrine system, skin and lymph nodes.

Body Fat Mass
Body fat mass will be estimated from measurements with Lange skin-fold calipers at biceps, triceps, subscapular, and iliac crest sites.

Skin Thickness
Skin thickness will be measured at four sites ( the right and left hand and the right and left volar forearm) using Harpenden calipers.

Body Weight
Subjects will be weighed clothed without shoes.

3.5.2.9
Waist/Hip Measurements Waist will be measured at the smallest abdominal circumference while hips will be measured at the largest gluteal circumference using a tape measure.

Drug Concentration and Pharmacokinetic Evaluations
Not applicable.

Study Objectives
This is a Phase II, placebo-controlled, comparative study. The primary objective is to evaluate the safety of two doses (1 mg and 2 mg by daily subcutaneous injection) of TH9507 relative to placebo administration, over a 12-week period in patients with stable, type 2 diabetes.
The primary endpoint is the change in relative insulin response following the oral ingestion of glucose over the 12-week treatment period. The relative insulin response is defined as the ratio of the incremental plasma insulin response above basal at 30 minutes to that of plasma glucose, divided by basal plasma insulin levels 21 .
The secondary objectives are to evaluate the effects of 12 weeks of daily treatment with TH9507 on HbA 1c , blood glucose measurements, use of oral hypoglycemic agents and/or insulin and control of diabetes.
The secondary endpoints include the change in HbA 1c at Week 12 compared to baseline and changes in mean daily serum glucose concentrations compared to the 14 day lead-in period values, changes in the number of dose adjustments per week for insulin and/or oral hypoglycemic agents compared to the 14 day lead-in period, and the number of subjects with a change in the control of diabetes.

Study Population
The sample in this study is to be drawn from a target population of stable, type 2 diabetic patients. Satisfying the inclusion and exclusion criteria, these patients will constitute a recognizable and identifiable group as they will specifically  Have a documented diagnosis of type 2 diabetes mellitus according to the American Diabetes Association,  Demonstrate stable type 2 diabetes mellitus for at least 3 months prior to study entry,  On stable diabetes treatment regimen (oral hypoglycemics with or without insulin) for at least 2 months prior to screening,  Have screening HbA 1c 10.0%,  Have a Body Mass Index between 25 and 38 add kg/m 2 , and  Will not have used oral or parenteral glucocorticoids for at least 30 days prior to screening.

Statistical Model/Design
The study design is that of a multicenter, double-blind, placebo-controlled, parallel group evaluation of the effects of two doses of TH9507 over 12 weeks. Serial determinations will be assessed using a repeated measures parallel group design.

Null and Alternative Hypotheses
The null hypothesis is that each active dose does not result in a change in the relative insulin response over the 12-week treatment period. The alternative hypothesis is that at least one of the two doses of TH9507 or placebo produces a change in the primary endpoint over the 12-week treatment period. Thus the primary analysis is two-sided since the direction of the putative difference is not specified.
Assessment of these hypotheses may be conducted by comparing the changes from baseline at Week 12 across the three treatment groups (including placebo) using a repeated measures ANOVA model including a treatment effect and a random time effect and adjusting for possible effects of investigational site and insulin use. Due to the size of this study relative to the number of factors under consideration, F-tests for main effects (treatment, insulin use, center, time) will be constructed ignoring possible interactions. Comparisons of active treatment group relative to placebo may be performed using a two-sided alternative.
In a secondary analysis, paired t-tests will be used to compare the baseline (Week 0) and Week 12 values of HbA 1c for each treatment group. Additionally, a repeated measure analysis, including terms for the fixed effects, treatment, insulin use, and center, and the random effect:time, may be implemented to assess change from baseline in HbA 1c over the 12-week treatment period.

Sample Size Estimation
Available trial data from each subject who received at least one dose of study medication will be used in the primary safety analysis. Using PASS2000 (NCSS Software), a total of 45 subjects (15 per group) will be enrolled into the study to ensure that approximately 39 subjects (13 per group) complete the study under the following sample size assumptions: -A parallel group design is employed, with equal randomization between the groups.
-The primary endpoint is relative insulin response over time.
-The comparison is made using a Type I error rate of 0.05.
-The comparison is assessed using a Type II error rate of, at most, 0.2 which provides a minimum power to detect the specified difference 80%. -An F-test from a repeated measures ANOVA model including a fixed treatment effect and a random effect for time is used to test the null hypothesis of no treatment difference. -The baseline value for the placebo group is 0.23. A 15% difference is expected in each of the treatment groups. A constant standard deviation of 0.20 is expected 21 . -The relative insulin response is calculated at baseline, week 1, week 4, week 8, and week 12. Similar calculations suggest that a sample size of 13 subjects per group will be sufficient to detect a 5% change from baseline in HbA 1c for each treatment group (including placebo) at week 12 under the following sample size assumptions: -Each comparison is made using a Type I error rate of 0.05.
-Each comparison is assessed using a Type II error rate of, at most, 0.2 which provides a minimum power to detect the specified difference 80%. -An effect size of 1 is expected. -A paired t-test is used to test the null hypothesis of no treatment difference.

4.1.6
Randomization Within each center, the investigator or his/her designate will determine whether the patient has met all inclusion/exclusion criteria and is eligible for entry into the study. Patients meeting all inclusion/exclusion criteria and providing written informed consent will be randomized at Visit 3, after completion of the lead-in period, which begins at Visit 2.
To maintain balance of treatment assignments among insulin use groups (insulin use, no insulin use), eligible patients will be randomly allocated in balanced blocks to either the TH9507 1 mg, TH9507 2 mg, or placebo treatment groups according to computer generated randomization codes for each insulin use group maintained by an external randomization center. To ensure that at least 3 subjects either in the insulin use or non-insulin use group complete the study for each treatment arm, enrollment for the larger group may be halted after 33 patients have been randomized for that group. Enrollment would continue for the smaller group until approximately a total of 12 subjects have been randomized for that group.
Study drug supplies will be assigned sequentially by the investigator, or his/her designate, within each center, using the subject randomization number assigned by the randomization center. Subjects may not be randomized into the study more than once, and once a subject randomization number has been assigned, it may not be reused.
Assignment of the randomization number to a subject defines enrollment into the study.

4.1.7
Blinding The study is designed to be double-blind. Active drug and placebo will be provided as lyophilized powder in vials of identical appearance and supplied in blister cards covering a one month period at each monthly visit. Each dosage regimen is supplied as two vials according to the following 'double-dummy' specification: -1 mg TH9507 as one vial of 1.1 mg active drug and one vial of placebo -2 mg TH9507 as two vials of 1.1 mg of active drug -placebo as two vials of placebo The randomization code for each subject is supplied to the participating center in sealed envelopes that will only be opened in case of emergency. The study blind will be broken and treatment assignment will be made available for data analysis after the database has been locked and protocol violations have been determined.

Data Transformations
It is intended that the analysis of the primary endpoint will be based on relative insulin response. However, appropriate transformations will be performed as required to satisfy assumptions required to perform statistical analyses. Descriptive statistics will be provided for these transformed variables. The safety population is defined as all subjects who were randomized and received at least one dose of study medication (1 mg TH9507, 2 mg TH9507, or placebo) during the course of the trial. This is the primary population for analysis.
The change from baseline values for biochemical laboratory parameters (secondary endpoints) will be analyzed using analysis of variance techniques (ANOVA) which focus on the between (different regimens) and within (same regimen) comparisons of these measurements over time, with center and insulin use group included as fixed effects. Analyses may be conducted as repeated measures analyses or individual analyses of specific study visits.
Glucose values will be obtained at home four times per day using a standardized glucose meter. Subjects will record glucose values in their diary. Glucose values, downloaded electronically from the glucose meters, will be used for statistical analysis.
The assessment of safety will be based mainly on the frequency of adverse events and on the number of laboratory values that fall outside of predetermined ranges. Other safety data (e.g. vital signs, special tests) will be considered as appropriate.
Adverse events will be summarized by presenting, for each treatment group, the number and percentage of subjects having any adverse event, having an adverse event in each body system and having each individual adverse event. Any other information collected (e.g. severity or relatedness to study medication) will be used to categorize the adverse event data as appropriate.
Laboratory data will be summarized by presenting shift tables using extended normal ranges (baseline to most extreme post-baseline value) by presenting summary statistics of raw data and change from baseline values (means, medians, standard deviations, ranges) and by flagging of notable values in data listings.

Interim Analyses
No formal interim efficacy analyses are planned.

Dropouts, Protocol Deviations and Exclusions
Subjects may end their participation in the study at any time for any reason(s). These subjects will be encouraged to provide a termination assessment at this time.
Patients screened for enrollment into the study but found to be ineligible will be excluded from entry. A log of exclusions, along with the reasons for exclusion, will be maintained. Ideally, this information will consist of the inclusion/exclusion case record form criteria for each excluded subject. The extent of the information collected will depend on the ethical guidelines within each center. This information can then be used to characterize the population being screened but excluded from the trial. Should enrollment problems be encountered during the trial, this information may indicate the primary reason(s).