HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment

This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis. Trial Registration: ClinicalTrials.gov NCT01830127.

Chronic infection with hepatitis C virus (HCV) represents a major public health problem worldwide. The World Health Organization (WHO) estimates that approximately 3% of the world population are infected. Approximately one third of those infected will develop cirrhosis in less than 20 years, and as many as 7% may develop hepatocellular carcinoma (P00-15027).
Different HCV genotypes prevail in different geographic regions, with genotype 1 (GT1) being the predominant genotype (70%) in United States, Asia, and Europe. Sub-GT1a is more prevalent in North and South America and common in Australia, while sub-GT1b is more prevalent in Europe and Asia.
Currently, two direct acting antiviral agents (DAAs) (HCV protease inhibitors, telaprevir and boceprevir) have been approved for HCV treatment in selected countries. Treatment with 12 weeks of telaprevir in combination with pegylated alfa interferon (PegIFN) and ribavirin (RBV) for either 24 or 48 weeks demonstrated sustained virologic response (SVR) rate of 74% or 79% at Week 24 (ILLUMINATE or ADVANCE studies, R12-0262). Boceprevir given for 24 or 44 weeks in combination with PegIFN/RBV achieved SVR rates of 63% to 66%, respectively (SPRINT-2 study, R12-0263). These combination therapies represent the new Standard of Care (SOC) for HCV patients with chronic GT1 infection with compensated liver disease (mild hepatic impairment or CPA). However, both these compounds are given three times daily (t.i.d.), are associated with substantial side effects, and are not approved regimens for patients with moderate hepatic impairment (CPB).
Despite the improved virologic response rates in patients with HCV GT1 infection following the recent approvals of new DAAs, the increasingly aging population with co-morbidities and contraindications to PegIFN, and the limiting side effects of this current SOC underscores the remaining urgent need for more effective, less toxic, shorter, more convenient and less invasive therapy for these patients. Effective antiviral therapy without PegIFN would constitute a major breakthrough in HCV treatment. PegIFN is contraindicated in CPB patients since it is poorly tolerated and associated with serious adverse events, high discontinuation rates and a faster liver progression in this population. Therefore, this patient population has a high unmet medical need and an interferon-free regimen may represent the only treatment option for patients with progressive liver cirrhosis or with HCV re-infection after liver transplantation.
BI is investigating the safety and efficacy of BI 207127, an oral, specific and reversible non-nucleoside HCV specific ribonucleic acid (RNA)-dependent RNA polymerase inhibitor, in combination with faldaprevir (FDV), a potent, oral HCV NS3/4a protease inhibitor, and RBV in patients with moderate hepatic impairment.

DRUG PROFILE
Detailed descriptions of drug substance, pharmacology, safety, pharmacology, toxicology and pharmacokinetics from preclinical and clinical studies are available in the current version of the Investigator's Brochures (IB) for BI 207127 (U06-1740) and FDV (U04-3332).

Faldaprevir (FDV)
FDV (also known as BI 201335) is a potent and specific HCV NS3/4A protease inhibitor. FDV is currently being evaluated in combination with PegIFN and RBV in Phase 3 of clinical development.
Clinical drug interaction studies of FDV with CYP3A4/5, CYP2C9 and P-gp have shown moderate inhibition of CYP3A4 and mild inhibition of CYP2C9. These drug interactions can be effectively managed. Specific recommendations for co-medications, including substrates of CYP3A4/5 or CYP2C9 which have a narrow therapeutic range, were developed with external clinical pharmacology experts and are provided in the Investigator Site File (ISF) (lists of restricted concomitant drugs and of drugs that need to be used with caution). For more information refer to the current IB version (U04-3332).

BI 207127
BI 207127 is a specific and reversible non-nucleoside inhibitor of HCV specific RNA-dependent RNA polymerase and is being developed in combination with FDV. Phase 2b evaluation of BI 207127 is ongoing in trial 1241.21 (SOUND-C studies) with Parts 1 and 2 complete and Part 3 in progress.
1241.21 Part 2 (SOUND-C 2) is a 5-arm, open-label, randomized, phase 2b study evaluating efficacy and safety of interferon-free oral combination regimens of BI 207127 and FDV with and without RBV for up to 40 weeks of treatment. A total of 362 treatment-naïve HCV GT1 patients were randomized and treated in 5 treatment arms. In the combined interim analysis by viral subtype (1a vs. 1b), the highest SVR12 (85%) was achieved with the twice daily (BID) 28-week regimen in GT1b infected patients (Table 1.2: 1). This is the dose and target population to be studied in the phase 3 program starting in parallel. In contrast, GT1a, and especially the sub-population of 1a_non-CC achieved sub-optimal SVR12 rates ranging from 42% to 0% (Table 1.2: 1). Among GT1b patients with compensated liver cirrhosis in SOUND-C2 randomized to RBV-containing regimens, the SVR rate was between 57% and 80%. Among patients assigned to a BI 207127 600 mg t.i.d. regimen, patients randomised to 40 weeks experienced the highest rate of discontinuation due to adverse events (AEs). There was a 5%, 13% and 25% rate of early discontinuation due to AEs in the 16-week, 28-week and 40-week treatment arms, respectively. In the BI 207127 600 mg b.i.d. 28-week regimen, 8% patients discontinued due to AEs. As expected, the most frequent AEs reported on the FDV/ BI 207127 combination therapy are skin (rash, photosensitivity reactions) and gastrointestinal (GI) (nausea, vomiting and diarrhoea) events and indirect hyperbilirubinemia. Photosensitivity reactions and vomiting occurring during the first 10 days of treatment have been statistically associated with the extent of the exposure of the BI drugs.
BI 207127 and FDV plasma concentrations were higher when the two drugs are used in combination compared to when there are used as monotherapy or when combined with PegIFN and RBV. On-treatment, pre-dose plasma concentrations of both appeared to steadily decrease over the first few weeks of treatment reaching stable trough exposure approximately at treatment Week 4-6. In addition, a 2-fold increase in exposure of both FDV and BI 207127 in cirrhotic patients compared to non-cirrhotic patients was observed.
Drug metabolism, transport, and drug-drug interactions Two major metabolites of BI 207127 were identified in humans, CD 6168 (alkene reduction) and BI 208333 (BI 207127-acyl glucuronide), present in plasma at ~ 32 and 23% of BI 207127 related material. CD 6168 is formed in the GI tract, likely by gut bacteria and BI 208333 is formed by UGT1A1, 1A3, 1A7 and 1A8, of which UGT1A1 contribution appears to be predominant.
BI 207127 is a substrate of hepatic uptake transporters OATP1B1, OATP1B3 and OATP2B1. BI 207127 is also a substrate of hepatic and intestinal efflux transporters P-glycoprotein (P-gp) and BCRP.
BI 201335 is a substrate of CYP3A4, which metabolizes it to two hydroxy metabolites M2a and M2b. While together these were found to constitute up to 40% of the dose, M2A and M2b were predominantly found only in feces. The exposure of these metabolites in plasma was very low (<1% of total BI 201335 related material). BI 201335 is a substrate of hepatic uptake transporters OATP1B1, OATP1B3 and OATP2B1.
population treatment experienced patients (prior relapse, interferon intolerant, and [allowed in Cohort A only] prior partial response) will also be included (cf. Section 3.3.2 for definitions).
This trial will include a PK sub-study for Cohort B to further assess the BI 207127 b.i.d. dose selected in Cohort A in a larger group of CPB patients. Refer to Section 4.1.3 for selection of dose rationale. Rash and photosensitivity reaction were reported in 20-30% of patients. Rash was commonly reported as maculo-papular skin reaction on the trunk and extremities, while photosensitivity reactions were described as exaggerated sunburns in hands, face or any other sun-exposed skin area. Among patients who received 600 mg b.i.d. BI 207127 in combination with FDV and RBV, all skin events were mild. There were no moderate, severe, or serious skin events or discontinuation of treatment due to skin events reported. Serious rash and photosensitivity reactions were only reported with higher BI 207127 dose (600 mg tid) and none of the cases were considered life-threatening. There were no cases of Steven-Johnson, erythema multiforme, toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS) reported in any of the BI 207127-FDV combination trials to date. Rash and photosensitivity reactions will be carefully monitored and managed with a detailed dermatologic management plan (cf. Appendix 10.2). The dermatologic plan includes precautionary measures to restrict exposure to sun and artificial ultraviolet (UV) light.
GI events such as nausea, vomiting and diarrhoea were reported in BI 207127-FDV combination trials. The highest risk of vomiting in previous trials was observed during the first 2 days of treatment (17% cumulative risk of vomiting during the first 2 days) (U11-3471-01). There was an association between the high BI 207127 exposure at Day 1 and the risk of GI events (U11-3472-01). This may have been due to the administration of an induction dose of BI 207127 (1200 mg, 2 times the individual dose) on the morning of first day of dosing. Since there was no virologic benefit associated with the induction dose (no association between BI 207127 exposure and the initial HCV RNA decay kinetics), this induction dose will not be used in this trial. As such, the risk of vomiting during the first 2 days of treatment in this trial may be lower than in previous trials. PegIFN-free regimens of BI 207127 in Trial 1241.21 Parts 1 and 2 did not cause any relevant changes from baseline in laboratory parameters, except for a continuous drop in alanine aminotransferase (ALT) in all patients, a decrease in haemoglobin (Hb, consistent with RBV treatment) and increase in total bilirubin due primarily to increases in the unconjugated fraction (a known clinically benign effect of FDV treatment). Up to 25% of patients experienced jaundice due to increases in unconjugated bilirubin without concomitant increases in liver function tests (LFTs) or any sign of liver toxicity.
Of note, only approximately 10% of patients experienced anaemia (defined as Hb > 10g/dL) receiving the oral combination in SOUND-C2 compared to 36% of receiving telaprevir with PegIFN/RBV (R12-0262) or 49% of receiving boceprevir with PegIFN/RBV (R12-0263). This may be explained by the lack of PegIFN and its myelosuppressive effect which enhances the negative effect of RBV in the regimen.
Based on the current understanding that cirrhotic patients require longer treatment durations and the lack of substantial clinical data in cirrhotic patients treated for 16 weeks in phase 2, patients with compensated cirrhosis will receive treatment for 24 weeks.

Boehringer Ingelheim Clinical Trial Report BI Trial No.:
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Protocol and amendments
A potential risk with a PegIFN-free regimen is the selection of mutations conferring resistance to both compound classes which may limit future treatments options. However, it is currently not known if HCV resistant variants are archived and persist. Therefore it might be possible to retreat patients that had selected for resistance mutation on a given DAA(s) with the same regiment once the variants are no longer detectable. Additionally, major resistant variants associated with the use of BI 207127, such as P495L, would only confer resistance to another thumb site-1 nonnucleoside NS5B inhibitor. There are currently a number of DAAs with different MOA in development (including: thumb site-2 NS5B inhibitors, NS5A inhibitors, nuclotide NS5B inhibitors, cyclophlin inhibitors, etc.). Future treatment options will be expanded once some of these agents become available to patients in the near future. To maximize the chance to achieve SVR and reduce the chance of emergence of resistance only GT1b patients (which have the highest rate of response to this regimen) will be included.
Patients with decompensated cirrhosis randomised to placebo will not receive benefit from participating in the trial. However, the knowledge gained from this treatment group will be invaluable in understanding the emergence of AEs in decompensated cirrhotic patients during placebo treatment, and thus understanding of the safety profile of the tested regimen in this population. These patients currently have no HCV treatment options and participation in this trial will not compromise future treatment options for these patients. Patients randomised to receive placebo will be given the option of receiving Arm 5 treatment after completion of 24 weeks, if still eligible for treatment (cf. Section 3.1). In addition, an independent Data Monitoring Committee (DMC) will be established (cf. Section 3.1.1.1) and all patients will be frequently monitored. If the risk-benefit ratio changes upon favourable on-treatment clinical data in the active treatment arm 5 of Cohort B, the DMC may recommend that placebo arm patients are offered the option of receiving active treatment prior to completion of 24 weeks of placebo.
Other risks to the patients are the risks inherent to any clinical trial, such as unexpected adverse clinical or laboratory events. Patients will be closely monitored for AEs and rebounds of plasma HCV RNA.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and follow-up of laboratory abnormalities of selected liver laboratory parameters to ensure patients' safety.
Given the good safety profile of this PegIFN-free combination treatment, coupled with rapid and potent antiviral activity observed so far, the sponsor assesses benefit risk relationship in this study as positive, and the knowledge gained will outweigh the potential risk for this patient population with an unmet medical need.
Week 24 Day 1 Week4 Week 24 Day 1 Arm 5: dose selected 7127 bid + 120 mg FDV qd + RBV (CPB)  In total, approximately 165 patients are planned for inclusion in this trial. Refer to Table 3.1: 1 for details of HCV sub-type and Child Pugh score for each treatment arm.  Forty eight patients in Cohort B will be assigned via Interactive Response Tool (IRT) to participate in a PK sub-study (cf. Section 5.5).
"On-treatment" AEs are those AEs that begin during treatment with the trial medications or within 28 days of the End of Treatment (EOT) visit. For more details on safety assessments in this trial, cf. Section 5.2 and Section 7.3.3.
Upon EOT visit patients will complete an additional 96 weeks follow-up (FU) period. Individual patient participation is concluded when the patient has completed the last planned visit.
The end of the trial is defined as "last patient out", i.e. last scheduled visit completed by last patient.

Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim.
Boehringer Ingelheim (BI) will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities required in order to manage the trial in accordance with applicable regulations and internal standard operating procedures (SOPs), directing the clinical trial team in the preparation, conduct, and reporting of the trial, order the materials as needed for the trial, ensures appropriate training and information of Local Clinical Monitors (CML), Clinical Research Associates (CRAs), and investigators of participating countries.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs. For these activities, a Trial Data Manager and a Trial Statistician will be appointed.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined according to BI SOPs. A list of responsible persons will be given in the Clinical Trial Master File (CTMF) document.
The organisation of the trial in the participating countries will be done by the respective local BI-organisation (Operative Unit (OPU)) or by a Contract Research Organisation (CRO) with which the responsibilities and tasks will have been agreed and a written contract filed before initiation of the clinical trial. In each OPU participating in this study, a CML will be appointed responsible for coordinating the activities required in order to manage the trial in accordance with applicable regulations and internal SOPs in the countries covered by the respective BI OPU.
A Co-ordinating Investigator will be nominated to coordinate investigators at different sites participating in this multicentre trial. Tasks and responsibilities for the Co-ordinating Investigators will be defined in a contract filed before initiation of the trial.
Documents on participating (Principal) investigators and other important study personnel, especially their curricula vitae, will be filed in the CTMF.
Details of the trial supplies including responsible institutions are given in Section 4 of this protocol.
The ISF will be maintained at the sites as required by local regulation and BI-SOP. A copy of the ISF documents will be kept as an electronic CTMF document according to BI SOPs.
A central laboratory service and IRT will be used in this trial.

Data Monitoring Committee (DMC)
The study will have a DMC independent from the sponsor. The purpose of the DMC is to ensure that the welfare of patients participating in this trial is maintained by: • Monitoring the trial for possible untoward harmful effects or unexpected frequency of adverse safety events of study drugs; • Assessing whether the goals of the trial are unlikely to be achieved, based on emerging data.
The DMC will evaluate the unblinded accrued patient data in order to recommend whether the trial or program should continue, be modified or stopped for safety concerns or ethical reasons. The DMC will review pertinent trial data, including deaths, serious adverse events (SAEs) and AEs, laboratory data and efficacy markers (HCV RNA). Unless specified differently in the DMC charter, it is expected that the first DMC meeting will occur approximately 2 months after the first patient has entered the trial and then every 3-4 months thereafter, with more frequent reviews as deemed necessary by the DMC or the sponsor. The DMC will review Cohort A Week 4 data prior to the start of Cohort B. All materials provided to the DMC are confidential. The tasks and responsibilities of the DMC will be filed in a charter before initiation of the trial and will contain written operating procedures. The DMC will maintain written records of all its meetings. Sponsor will remain blinded to these ongoing data reviews.

Protocol and amendments
The study will include an independent committee of dermatology experts responsible for evaluation of protocol-defined significant skin AEs (cf. Section 5.2.2.1). The tasks and responsibilities for this committee will be established by contract before initiation of the trial and will contain written operating procedures.

Internal independent data review committee
The study will include a committee of sponsor members that are independent from the trial team. This committee will evaluate interim analysis data, including PK data, to select the BI 207127 dose for Cohort B. Refer to Section 7.3.4 for interim analysis plan and dose selection criteria.
The first interim analysis will be performed on Arm 1 and Arm 2 data up to Week 4 for submission to the committee. The BI 207127 dose for Cohort B will be selected or it will be determined that it is necessary to conduct Arm 3. If Arm 3 is needed, a second interim analysis will be performed on Arm 1 and Arm 3 data up to Week 4 for submission to the committee for Cohort B dose evaluation. Thus, randomisation in Cohort B will begin based on the Week 4 interim data of Cohort A.
The tasks and responsibilities for the Internal Independent Data Review Committee will be established before initiation of the trial and will contain written operating procedures.

DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS
The CPB patient population was selected because these patients, despite having the highest urgency for treatment, currently have no HCV treatment options and therefore have a high unmet medical need. Patients with poorly controlled ascites are excluded due to common fluctuations in ascites i.e. the distribution volume which could interfere with the PK analysis of both compounds.
The CPA control group was chosen because there is limited PK data in CPA patients in the phase II program for BI 207127.
Due to the low SVR rate seen in phase 2 studies in GT1a patients (cf. Table 1.2: 1), these patients are excluded from the program until a more effective treatment regimen has been identified.
The study is double-blind in order to eliminate the reporter/observer bias for the assessment of safety and of the treatment duration on efficacy between treatment Arm 4 and Arm 5.
The Arm 4 placebo group will allow comparison of safety between active treatment and placebo. It will be informative to assist in the identification of AEs related to active triple therapy versus symptoms associated with the underlying diseases and co-morbidities in CPB patients. The CPB placebo group is ethically acceptable since this population currently does not have an antiviral treatment option and their participation will be closely monitored by the The smaller sample size of the PBO group was selected as a compromise between the expectation of spontaneous symptoms and (S)AE of patients due to underlying severe liver disease and the withholding of active treatment from such patients with high treatment need. It is recognised that double-blinding of such a treatment group will be challenging because of multiple laboratory test changes, specifically viral load, bilirubin, liver enzymes and hematologic changes that are related to the administration of active triple therapy vs. no such changes in patients in Arm 4. Nevertheless, extensive efforts will be made to overcome these difficulties through blinding selected laboratory tests for Arm 4 and Arm 5 to investigator, patient and sponsor (cf. Section 4.1.5.1).
PegIFN is not used in the trial and therefore, contraindications to use of PegIFN do not apply as exclusions in the eligibility criteria. Patients with retinopathies, history of psychiatric diseases, autoimmune diseases, thrombocytopenia and other conditions that contraindicate the use of PegIFN, may be entered in the study as long as their co-morbidities are considered clinically stable and with appropriate treatment, if necessary. This will ensure that the trial population is as representative as possible of the patient population seen in clinical practice.
Extended 96-week FU period will allow assessment of the persistence of the virological response, assessment of the progression of the liver disease and resistance profile of HCV over time. In case of re-detection of HCV RNA during the FU period, assessment will be made whether this represents a relapse or a subsequent re-infection.

SELECTION OF TRIAL POPULATION
A sufficient number of patients will be screened for the trial to ensure that approximately 165 patients are randomised to trial treatment (15 patients in each treatment Arm 1, Arm 2, and Arm 3; 30 patients in Arm 4, and 90 patients in Arm 5).
Demographic information, including patient gender, race and ethnicity, will be collected at screening.
Treatment Arm 1, Arm 2 and Arm 3 will be stratified by gender with a minimum of 8 females per arm (cf. Section 7.5).
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all centres when such a number of patients has been screened that it is anticipated that a sufficient number of patients will be randomised to trial treatment. This process of competitive screening will be carried out independently for each screening stage (cf. For Cohort A, patient replacement will be permitted (i.e. those patients who were assigned to a treatment group but did not receive any study drug will be replaced and those that discontinued study drug prior to Week 4 may be replaced as needed to ensure sufficient PK sample size).

Protocol and amendments
For Cohort B, patients assigned to a treatment group who discontinue from the trial after start of treatment will not be replaced (i.e. those patients who were assigned to a treatment group but did not receive any study drug will be replaced to ensure that patients will receive study drug in each treatment group).
Re-screening of patients will not be permitted.
A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not.

Main diagnosis for study entry
This study will be performed in treatment naïve and experienced patients (see inclusion criteria 4 for definitions) with chronic HCV infection of GT1, sub-GT1b virus only.

Inclusion criteria
Chronic HCV infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening in addition to at least one of the following: a) positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening b) liver biopsy consistent with chronic HCV infection c) history of elevated ALT levels at least 6 months prior to screening 1. HCV infection, confirmed by genotypic testing at screening, of GT1, sub-GT1b virus. 2. HCV viral load ≥ 1,000 IU/ml at screening 3. Previous treatment status must be one of the following: a) Treatment naïve: defined as patients who have never been previously treated with any interferon, with an investigational/approved DAA or any other HCV treatment regimen. b) Treatment experienced with prior relapse: defined as HCV RNA level > 25 IU/mL during the post-treatment period in patients who had plasma HCV RNA level undetected at end of all treatment c) Treatment experienced interferon intolerant: defined as patients who had to stop a previous PegIFN/RBV regimen before week 12 of treatment due to safety or tolerability issues. Confirmed or suspected active malignancy or history of malignancy within the last 5 years prior to screening (with an exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix). 6. History of chronic alcohol abuse or illicit drug use other than cannabis within 12 months prior to randomisation, in the opinion of the investigator. 7. Patient is not willing to comply with the restriction of no alcohol consumption. 8. Patient is not willing to comply with the precautionary measures to prevent photosensitivity (avoid excessive sun exposure and use sun block on a daily basis). 9. A condition that is insufficiently diagnosed, treated or clinically unstable which, in the opinion of investigator, may put the patient at risk because of participation in this study, influence the results of this study, or limit the patient's ability to participate in this study, including but is not limited to severe chronic obstructive pulmonary disease and uncontrolled psychiatric disease. 10. Total bilirubin > 3 mg/dL with ratio of direct/indirect > 1 11. Serum albumin < 2.8 g/dL 12. Prothrombin time International Normalised Ratio (INR) > 2.3 13. History or active poorly controlled ascites 14. Encephalopathy graded as other than minimal 15. Clinical evidence of unstable cardiovascular disease which may further decompensate due to anemia, including unstable angina, recent myocardial infarction, cardiomyopathy, congestive heart failure, uncontrolled hypertension or significant arrhythmia. 16. Red blood cell (RBC) disorders, including thalassemia major, sickle cell anemia or G6PD deficit. Patients with traits or minor diseases (e.g. sickle cell trait or thalassemia minor) may be enrolled if the disease did not result in anemia according to the investigator's clinical judgement. 17. Body weight < 40 or > 125 kg 18. Usage of any investigational drugs within 28 days prior to randomisation, or planned usage of an investigational drug during the course of this study 19. Received concomitant immunomodulatory treatment within 28 days prior to screening 20. Received silymarin (milk thistle), glycyrrhizin, Sho-saiko-to (SST) or any medication listed in a restricted medication list provided in ISF within 28 days prior to randomisation, with the exception of parenteral analgesics used during liver biopsy procedure. 21. Known hypersensitivity to any ingredient of the study drugs 22. Hb < 11 g/dL for women and < 12 g/dL for men 23. Absolute neutrophil count < 1,000 cells/mm3 24. Creatinine clearance ≤ 50 ml/min

3.3.4
Removal of patients from therapy or assessments

Removal of individual patients
Patients have the right to withdraw from the study at any time without the need to justify the decision. The investigator has the right to remove patients from the study for non-adherence. Furthermore, patients' treatment should be discontinued early due to lack of viral response or other reasons (as described below). The sponsor reserves the right to terminate a patient from the trial for non-adherence. It is understood that an excessive rate of withdrawals can render the study results uninterpretable; therefore unnecessary withdrawal of patients should be avoided. Patients who discontinue their treatment early will be followed throughout the course of the study and undergo all study required procedures as defined in Section 6.2.3.
Patients will discontinue their assigned treatment earlier than planned due to lack of on-treatment viral response: a) If they have virologic breakthrough defined as: 1) Increase of ≥1 log10 in plasma HCV RNA from a quantifiable nadir*; or, 2) HCV RNA ≥25 IU/mL after previous plasma HCV RNA <25 IU/mL, which must be confirmed by a second consecutive plasma HCV RNA measurement as soon as possible and within 2 weeks time. (Note: If HCV RNA <500 IU/mL, the retest should be greater than the first HCV RNA measurement of ≥25 IU/mL before treatment is discontinued.) b) If they never achieve plasma HCV RNA <25 IU/mL and have plasma HCV RNA ≥25 IU/mL at any time from Week 12 of active treatment onwards (Note: Patients with virologic breakthrough as defined above are not included) * HCV RNA nadir refers to the lowest HCV RNA measurement while on treatment.
These rules will be used only while patients are on-treatment (i.e. in order to stop treatment due to lack on-treatment viral response). Once patients stop treatment, the retest requirements as described in Section 5.1.1 for SVR endpoints will apply.
Patients may discontinue their assigned treatment earlier than planned due to reasons other than lack of viral response, as listed below and based on the clinical judgement of investigator: • Development of a toxicity or AE which warrants drug discontinuation.
• Development of any potentially life-threatening toxicity.
• Patient has to take any concomitant drug interfering with the study medications (list provided in ISF: this should be discussed with the BI Clinical Monitor prior to discontinuation).

Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site at any time for the following reasons: 1. Failure to meet expected enrolment goals overall or at a particular trial site, 2. Emergence of any efficacy/safety information that could significantly affect continuation of the trial, 3. Violation of Good Clinical Practice (GCP), the clinical trial protocol (CTP), or the contract by a trial site or investigator, disturbing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of trial termination (except in case of the third reason).

Identity of BI investigational products and comparator products
The following tables summarise the information about the investigational, non-investigational medicinal products, and comparator products as used in this trial.

Method of assigning patients to treatment groups
After assessment of all entry criteria, the investigator or designee at the site will follow the process outlined in the ISF to assign the patient to a treatment group at visit 2. This will involve the use of an IRT system which will assign eligible patients to a treatment arm according to current screening stage of the trial (cf. Figure 3.1: 2). Treatment group assignment will be recorded on the eCRF and source document. For statistical features of the treatment allocation process refer to Section 7.5.
IRT will assign the first 48 patients randomised in Cohort B to participate the PK sub-study (cf. Section 5.5 and Appendix 10.1). In SOUND-C2, the doses of BI 207127 600 mg b.i.d. in combination with FDV 120 mg q.d. and RBV demonstrated a favourable safety profile with a low rate of discontinuations due to AEs, and the absence of moderate or severe skin events or discontinuations due to skin events (rash or photosensitivity).
Safety and efficacy results from SOUND-C2 in patients with compensated liver cirrhosis were favourable (cf. Section 2.3). However, a 2-fold increase in exposure of both FDV and BI 207127 in cirrhotic patients compared to non-cirrhotic patients was observed. As such, it is expected that FDV and BI 207127 exposure in CPB patients will be at least 2-fold higher than that of non-cirrhotic patients. Therefore, a 400 mg b.i.d. dose of BI 207127 in combination with 120 mg FDV q.d. and RBV in CPB cirrhotic patients is expected to achieve similar or higher exposure than 600 mg b.i.d. dose group in non-cirrhotic patients. If this is not the case and exposure is lower, Arm 3 will be conducted to test the 600 mg b.i.d. dose in CPB patients before the start of Cohort B. The dose for Cohort B will be selected and released by the internal data review committee.
PK / pharmacodynamic (PD) analyses performed in SOUND-C1 and 2 indicate that a PK exposure higher than the one achieved with BI 207127 600 mg b.i.d. does not provide an efficacy benefit in target patient population but rather negatively affects the safety profile. In particular, PK trough levels achieved with the 600 mg b.i.d. dose of BI 207127 were already beyond the exposure-response threshold for GT1b virus. BI 207127 doses higher than 600 mg b.i.d. did not increase viral response but impacted negatively on the safety profile (more severe skin and GI events).
No BI 207127 induction dose will be used (cf. Section 2.3).
Based on the current understanding that cirrhotic patients require longer treatment durations and the lack of substantial clinical data in cirrhotic patients treated for 16 weeks in phase 2, patients in this trial are planned to receive treatment for 24 weeks only.

Drug assignment and administration of doses for each patient
For Cohort A (Arm 2 and Arm 3 only), once an investigator establishes that a CPB patient meets all entry criteria, the investigator will send electronically to the TCM a written request for assignment of the treatment visit date. The investigator will be required to receive written approval from the sponsor before confirming the appointment for the treatment visit with the patient (cf. ISF for request/approval form to be used).
The investigator will make a randomisation call to IRT to randomise/assign an eligible patient. Dispensing of study drugs will begin at Visit 2.

Protocol and amendments
IRT will assign the medication number(s). The assigned medication number(s) must be entered in the eCRF, and the corresponding medication unit(s) must be given to the patient. Each medication unit will have a unique medication number and more than one medication unit may be assigned by IRT dependent on the visit schedule. The visits at which medication is dispensed to patients are specified in the Flow Chart. For details please refer to the ISF.
FDV (or matching placebo) loading dose on Day 1 will include an additional 120 mg capsule for a total of 240 mg for the first active dose. FDV (or matching placebo) should be taken q.d. in the morning together with the morning doses of BI 207127 and RBV (or matching placebo), and together with food. The evening doses of BI 207127 and RBV (or matching placebo) should be taken together with food 12 hours after the morning dose.
Patients in all groups are planned to receive study drugs (active or placebo) for a total of 24 weeks. Early treatment discontinuation rules for lack of viral response or other reasons are defined for all groups (cf. Section 3.3.4.1).
If either of FDV or BI 207127 needs to be discontinued early all three trial medications need to be discontinued. Dose reductions of FDV or BI 207127 are not allowed in this trial. The dose of RBV may be reduced or RBV may be temporarily discontinued due to anaemia (cf. Section 4.2.1) while still continuing FDV and BI 207127 treatment. However, RBV should be reintroduced even at a reduced dose as soon as clinically possible.
Treatment interruptions must be avoided as much as possible. If the combination therapy is interrupted due to an unavoidable reason, it should restart no later than 3 days after the treatment was interrupted. Treatment interruptions for more than 3 days are not allowed and in these cases, treatment has to be stopped permanently and an EOT visit should be performed (cf. Section 6.2.3).

Cohort B
Study medications will be administered double blinded in treatment Arm 4 and Arm 5.
It is recognised that this blinding will be challenging because of multiple laboratory test changes, specifically viral load, bilirubin, liver enzymes and hematologic changes that are related to the administration of active triple therapy vs. no such changes in patients with placebo. However, it is important to maintain the blinding through the blinding of specific laboratory assessments (cf.

Protocol and amendments
In order to mitigate the risk of indirect unblinding and to maintain the integrity of the blinded assessments, Arm 4 and Arm 5 results of plasma HCV RNA levels and a series of safety laboratory tests after start of the treatment will be blinded to investigators, patients and sponsor for up to Week 24 visit (non-inclusive, i.e., Week 24 results will be reported to investigators) (cf. Table 4.1.5.1: 1). These safety laboratory results will be made available to the investigator if any of the criteria are met as described in Table 4.1.5.1: 1.
Central laboratory service will disclose the results of safety laboratory parameters when the unblinding criteria for those laboratory tests are met. If any of ALT or AST meets the criteria for unblinding, results for both laboratory tests will be disclosed from that time-point forward. If Hb meets the criteria for unblinding results for RBC count, Hb, hematocrit will be disclosed from that time point forward. If for the patient care management the investigator needs to know the blinded laboratory results even prior meeting the criteria established in Table 4.1.5.1: 1, the investigator will be able to request these laboratory tests (except HCV RNA) from central laboratory service after consultation with BI Clinical Monitor.
Central laboratory service will inform the investigator whether the patient meets lack of on treatment viral response criteria based on HCV RNA, without disclosing the actual results of HCV RNA. If any of these stopping rules are met, the investigator will receive a notification for repeat testing or treatment discontinuation.
Note that treatment code will be only broken upon investigator's request as per procedures described in Section 4.1.5.2.

Protocol and amendments
According to BI's SOPs, suspected unexpected serious adverse reactions (SUSARs) will be unblinded for reporting to competent authorities. In such cases, access to the code will only be permitted by authorized drug safety representatives via IRT. 4.1.5.2 Procedures for emergency unblinding An emergency code break will be available to the investigator/pharmacist/investigational drug storage manager via IRT. Details are included in the ISF. This code break may only be used in emergency situations when the identity of the trial drug must be known to the investigator in order to provide appropriate medical treatment or if required to assure safety of trial participants.
If the code break for a patient is used, the sponsor must be informed immediately. The reason for using the code break, the date when the code was broken and initials of person who broke the code must be documented on the appropriate electronic case report form (eCRF) page.

4.1.6
Packaging, labelling, and re-supply Supply and re-supply will be managed by IRT.
For details of packaging and the description of the label, refer to the ISF.

Storage conditions
Drug supplies will be kept in their original packaging under the recommended storage conditions indicated on the label. Storage temperature should be monitored and documented.
The trial medication must be stored securely, e.g. in a locked cupboard or at a pharmacy. It may only be dispensed to trial patients according to the protocol by authorised personnel as documented in the form "Investigator's Trial Staff".
All unused medication must be returned to the sponsor. Receipt, usage and return must be documented on the respective forms. Account must be given for any discrepancies. Drug supplies, which will be provided by the sponsor or a CRO appointed by the sponsor, must be kept in a secure, limited access storage area under the storage conditions defined by the sponsor. Where necessary, a temperature log must be maintained to make certain that the drug supplies are stored at the correct temperature.
The investigator/pharmacist/investigational drug storage manager will receive the investigational drugs delivered by the sponsor when the following requirements are fulfilled: • approval of the study protocol by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC), • availability of a signed and dated clinical trial contract between the sponsor and the Head of Trial Centre, • approval/notification of the regulatory authority, e.g. competent authority (CA), • availability of the Principal Investigator's (PI's) CV, • availability of a signed and dated CTP or immediately imminent signing of the CTP (in exceptional cases, medication could already be sent to the site, before its activation via IRT), • availability of the proof of a medical licence for the PI, if applicable • availability of the Form 1572 (for USA).
The investigator/pharmacist/investigational drug storage manager must maintain records of the product's delivery to the trial site, the inventory at the site, the use by each patient, and the return to the sponsor or alternative disposition of unused product(s).
These records will include dates, quantities, batch/serial numbers, expiry ('use by') dates, and the unique code numbers assigned to the investigational product(s) and trial patients. The investigator/pharmacist/investigational drug storage manager will maintain records that document adequately that the patients were provided the doses specified by the CTP and reconcile all investigational product(s) received from the sponsor. At the time of return to the sponsor or appointed CRO, the investigator/pharmacist/investigational drug storage manager must verify that all unused or partially used drug supplies have been returned by the clinical trial patient and that no remaining supplies are in the investigator's possession.

Protocol and amendments
All dose adjustments of RBV, discontinuations and rescue medications must be documented in the patient source documentation and corresponding eCRF.
Management of drug-related skin events: In case of drug-related skin events, the investigator should follow the dermatologic management plan, as specified in Appendix 10.2.

Management of gastrointestinal (GI) events:
GI AEs such as nausea, vomiting or diarrhoea have been reported during treatment with BI 207127 and FDV. The highest onset rate of these AEs was during the first week of treatment, particularly Day 1 and 2, followed by a significant decrease over time.
The following general measures are strongly recommended in order to prevent and manage these AEs: • BI 207127 doses should be taken along with food avoiding intake in fasting conditions. Patients should be instructed to take their medications with food, preferably during breakfast and dinner. • Early symptomatic treatment is recommended particularly during the first days of treatment.
• Antiemetic treatments such as ondansetron 8 mg tablets starting with one tablet b.i.d.
or metoclopramide 10 mg tablets (orally dissolved) one tablet b.i.d. or q8h are recommended for nausea and vomiting. These agents may be taken approximately 30 minutes before BI 207127 intake if needed, and continued depending upon response. Re-taking study medications after vomiting is not recommended; patients should follow their regular schedule. • Antimotility agents such as loperamide 2 mg caplets (or capsules) are recommended for non-infectious diarrhea; starting with 4 mg dose (2 caplets) and continue with 2 mg after each subsequent loose stool but no more than 4 caplets in 24 hours.

Management of anaemia
For RBV dose modification guidance for management of anaemia cf. to   1 If the abnormality is reversed, Ribavirin should be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.
Of note, other ribavirin dosage modification guidelines due to anaemia may apply according to local approved Copegus ® label.
The use of eyrthropoiesis stimulating agents (ESA), is permitted at the discretion of the investigator. If ESA are being prescribed, the following guidelines have to be followed: • ESA should not be initiated until haemoglobin levels falls below 10g/dL • Iron studies should be obtained prior to and during ESA treatment • Iron supplementation should be initiated for deficient patients and to maintain transferring saturation at levels supporting erythropoiesis • Once an ESA is initiated, haemoglobin levels and blood pressure must be monitored weekly until stabilisation of haemoglobin • Treatment should target a haemoglobin level sufficient to avoid transfusion • ESA dose should be titrated to treatment response • ESA dose should be reduced if the haemoglobin rises by more than 1 g/dL in a 2-week period • ESA dose should not exceed those recommended for currently approved indications • ESA should not be used in patients at increased risk for thromboembolic events, cardiovascular events, including those with inadequately controlled hypertension, and patients with diagnosed malignancies • Patients must be informed about the risks associated with ESA use, as described in the patient information • Dose and duration of treatment must be documented in the eCRF Treatment option for patients that complete Arm 4 Eligible patients who accept the offer to receive active treatment (corresponding to Arm 5) will follow the visit order and procedures specified in Table 4 Selected laboratory tests will be performed (cf. Laboratory Manual) 2 FU (follow-up) visits are counted from EOT (end of treatment). 3 Loading dose of FDV is needed. 4 All AEs with onset date up to 4 weeks after A-EOT will be recorded. Only related to FDV or related to BI 207127 or fatal SAEs will need to be reported through SAE form if onset date is 4 weeks after A-EOT. 5 "X T " is a targeted physical examination including measurements of vital signs, and evaluation of organ systems particularly associated with AE(s) symptoms.

Restrictions regarding concomitant treatment
Concomitant use of medications should be guided by the 'restricted' and 'use with caution' drug lists provided in the ISF.
Concomitant immunomodulatory treatment, including the chronic administration of systemic corticosteroids, is discouraged and if clinically possible should be postponed until EOT. Note that topical, nasal, or pulmonary steroids may be used (if not listed as restricted in ISF).
Systemic antiviral treatment will not be allowed during treatment period this trial, with the exception of oral antiviral such as acyclovir, famiclovir or valacyclovir for mild, localised recurrent herpes simplex infection, or oseltamivir or zanamivir for Influenza A.
The use of silibinin or other medications extracted from the milk thistle is not allowed during the treatment period of this trial.
The co-administration of drugs which may cause photosensitivity reactions should be avoided throughout the treatment duration and up until 28 days after all treatment discontinuation, unless the benefit outweighs the risk based on the investigators' clinical judgment. The restriction of drugs with photosensitivity potential includes and is not limited to tetracyclines (e.g. tetracycline, doxycycline), fluoroquinolones (e.g. ciprofloxacin, ofloxacine), sulfonamides, sulfonylureas (e.g. glipizide), psoralens, oral retinoids (e.g. isotretinoin, acitretin), phenothiazines and amiodarone. Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. All concomitant and/or rescue therapies will be recorded on the appropriate pages of the eCRFs.

Restrictions on diet and life style
Patients must be willing to protect any uncovered skin area (including hands, face and lips) from sun-or UV-light exposure using sun-blocker cream with an SPF ≥50 providing UV-A and -B protection during treatment period on a daily basis. Lip balm with the highest SPF locally available should be used. Patients should avoid unnecessary or prolonged exposure to sunlight and wear protective clothing, sunglasses and hats in addition to sun-block. It is recommended to avoid direct sun exposure as much as possible. Tanning booths must be avoided during treatment period. No alcohol consumption during screening, treatment, and follow-up periods of the trial.

TREATMENT COMPLIANCE
Study medication will be dispensed to the patient at the study site by responsible site personnel. Details regarding dispensing of the study medication to each participating patient, including patient identification, the amount of study drug dispensed, the date the drug was dispensed, and the numbers of capsules/tablets/vials returned to the site will be recorded in the drug dispensing log. All dispensed study drug should be recorded in the drug-dispensing log in the ISF.
Patients must return to the site drug packaging including unused or empty medication packages at each visit. Study medication usage and return must be documented on the respective form and account must be given for any discrepancies.
Treatment compliance for all three drugs will be strictly monitored and assessed at each relevant visit through pill-count by Investigator (or designated site personnel) according to worksheets provided in ISF. For more information regarding FDV pill-count procedure, please cf. ISF. Compliance worksheets must be kept as a source documents. BI Clinical Monitor should be contacted for cases of suspected non-compliance.
Compliance will be calculated according to the formula: • Compliance (%) = Number of medications actually taken since last count / Number of medications which should have been taken in the same period ×100% Planned interruptions and dose reductions in treatment (applicable for RBV) in accordance with the protocol and prescribed by the investigator should be taken into account when calculating compliance.
If the treatment compliance cannot be assessed in a specific visit (e.g., bottle is lost or forgotten), the eCRF compliance page at that visit should be left blank.
Compliance to the BI 207127, FDV, RBV and matching placebos should be between 80% and 120%. Patients who are non-compliant according to this definition will be treated as protocol violations. The identification, handling and inclusion/exclusion of these and other protocol violations will be discussed in the trial statistical analysis plan (TSAP).
Patients who are non-compliant (e.g., have low treatment compliance, do not attend trial visits or violate the restrictions) may be withdrawn from the trial and the eCRF will be completed accordingly (for further procedures cf. Section 3.3.4), following discussion with BI Clinical Monitor.
Patients should take their medication regularly at the same time every day (BI 207127 and RBV every 12-hour and FDV every 24-hour). Excursions ± 1 hour outside from the regular times of intake should be avoided since this may lead to viral resistance and treatment failure.
If a patient misses a scheduled BI 207127 dose, and discovers this error: • Less than 6 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit.
• 6 hours or more after the scheduled dose time, the patient must: take the next scheduled dose at the next scheduled time; not take the missed dose; and, report the error at the next study visit.
If a patient misses a scheduled FDV dose, and discovers this error: • Less than 12 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit.
• 12 hours or more after the scheduled dose time, the patient must: take the next scheduled dose at the next scheduled time; not take the missed dose; and, report the error at the next study visit.
If a patient misses a scheduled RBV dose, and discovers this error: • Less than 6 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit.
• 6 hours or more after the scheduled dose time, the patient must: take the next scheduled dose at the next scheduled time; not take the missed dose; and, report the error at the next study visit. Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.

VARIABLES AND THEIR ASSESSMENT
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
-ALT and aspartame aminotransferase (AST) in normal range at EOT • -ALT and AST in normal range post-treatment Events of liver disease progression (cf. Section 5.3.2.2)

Assessment of efficacy
A plasma sample will be obtained from all patients at each visit for the measurement of HCV RNA. The plasma HCV RNA level will be measured using the quantitative Roche COBAS ® Taqman HCV/HPS assay (Version 2), a test that utilises real-time reverse transcription polymerase chain reaction (PCR) technology. The assay has a limit of detection between 10 and 20 IU/mL and a linear range of 25 IU/mL to 3.91x10 8 IU/mL.
The results below the linear range, HCV RNA levels <25 IU/mL, will be reported as being undetected or detected. For assessment of HCV RNA related endpoints, HCV RNA level <25 IU/mL is regardless whether HCV RNA is detected or undetected. HCV RNA undetected will be reported as <25 IU/mL, undetected.
Detailed instructions for obtaining, handling, and shipping HCV RNA measurement samples are provided in the ISF. Samples will be processed by a central laboratory service.

Endpoints of safety
The following safety endpoints will be assessed: • AEs, including Division of Acquired Immunodeficiency Syndrome (DAIDS) grades • AEs leading to treatment discontinuation of all trial medications

Serious adverse event
An SAE is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical event when based upon appropriate medical judgement which may jeopardise the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions.

Intensity of adverse event
All AEs with the exception of photosensitivity reaction will be graded according to DAIDS grading scale (see DAIDS grading scale in ISF (R10-1332)). Photosensitivity reactions will be graded according to a scale provided in the Dermatology Management Plan in Appendix 10.2.
The intensity of the AE should be judged based on the DAIDS Grading Scale: • Yes: There is a reasonable causal relationship between the investigational product administered and the AE. No: There is no reasonable causal relationship between the investigational product administered and the AE.
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. any active comparator or placebo according to the trial design).

Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the eCRF.

Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator. Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
As described in Section 4.1.5.1 selected laboratory tests results in Arm 4 and 5 will be blinded to investigator, patients and sponsor. Therefore, it is understood that by design investigator will not be able to report laboratory related AEs, unless they are in the range that require unbinding of the investigator to the results (cf. Table 4.1.5.1: 1). The blinding ranges were set to exclude values that may be clinically relevant to avoid an effect on the AE reporting rates. In the Clinical Trial Report (CTR), all laboratory tests will be analyzed and presented to demonstrate any potential effect of laboratory test blinding on AE reporting rates.
Protocol-specified significant events The following are considered as protocol-specified significant events: • Skin rash cases of Grade ≥2 severity or photosensitivity reactions of moderate or greater severity.
Protocol-specified significant events are to be reported in an expedited manner similar to SAEs, even if they do not meet any of the seriousness criteria. For details please see Section 5.2.2.2.

Adverse event and serious adverse event reporting
All AEs, serious and non-serious, with onset date from signing the informed consent until 28 days after all treatment discontinuation (EOT), defined as the FU1 visit, and all related to study medication or fatal SAEs with onset date after FU1 visit will be collected, documented and reported to the sponsor by the investigator on the appropriate eCRFs/SAE reporting forms. Reporting will be done according to the specific definitions and instructions detailed in the 'Adverse Event Reporting' section of the ISF.
For each AE, the investigator will provide the onset date, end date, intensity, treatment required, outcome, seriousness, and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1. For details refer to the subsections of this Section.
If not stipulated differently in the ISF, the investigator must report the following events 1) if using paper process SAE form via telephone/fax or 2) if available for the trial, using the electronic submission process (RDC) immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically related to the SAE(s), and protocol-specified significant events.
BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these "always serious adverse events", if a non serious AE is identified to be serious per BI definition, a query will be raised. The investigator must verify the description and seriousness of the event. If the event description is correct, the item "serious" needs to be ticked and an SAE has to be reported in expedited fashion following the same procedure as above. The list of these AEs can be found via the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU (country-specific contact details will be provided in the ISF) or by using the electronic submission process. This immediate report is required irrespective of whether the investigational product has been administered or not and irrespective of causal relationship.
It also applies if new information to existing SAEs or protocol-specified significant events becomes available.
Reporting AEs occurring up to 28 days after all treatment discontinuation (FU1 visit): The investigator has the responsibility to report all AEs occurring up to 28 days after all treatment discontinuation (FU1 visit), regardless whether they are serious, non-serious, related or not-related to the trial medication. Any AEs persisting after FU1 visit must be followed until they have resolved, or as deemed reasonable by the investigator in consultation with BI Clinical Monitor. These AEs will be considered "on-treatment", except if the onset date was after the start of the active treatment option (for Arm 4 patients only).
Reporting AEs occurring later than 28 days after all treatment discontinuation (FU1 visit): AEs that occur after FU1 visit will be reported only if serious and deemed related to the trial medication or study design or if fatal. These events will be attributed to the "post-treatment period." After the study completion (End of Observation (EOO) visit), the investigator has the responsibility to report only AEs that are serious and deemed related to the trial medication or study design, if the investigator becomes aware of them, but no active FU is necessary after EOO visit. These events will be attributed to the "post-study period."

Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been enrolled into the clinical trial, after having taken study medication, the investigator must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 hours or next business day whichever is shorter) to the defined unique entry point for SAE forms of the respective BI OPU (country-specific contact details will be provided in the ISF). The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up. SAE/Significant AE form immediately (within 24 hours or the next business day whichever is shorter even if not serious) as well as on the AE eCRF page and the skin eCRF page.
Please note, the event should NOT be reported as serious on the SAE form unless it meets the regulatory definitions of a SAE defined in the "Adverse Event Reporting" section of the ISF. It is recommended that all patients with protocol-defined significant AEs should see be referred to a local dermatologist for diagnosis, confirmation of severity, and treatment advice. All patients with protocol-defined significant AEs should have a photo-documentation of their lesions. For instructions on photo-documentation, please refer to the ISF. For specific management and grading guidelines for patients developing rash and photosensitivity reactions, please cf. Appendix 10.2 and Dermatologic Operations Manual in the ISF.
Grade 1/mild skin AEs are not considered "protocol-defined significant AEs" and should be reported in the AE eCRF and skin eCRF. Skin AEs with a known etiology (e.g. viral exanthema, collagen vascular disease, neoplasia, bacterial infection, psoriasis, fungal skin infection, or autoimmune blistering disease) deemed not related to the trial medications are not considered "protocol-defined significant AEs" and should be reported in the AE eCRF page only. A skin eCRF page is not required.
Protocol-defined significant AEs will be subject to review by the dermatological adjudication committee.
BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these "always serious adverse events", if a non serious AE is identified to be serious per BI definition, a query will be raised. The investigator must verify the description and seriousness of the event. If the event description is correct, the item "serious" needs to be ticked and an SAE has to be reported in expedited fashion following the same procedure as above. The list of these AEs can be found via the RDC-system.

Assessment of safety laboratory parameters
The safety laboratory will be performed at the central laboratory service provider. Reference ranges and instructions on sample collection, handling/processing, and shipping will be provided in the ISF.
Patients should be fasting for at least 6 hours prior to the blood sample being taken (except screening visit). For time points of sampling refer to the Clinically relevant laboratory values should be commented on lab report print-outs. A clinically relevant value may be either in-or outside the reference range. Clinically relevant abnormal laboratory test results must be confirmed using an unscheduled visit lab kit and should be repeated until normalisation or stabilisation or until an alternative explanation has been found. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
The following laboratory results will be flagged by the central laboratory for further assessment of potential DILI cases: • ALT or AST 2x baseline that is at least 100 IU/L higher than baseline, • Total bilirubin >3x ULN combined with direct /indirect bilirubin >1 Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.  Alpha-fetoprotein Autoimmune serum markers 1 Anti-nuclear antibodies (ANA) Other laboratory parameters 1 IP-10 (IFN-gamma inducible protein-10) Glycosylated Hb (HbA1c) Homeostatic model assessment of insulin resistance (HOMA-IR) Parathyroid hormone Vitamin D measurement LDL, VLDV and HDL Drug screening (urine) 1,3 Cannabis Benzodiazepine Barbiturates Opiates Cocaine Amphetamines Methadone

Specific immunoglobulin (Ig) measurement
Total serum IgE 5 1 At Visit 1 only 2 At liver disease progression assessment time-points 3 Results will not be captured in the sponsor's database 4 DAIDS grading does not apply 5 IgE only in case of moderate or severe rash

Pregnancy tests
Serum pregnancy tests will be performed at screening (Visit 1) and at every visit for all female patients. In addition to serum pregnancy test at all study visits, a urine (dipstick) pregnancy test will be performed before receiving the study drugs at Day 1 (Visit 2). Only female patients with negative urine pregnancy test will receive study medication at Day 1 (Visit 2). Urine (dipstick) pregnancy tests will not be captured in the database.
When visits are more than 4 weeks apart and/or due to early treatment termination, female patients will be provided with urine pregnancy tests to perform monthly pregnancy tests at home between visits until 7 months after EOT. It is strongly recommended that female partners of male patients also perform monthly pregnancy test at home and the sponsor will provide urine (dipstick) pregnancy tests for this purpose.

Boehringer Ingelheim Clinical Trial Report BI Trial No.:
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
It will be recorded after the patients have rested for at least 5 minutes in supine position at Visit 1. Six limb leads, as specified by Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and six pre-cordial leads (V1-V6), according to Wilson, will be used. The investigator or a designate will evaluate whether the ECG is normal or abnormal and, if abnormal, whether it is clinically significant. Additionally, any occurrence of re-or depolarization disorders, arrhythmic disorders or other abnormalities will be assessed.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will be stored in the patient's medical file.
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant abnormal findings will be reported as AEs.

Physical examination
Complete and target physical examinations will be carried out as described in the Flow Chart.
A complete physical exam consists of an evaluation of organ systems with vital signs (including respiratory rate, temperature, pulse rate, and systolic/diastolic blood pressure). Respiratory rate, temperature, pulse rate, and blood pressure will be measured after patients have been sitting comfortably for at least five minutes.
A targeted physical examination includes an evaluation of organ systems only associated with an AE symptom(s) (as needed,and particularly focused on hepatic-related events) and evaluation of vital signs.
Clinically relevant abnormal findings will be reported as AEs.

FibroSURE TM
Non-invasive method for lived fibrosis assessment, FibroSURE TM , will be assessed at the time-points specified in the Flow Chart. FibroSURE TM is an algorithm based on a composite of five serum biochemical markers (alpha-2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin) that is used to assess liver fibrosis with its different degrees. The algorithm generates a score that correlates with the level of fibrosis and the presence of cirrhosis. For the purpose of a separate health economic analysis (such as cost-utility analysis), HCRU data will be collected throughout the study. Resource use data collected for calculating direct costs will include unscheduled hospitalisations, healthcare provider visits, and emergency room/ICU use. Information on work productivity will also be collected.
The economic evaluation of the HCRU data will not be part of the CTR but reported separately.

EQ-5D
Health related quality of life will be assessed using the EQ-5D at the visits indicated on the Flow Chart. EQ-5D is a standardized instrument for use as a measure of health outcome. It is a generic measure, rather than disease-specific, and is therefore applicable to a wide range of health conditions and treatments. It provides a simple descriptive profile and a single index value for health status. EQ-5D is designed for self completion by patients.
The EQ-5D self-report questionnaire (EQ-5D) essentially consists of 2 pages comprising: • The descriptive system (five dimensions of health; namely mobility, self care, usual activities, pain/discomfort, anxiety/depression). Each dimension comprises three levels (no problems, some/moderate problems, extreme problems).
• The EQ-VAS (visual analogue scale) which records the patient's self-rated health status on a vertical graduated (0 -100) VAS.
The paper-and-pen version in the required native language of the patient will be used. If the required language is not available then the patient is not required to complete the questionnaire.
A patient can self-administer the EQ-5D in a few minutes, and the Investigator (or designated site-personnel) should ensure that the patient has access to a quiet area at the site where he can be left alone to record a response to the descriptive system and VAS. In instances where a patient cannot give or decide upon a response, no response should be recorded. The Investigator (or designated site-personnel) should check that all items have been completed by the patient, but the response to each item should not be scrutinized. Instructions to patients are included in the questionnaire. In this study of FDV and BI 207127 combination therapy, genotypic resistance monitoring (sequencing) will focus on the NS3/4A and NS5B genomic segments. Samples for genotyping the HCV NS3/4A protease and NS5B polymerase will be collected at screening (Visit 1) and at all patient visits. Viral genotyping will be performed for patients who discontinue study treatment. HCV RNA plasma viral load data will guide which additional samples are examined; genotyping will be performed on samples in which the HCV RNA plateaus above the lower limit of quantification or in which the HCV RNA rebounds during trial period (before or at EOO visit) and compared to baseline sequence. These include FU isolates (as detailed in Flow Chart) from individuals whose on-and post-treatment viral samples are genotyped to assess the persistence of resistance mutations during the outgrowth of wild-type virus.
The viral RNA will be extracted, cDNA synthesized and amplified using reverse transcriptase-PCR. The length of amplified product potentially limits the detection to samples with HCV RNA >10 3 IU/mL. The NS3/4A protease and NS5B polymerase nucleotide sequences will be obtained by direct DNA sequencing of the amplified product that allows for the detection of variants present at approximately ≥30%.

Phenotypic Resistance
The virology samples obtained for genotypic resistance monitoring are also suitable for phenotyping. NS3 protease or NS5B polymerase replicon-based phenotyping will be performed on samples in which the HCV RNA plateaus above the limit of quantification or in which the HCV RNA rebounds during trial period (before or at EOO visit) and which are associated with unique resistant mutants that have not been previously phenotyped. Representatives of the most common and well characterized pathways in assays will be included as references. In addition to patient-derived NS3 or NS5B samples, novel amino acid substitutions will also be characterized phenotypically using site-directed mutagenesis if they are observed repeatedly in genotyped subjects.

Methods and timing of sample collection
At least 4 mL of plasma from 8 mL of blood sample will be collected for virology samples (genotyping and phenotyping analyses) at each visit. These will be divided into two 2 mL aliquots: one primary and one back-up. Samples will be shipped to the central laboratory on dry ice. The central laboratory will store samples at -80°C until processing. Detailed instructions for obtaining, handling, and shipping virology samples are provided in ISF.

Assessment of liver disease progression
Markers of liver disease progression will be collected as occurrence of any of the following clinical outcomes and assessed at the time points specified in the Flow Chart: Proprietary confidential information. © 2012 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Pharmacogenomic evaluation The first sample, a mandatory part of the protocol, collected at Visit 2 will be used for DNA extraction and subsequent genotyping of genotyping of IL-28b rs12979860, as well as other genes involved in the activity and/or efficacy of the drug within the context of the clinical trial. In addition, genes influencing assimilation and/or metabolism like UGT1A1, HLA class I and II molecules, CYP450 enzyme and drug transporter genes, like OATPs, genes influencing the therapeutic outcome like interferon signalling pathway genes and/or interferon stimulated genes may be evaluated. After successful analysis, the remaining material will be destroyed.
The second sample collected at Visit 2 sample is voluntary and will be taken and processed or stored only after a separate informed consent is given in accordance with local ethical and regulatory requirements. This sample will be completely anonymised. The anonymization procedure will guarantee a very high level of data protection for the donor. Once the anonymization has been carried out, there will be no way to trace back to the identity of the donor through the coding keys. The anonymised DNA may be analysed at a later time to identify whether there are genetic factors that could contribute to a better therapeutic outcome or a higher risk of developing treatment-related adverse drug reactions. These analyses may include genes related to efficacy, safety and PK. After anonymization, the third sample (or the DNA derived thereof) will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests.

Methods and timing of sample collection
One mandatory and one optional 8.5mL blood sample will be taken at Visit 2 for pharmacogenetic testing with PaxGene DNA blood sampling tubes. The Paxgene Blood DNA tubes can be stored and shipped at room temperature within 14 days. If a longer storage and shipment period for Paxgene Blood DNA tubes is necessary, the blood samples have to be stored at a temperature of -20° C or below. Once frozen, thawing of the samples should be avoided. Detailed instructions for pharmacogenetic sampling, handling and shipment of samples are provided in the ISF. Genomic DNA will be extracted from blood samples according to standard molecular genetics methods and analyzed by TaqMan® or other standard genotyping technologies.

APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements in HCV treatment trials and will be performed in order to monitor safety aspects or assess treatment response in an appropriate way.
The scheduled measurements are appropriate to see drug induced changes in vital signs, standard laboratory values and ECG. These primary and secondary endpoints are standard and accepted for evaluation of safety and tolerability of an oral drug, and they are widely used in this kind of studies.
Therefore, the appropriateness of all measurements applied in this trial is given.

Pharmacokinetic endpoints
The following primary PK parameters will be calculated for patients participated in Cohort A: • C max (maximum measured concentration of BI 207127 & metabolites, FDV and RBV) • AUC 0-12 (area under the concentration-time curve of BI 207127 & metabolites and RBV in plasma over the time interval from 0 to 12 hour) • AUC 0-24 (area under the concentration-time curve of FDV in plasma over the time interval from 0 to 24 hour) • C 12 ( plasma concentration of BI 207127 & metabolites and RBV at 12 hour) • C 24 (plasma concentration of FDV at 24 hour) Other PK parameters will be determined for the analyte if feasible in Cohort A: • t max (time to reach maximum concentration C max in plasma) • λ z (terminal rate constant in plasma) • t 1/2 (terminal half-life of the analyte in plasma) • MRT po (mean residence time of the analyte in the body)

Protocol and amendments
• CL/F (apparent clearance of the analyte in the plasma after extravascular administration) • V z /F (apparent volume of distribution during the terminal phase λ z ) In addition plasma protein binding of BI 207127 & metabolites and FDV will be determined in Cohort A only.

Methods of sample collection
The date and clock time of the most recent drug intakes, and date and clock time of the blood sample collection will be entered in the eCRF. Further details on collection, preparation, and shipping will be included in ISF. For all patients in Cohort A and Cohort B, pre-dose PK blood samples will be collected according to the Flow Chart. If patient is subjected to intensive PK on same visit day, only collect intensive PK samples. Patients should not take study medication the mornings of treatment period visits. Administration of the study drug will be done under the supervision of the investigator or his designee after the pre-dose sample has been collected. The time elapsed since the last dose of FDV should be as close to 24 hours as possible and the last dose of BI 207127 should be as close to 12 hours as possible.
For quantification of FDV and RBV plasma concentration, 2.0 mL of blood will be drawn from a forearm vein in an EDTA-anticoagulant blood drawing tube. For quantification of BI 207127, CD 6168, BI 208333 (BI 207127 acylglucuride) and CD 6168-acylglucuronide, 4.5 mL of blood will be drawn from a forearm vein in a blood drawing tube containing citrate or citrate and citric acid.

VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit date (with its window) is to be counted from Day 1. Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may be included as deemed necessary by the investigator.

DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
For detailed description of the trial procedures to be performed at each visit, refer to the Flow Chart and respective protocol sections. Explanations of procedures are provided in Section 5. Additional details regarding visit procedures are provided below.
All visits, except Visit 1 (screening), must be performed in fasted state.

Screening and run-in periods
No procedures should be done unless the patient has provided written informed consent in accordance with GCP and local legislation to taking part in the trial.
Once consented, a patient is considered to be enrolled in the trial and have started screening. The patient should be assigned a patient number, recorded on the enrolment log, registered in IRT, and recorded on the eCRF as a screened patient.
Screening (Visit 1) should normally take place no more than 42 days before Visit 2; however the time window for Visit 1 may be extended at the discretion of the CML in conjunction with the TCM on a case by case basis.
Re-screening a patient will not be permitted. Patients who have a laboratory test value outside the range specified by the entry criteria may have the test repeated once to determine eligibility and the result must be available prior to Visit 2 (Day 1). Screening visit (Visit 1) activities may be extended to two physical visits if needed.
Prior liver biopsy or fibroscan results will be recorded in the eCRF as medical history.
Patients who fail screening following Visit 1 procedures should be registered as a screen failure in IRT.

Treatment period
The treatment period is from Visit 2 to EOT Visit. Patients will be dispensed medication at visits according to the Flow Chart and new medication unit number(s) will be provided through the IRT on each occasion.
Instruct patient NOT to take study medication on the morning of all visits.

Protocol and amendments
Administration of the morning dose of study drug will be done under the supervision of the investigator or his designee after the pre-dose PK sample has been collected. Note that the routine laboratory samples are to be collected in fasted condition and only afterwards patients must take their medication with food.

Randomization/treatment assignment visit (Visit 2)
Patients will begin treatment as assigned by the IRT at Visit 2 with the first dose administered in the office (Day 1) including an additional 120 mg loading dose of FDV (or placebo) (cf. Section 4.1.4).
For Cohort B, IRT will assign mandatory PK sub-study participation (cf. Section 5.5).

Visit 3 to Visit 12
For Cohort B, results of plasma HCV RNA levels and a series of safety laboratory tests after start of the treatment will be blinded to investigators, patients and sponsor (cf. Section 4.1.5.1). The Investigator will be informed by the central laboratory when a criteria for treatment discontinuation due to lack of virologic response (cf. Section 3.3.4.1) are met for a given patient during this period.

EOT Visit
Planned EOT visit will occur at Week 24 according to the planned treatment duration. These patients should be registered as completed in IRT.
Patients who discontinue treatment early due to either lack of efficacy or safety reasons will be required to have an EOT visit (if the patient is at the research site), or have EOT visit scheduled within 2 weeks from the last intake of study medication. These patients should be registered in IRT as early discontinuation of trial medication. Please note that if either BI 207127 or FDV is permanently discontinued, all study medication including RBV must be discontinued immediately (cf. Section 4.2.1).
For Cohort B, the sponsor, patient, and investigator will be unblinded to all laboratory values and treatment (active or placebo) for each patient at their EOT visit.

End of trial and follow-up period
Termination of trial medication and trial completion must be recorded on the corresponding eCRFs for all randomised/treatment assigned patients.

Follow-up (FU)
If HCV RNA is detected during a FU visit, a subsequent confirmatory testing should be performed.
If a patient receives any other HCV treatment outside this protocol during the FU period the patient will need to be discontinued from the trial and have EOO visit prior to the start of that treatment. Efficacy data collected after the start of such treatment will not be attributed to the trial treatment. Any subsequent end-points will be considered as not achieving treatment response.
Patients with EOT at Week 24 Patients who successfully complete the 24-week treatment period should return to the clinic for FU visits according to the Flow Chart. FU1 visit will occur 4 weeks after the discontinuation of trial treatment. This is the last at which the investigator has the responsibility to report every AE. During the next FU visits, only SAEs fatal or considered by the investigators as related to study medication will be reported. Refer to Flow Chart and Section 5.2.2.

Patient with early treatment termination
Patients who stop study treatment prior to completion of the treatment period should return to the clinic for all FU visits per the Flow Chart starting with a FU1 visit 4 weeks after EOT.
It is understood that a patient may withdraw consent at any time and decide not to complete FU, but such FU is to be encouraged.

End of Observation
EOO will be performed for all patients at 96 weeks after EOT.
Patients who discontinue the FU period early will be required to have an EOO visit (if the patient is at the research site), or have EOO visit scheduled within 3 weeks from discontinuation of the FU.

Treatment Option for Arm 4
For patients that participated in Arm 4, an option to received trial treatment according to Arm 5 may be offered, if patient is still eligible for treatment (cf. Section 3.1). The trial Flow Chart will not be followed; instead these patients will follow the treatment visit schedule and procedures as listed in

Protocol and amendments
SVR12 will be assessed based on the observed HCV RNA result taken at least 8 weeks (to allow an appropriate visit window) after treatment discontinuation. This definition will also hold for patients that discontinue treatment early, i.e. if the patient has HCV RNA undetected at least 8 weeks after stop of all treatment, they will be considered a responder in the primary analysis.
If a patient has detectable HCV RNA at the FUP2 visit but had undetectable HCV RNA at the previous visit, a confirmation sample will be used to determine SVR12. This procedure will also be implemented for patients who have multiple observations in the SVR12 window (≥10 weeks after the planned treatment period) -that is, if a patient has a detectable HCV RNA after being undetectable, confirmation will be required before classifying the patient as a SVR12 failure. Patients that take other HCV therapies after stopping all trial medication will also be considered SVR12 failure in the primary analyses.

Secondary analyses
Sensitivity analyses of the primary endpoint will be performed for the per-protocol set and completers set to assess the impact of important protocol violations and premature discontinuation on the primary endpoint.
A further sensitivity analysis will be performed imputing missing SVR data by last available post-treatment result (SVR12).
The secondary endpoints SVR4 and SVR24 will be evaluated with the same statistical method that is described for the primary endpoint in Section 7.3.1.
Ninety-five percent confidence intervals (CIs) will be reported for the differences in response rates between treatment groups for SVR12, SVR4, and SVR24.
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA) coding dictionary. All events with an onset after the first dose of study medication up to a period of 28 days after the last dose of study medication will be assigned to the treatment phase for evaluation. Other AEs will be assigned either to the screening or FU phase as appropriate. Frequency tables of patients who experience AEs leading to discontinuation will be provided. Kaplan-Meier curves might be used to investigate the time to an event for considerations of special interest, for example rash event. More details of these analyses will be included in the TSAP.
Laboratory values taken after the first dose of randomised treatment up to a period of 7 days after the last intake of treatment will be assigned to the treatment phase for evaluation. Frequency tables with abnormal laboratory values defined by DAIDS grades (R10-1332) and, if necessary, the proportion exceeding multiples (2*, 3* …) of the upper normal range limit will be provided. Changes in bilirubin (direct, indirect, total) values will be described in the context of being associated with clinical events. The absolute value and the change from baseline in laboratory values will be summarized by treatment group. Baseline is defined as the last observed measurement prior to administration of any randomised study medication.
A DMC will be set up with primary responsibility to review the safety database on an ongoing basis. Refer to Section 3.1.1 for more details.

Interim analyses
For Cohort A, PK parameters AUC 0-12 , Cmax, C 12 of BI 207127 and AUC 0-24 , Cmax, C 24 of FDV will be calculated and provided to evaluate the systemic exposure of BI 207127 and FDV in CPB patients after receiving 400 mg BI 207127 compared to BI 207127 and FDV in CPA patients after receiving 600 mg BI 207127. Geometric mean of difference, sd, 90% CI will be calculated for these parameters between treatment arms. The results will be presented descriptively and no statistical testing will be performed. The lower bound of the 90% CI for the geometric mean test arm (Arm 1): control arm (Arm 2) of C 12 will be compared to 0.5 while the upper bound will be compared to 2. The boundaries were derived based on SOUND-C2 results. Whether the lower BI 207127 dose treatment in Arm 1 will provide proper exposure to CPB patients will be decided by assessment of the descriptive statistics listed above along with the efficacy and safety profile of the patients by an independent internal review committee (cf. Section 3.1.1). This committee will either select a dose for Cohort B or determine that Arm 3 should be conducted and the same analysis performed comparing Arm 1 to Arm 3.
The relationship between patient response and exposure will be investigated. HCV RNA change from baseline over time will be regressed on corresponding BI 201335 and BI 207127 concentrations to assess saturation of the exposure-response relationship.
Biochemical response and liver disease progression will be presented descriptively.

HANDLING OF MISSING DATA
All randomised patients who discontinue from the trial without reaching the SVR time points will be counted as treatment failures. Patients with missing SVR4 will be imputed by SVR12, if available. Patients with missing SVR12 will be imputed by SVR24, if available. Likewise, patients with missing SVR24 will be left as missing at the time of the interim database lock. Sensitivity analyses for missing SVR12 values due to early discontinued patients will be described in the TSAP.
It is not planned to impute missing values for safety data with the exception that missing AE start and end dates will be estimated (details to be written up in the TSAP).

RANDOMISATION
Cohort A: Eligible patients will be assigned to a treatment arm according the patient's Child Pugh score and the current screening stage of the trial. No randomisation is needed. All treatment arms will require a minimum of 8 females per arm.
Cohort B: Eligible patients will be randomly assigned to one of the two treatment regimens to avoid possible biases due to subjective patient selection. An allocation ratio of 1:3 for Arm 4 and Arm 5 is planned.
The randomisation list will be generated using a validated system, which involves a pseudorandom number generator to guarantee the reproducibility of the assignments. This randomisation list will be checked by an independent statistician and used by a third-party IRT system to assign randomisation numbers to eligible patients. Computed with proc power of SAS version 9.2 (assuming log normal and using exact method) Cohort B: Thirty patients will be recruited for the placebo group and 90 will be recruited for the active treatment group. The response rate for the placebo group is expected to be zero. For calculation purpose, it is set to 1%. The reference response rate for the active treatment group has not been set yet because no such treatment combination was tested on such patient population. The trial will have a power of 81% to detect, with a 2-sided alpha=0.05, an SVR12 incidence rate of 20% on active treatment group using Fisher's exact test. If the incidence rate reaches 30%, the power will be greater than 99% (Table 7.6: 2).

Protocol and amendments
The investigator should inform the sponsor immediately of any urgent safety measures taken to protect the study subjects against any immediate hazard, and also of any serious breaches of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract. As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Cover: The terms and conditions of the insurance cover are made available to the investigator and the patients via documentation in the ISF.

STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and approved by the respective IRB / IEC and CA according to national and international regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each patient (or the patient's legally accepted representative) according to ICH GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory and the informed consent and any additional patientinformation form retained by the investigator as part of the trial records. A signed copy of the informed consent and any additional patient information must be given to each patient or the patient's legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.

DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or sponsor's designees or by IRBs / IECs or by regulatory authorities. The quality assurance auditor will have access to all medical records, the investigator's trial-related files and correspondence, and the informed consent documentation of this clinical trial. Data entered in the eCRFs that are transcribed from source documents must be consistent with the source documents or the discrepancies must be explained. The investigator may need to request previous medical records or transfer records, depending on the trial; also current medical records must be available.
For eCRFs all data must be derived from source documents.

Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and regulatory inspection, providing direct access to all related source data / documents. CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and medical test results must be available at all times for review by the sponsor's clinical trial monitor, auditor and inspection by health authorities (e.g. FDA). The CRA / on site monitor and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by reviewing the documents described in Section 8.3.1.

Listedness
To fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates whether a particular AE is "listed", i.e. is a known side effect of the drug or not. Therefore a unique reference document for the evaluation of listedness needs to be provided. For the BI 207127 and FDV this is the current version of the IB (U06-1740 and U04-3332). For RBV this is EU SmPC. The current versions of these reference documents are to be provided in the ISF. No AEs are classified as listed for matching placebo, study design, or invasive procedures.

Expedited reporting to health authorities and IECs / IRBs
Expedited reporting of SAEs, e.g. SUSARs, to health authorities and IECs / IRBs, will be done according to local regulatory requirements. Further details regarding this reporting procedure are provided in the ISF. Individual patient medical information obtained as a result of this trial is considered confidential and disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient's personal physician or to other appropriate medical personnel responsible for the patient's welfare. Data generated as a result of the trial need to be available for inspection on request by the participating physicians, the sponsor's representatives, by the IRB / IEC and the regulatory authorities.

Evaluation of Pharmacokinetic Parameters
For the calculation of PK parameters, only concentrations within the validated concentration range will be used. The actual sampling times will be used. For pre-dose samples, the actual sampling time will be set to zero.
Noncompartmental PK parameters will be determined using WinNonlin or another validated program.
C max and t max : Individual C max and t max values will be directly determined from the plasma concentration time profiles of each subject. If the same C max concentration occurs at different time points, t max is assigned to the first occurrence of C max .
AUCs: The areas under the curve spanning various time intervals will be calculated using the linear up/log down algorithm. If a drug concentration is equal to or higher than the preceding concentration, the linear trapezoidal method will be used. If the drug concentration is smaller than the preceding concentration, the logarithmic method will be used.
Linear trapezoidal rule (t 2 > t 1 and C 2 ≥ C 1 ): The area of the trapezoid between the two data points (t 1 , C 1 ) and (t 2 , C 2 ) will be computed by: Logarithmic trapezoid rule (t 2 > t 1 and C 2 < C 1 ): The area of the trapezoid between the two data points (t 1 , C 1 ) and (t 2 , C 2 ) will be computed by: Estimation of λ z : Τhe apparent terminal rate constant λ z will be estimated from a regression of ln(C) versus time over the terminal log-linear drug disposition portion of the concentration-time profiles. The log-linear profiles, which include the regression line through the terminal points, will be checked via visual inspection, and it will be determined whether the regression appropriately represents the terminal slope. Only data points that describe the terminal log-linear decline will be included in the regression. A minimum of three points will be used in the determination of λ z . If the last concentration-time point increases, this time point may be included if the t 1/2 estimate is reasonable. If λ z is not determinable then consequently only parameters not requiring λ z will be reported. In addition, the lower (t λz,start ) and upper (t λz,end ) limit on time for values to be included in the calculation of λ z will be listed.  1 Administration of the study drug will be done under the supervision of the investigator or his designee after the pre-dose sample has been collected. The time elapsed since the last dose of FDV should be as close to 24 hours as possible and the last dose of BI 207127 should be as close to 12 hours as possible. 2 Pre-dose blood sample is collected within 10 minutes prior to the first drug administration of the day (nominal time 08:00). This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Blood sample collection time window 2 (hours relative to first drug administration of the day) 3 Sample 1 4 Sample 2 5 Sample 3 5 Sample 4 5 Sample 5 5 January -0.05 (pre-dose) 0.5 -1.5 3 -4 5.5 -6.5 8 -9 February -0.05 (pre-dose) 1 -2 3.5 -4.5 6 -7 8.5 -9.5 March -0.05 (pre-dose) 1.5 -2.5 4 -5 6.5 -7.5 9 -10 April -0.05 (pre-dose) 0.5 -1.5 3 -4 5.5 -6.5 8 -9 May -0.05 (pre-dose) 1 -2 3.5 -4.5 6 -7 8.5 -9.5 June -0.05 (pre-dose) 1.5 -2.5 4 -5 6.5 -7.5 9 -10 July -0.05 (pre-dose) 0.5 -1.5 3 -4 5.5 -6.5 8 -9 August -0.05 (pre-dose) 1 -2 3.5 -4.5 6 -7 8.5 -9.5 September -0.05 (pre-dose) 1.5 -2.5 4 -5 6.5 -7.5 9 -10 October -0.05 (pre-dose) 0.5 -1.5 3 -4 5.5 -6.5 8 -9 November -0.05 (pre-dose) 1 -2 3.5 -4.5 6 -7 8.5 -9.5 December -0.05 (pre-dose) 1.5 -2.5 4 -5 6.5 -7.5 9 -10

Footnotes:
1 Pseudo-randomised scheme based on patient's birth month. PK samples are collected at different time windows depending on birth month of patient as specified in the table above. 2 For collection of PK sub-study samples, patients will be assignment via IRT at Visit 2 to one of the following collection schedules: Day 1 and Day 8; Day 1 and Week 4; or Day 1 and Week 16. 3 Administration of the study drug will be done under the supervision of the investigator or his designee after the pre-dose sample has been collected. The time elapsed since the last dose of FDV should be as close to 24 hours as possible and the last dose of BI 207127 should be as close to 12 hours as possible. 4 Pre-dose blood sample (Sample 1) is collected within 10 minutes prior to the first drug administration of the day (nominal time 08:00). 5 Post-dose blood samples (Sample 2 to Sample 5) are collected at any time within the collection window and are relative to the first drug administration of the day (nominal time 08:00).

Boehringer Ingelheim Clinical Trial Report BI Trial No.:
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Introduction and scope
Drug-induced skin reactions (rash and photosensitivity reactions) have been reported with the use of FDV and BI 207127 combination therapy. The aim of this plan is to provide guidance for the management of suspected or confirmed drug-induced skin reactions. This section is not intended to provide guidance for skin events with known aetiologies in which a drug-relatedness has been ruled out (e.g. measles, skin cancer, scabies, etc).
For the management of skin rash cases refer to Section 10.2.3 and of photosensitivity reactions refer to Section 10.2.4. Skin rash cases may be reported as rash, or other specific diagnoses, e.g. urticaria, exanthema, etc. Photosensitivity reactions may be reported as phototoxic reaction, sunburn, etc.

General measures for skin protection
Patients should be instructed to protect any uncovered skin area (including hands, face and lips) from sun-or UV-light exposure using sun-blocker cream and lip balm with an SPF ≥50 providing UV-A and -B protection during treatment period on a daily basis. Patients should avoid unnecessary or prolonged exposure to sunlight and wear protective clothing, sunglasses and hats in addition to sun-block. It is recommended to avoid direct sun exposure as much as possible. Tanning booths must be avoided during treatment period.
All patients should be instructed to report all skin reactions and be seen by study medical staff as soon as possible. If a patient has photosensitivity reaction, the patient should be instructed to be even more consistent with the measures described earlier and stay away from windows as much as possible.

Drug-induced skin rash
These skin reactions may manifest with a multitude of clinical presentations and variable severity, ranging from mild rashes to life-threatening reactions such as Steven-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP). Medium to high potency topical corticosteroids (potentially combined with oral antihistamines) should be prescribed as early as possible. Other non-prescription remedies such as oatmeal baths may be used to provide temporary relief of skin sensitivity and pruritus.
The need for UV light protection should be reinforced (Section 10.2.2).
Treatment with study medication may be continued without interruption. Moderate: The patient should have a detailed photo-documentation of the skin, preferably prior to the administration of any therapy. The subject should be seen by a dermatologist as soon as possible, but no later than 72 hours for diagnosis, confirmation of severity and treatment. A non-progressive moderate skin rash, confirmed by the dermatologist should be closely and frequently monitored at the investigator's discretion taking into account recommendation by dermatologist.
Medium to high potency topical corticosteroids combined with oral antihistamines should be prescribed as early as possible, but preferably after detailed photo-documentation of the skin lesions. Other non-prescription remedies such as oatmeal baths may be used to provide temporary relief of skin sensitivity and pruritus. Systemic corticosteroids may be applied if deemed clinically necessary.
The need for UV light protection should be reinforced (Section 10.2.2).
These reactions do not require discontinuation of study treatment. Severe: Medium to high potency topical corticosteroids combined with oral antihistamines should be prescribed as early as possible. Systemic corticosteroids may be applied if deemed clinically necessary. Subjects should have a detailed photo-documentation of the skin and referred to a dermatologist immediately but no later than 24 hours for diagnosis, confirmation of severity, treatment and skin biopsy. These patients must be closely monitored.
The decision to stop or continue the study treatment should be based on the clinical judgement of the investigator taking into account the recommendation by the dermatologist.
Potentially Life-Threatening Patients with potentially life-threatening skin reactions should be referred immediately for emergency care. Subjects should stop all study medications. Patients should be seen by a dermatologist for diagnosis, confirmation of severity, treatment and skin biopsy. The patient should be followed up as appropriate.

Photosensitivity reactions
Photosensitivity reactions typically resemble exaggerated sunburn with erythema and edema often occurring within minutes to hours of sun exposure, and may involve vesiculation and desquamation in some cases. These photosensitivity reactions affect exclusively the sun-exposed skin areas; therefore, a clear delimitation of the erythema by garments is typically observed.

Definition of severity of photosensitivity reactions
Mild: Any localized superficial 1st degree burn: erythema and edema, peeling.
Severe: Extensive or full face 2 nd degree sunburn with blistering, serous exudates.

Management guidelines for photosensitivity reactions
Symptomatic management of photosensitivity reaction of any severity includes cool compresses, soothing lotions, topical corticosteroids and/or systemic non-steroidal antiinflammatory drugs (NSAID) or antipruritics. The need for UV light protection should be reinforced (Section 10.2.2).

Mild:
Treatment with study medication may be continued without interruption.

Moderate:
The patient should have a detailed photo-documentation of the skin and should be seen by a dermatologist as soon as possible but no later than 72 hours for diagnosis, confirmation of severity, and treatment. Confirmed moderate photosensitivity reactions should be closely and frequently monitored at the investigator's discretion taking into account recommendation by dermatologist. These reactions do not require study treatment discontinuation.

CHILD-TURCOTTE-PUGH CLASSIFICATION
Child-Turcotte-Pugh class and score (R99-1243 and R10-2440) employ five clinical measures of liver disease in the setting of liver cirrhosis: bilirubin, albumin, blood coagulation (as determined by prothrombin time [PT] or by INR), evidence of ascites, and evidence of encephalopathy.
To calculate the score, the limits presented in the  This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

Criteria for safety:
Safety endpoints to be assessed in this trial include: AEs, including Division of Acquired Immunodeficiency Syndrome (DAIDS) grades, AEs leading to treatment discontinuation of all trial medications, SAEs, Events of liver disease progression, Laboratory test abnormalities by DAIDS grades, Change in laboratory test values over time.

Statistical methods:
No hypothesis testing will be performed. The results will be presented descriptively. A null hypothesis of equal response rate of SVR12 between the treatment and placebo group will be tested by Fisher's exact test. Time to achieving HCV RNA undetected and time to virologic failure will be analyzed using the Cox model. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.  This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

Footnotes:
1 One mandatory and one optional pharmacogenomic (PG) samples will be collected at Visit 2.
2 Serum pregnancy tests for females of childbearing potential will be performed at all marked study visits. At Visit 2, an additional urine (dipstick) pregnancy test will be performed for all females and only those female patients with a negative result will receive study medication. When visits are more than 4 weeks apart, female patients of childbearing potential will be provided with urine pregnancy tests to perform monthly pregnancy tests at home until 7 months after the last dose of ribavirin. Urine pregnancy test for male participants' female partners of child-bearing potential will be provided to perform monthly testing until 7 months after the last dose of ribavirin. Male patients will provide and ensure pregnancy testing of his female partner. It is the responsibility of the investigator to remind the male patients of this.
BI is investigating the safety and efficacy of BI 207127, an oral, specific and reversible non-nucleoside HCV specific ribonucleic acid (RNA)-dependent RNA polymerase inhibitor, in combination with faldaprevir (FDV), a potent, oral HCV NS3/4a protease inhibitor, and RBV in patients with moderate hepatic impairment. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. 1241.21 Part 2 (SOUND-C 2) is a 5-arm, open-label, randomized, phase 2b study evaluating efficacy and safety of interferon-free oral combination regimens of BI 207127 and FDV with and without RBV for up to 40 weeks of treatment. A total of 362 treatment-naïve HCV GT1 patients were randomized and treated in 5 treatment arms. In the combined interim analysis by viral subtype (1a vs. 1b), the highest SVR12 (85%) was achieved with the twice daily (BID) 28-week regimen in GT1b infected patients (Table 1.2: 1). This is the dose and target population to be studied in the phase 3 program starting in parallel. In contrast, GT1a, and especially the sub-population of 1a_non-CC achieved sub-optimal SVR12 rates ranging from 42% to 0% (Table 1.2: 1). Among GT1b patients with compensated liver cirrhosis in SOUND-C2 randomized to RBV-containing regimens, the SVR rate was between 57% and 80%. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

RATIONALE FOR PERFORMING THE TRIAL
Patients with compensated liver cirrhosis have been included and successfully treated in SOUND-C2 with BI 207127 in combination with FDV and RBV. Trial 1241.30 will assess this combination treatment in patients with decompensated cirrhosis, a patient population with a high unmet medical need and no available antiviral treatment options, as PegIFN is contraindicated. This study will aim to define an interferon-free regimen that may offer an antiviral treatment option for patients chronically infected HCV GT1b with moderate hepatic impairment (CPB).

TRIAL OBJECTIVES
The objective of Cohort A is to evaluate the safety and pharmacokinetic (PK) profile of BI 207127 (potentially two doses) in combination with 120 mg once daily (q.d.) FDV and weight-based RBV in a small group of patients with moderate hepatic impairment (CPB) compared to patients with mild hepatic impairment (CPA) to define the BI 207127 dose to be used in Cohort B.
The objective of Cohort B is to assess efficacy, safety, and pharmacokinetics of 24-week treatment of the BI 207127 dose selected in Cohort A in combination with 120 mg once daily (q.d.) FDV and weight -based RBV in a larger group of chronically infected HCV GT1b patients with moderate hepatic impairment (CPB).

BENEFIT -RISK ASSESSMENT
Patients participating in this study have a high unmet medical need with their only available treatment option for decompensated cirrhosis being liver transplantation. Once cirrhosis has developed, mortality is approximately 10% over the subsequent 10 years. Clinical hepatic decompensation occurs in 30% of patients with cirrhosis and 5-year survival declines to about 50% (P97-2059).
The inclusion of treatment naïve patients is supported by data from the SOUND-C2 trial, the largest phase 2 trials with all-oral HCV treatment performed to date. Efficacy and safety in patients with compensated liver cirrhosis was studied in SOUND-C2 and the BI 207127 600 mg b.i.d. dose regimen demonstrated the best benefit/risk ratio in this population. Among GT1b patients with cirrhosis randomised to the b.i.d. group, the SVR12 rate was 80% and the rate of AEs leading to discontinuation of treatment was similar to the overall patients in same arm (approximately 8%). Most AEs were of mild intensity; the most common AEs were rash, photosensitivity reactions, asthenia, fatigue, jaundice (isolated indirect hyperbilirubinemia), nausea, vomiting and diarrhoea.
Many patients with progressive liver cirrhosis have been exposed to PegIFN/RBV in the past. Thus, to secure sufficient enrolment in this important study for a high-medical need population treatment experienced patients (prior relapse, interferon intolerant, and [allowed in Cohort A only] prior partial response) will also be included (cf. Section 3.3.2 for definitions).
This trial will include a PK sub-study for Cohort B to further assess the BI 207127 b.i.d. dose selected in Cohort A in a larger group of CPB patients. Refer to Section 4.1.3 for selection of dose rationale. Rash and photosensitivity reaction were reported in 20-30% of patients. Rash was commonly reported as maculo-papular skin reaction on the trunk and extremities, while photosensitivity reactions were described as exaggerated sunburns in hands, face or any other sun-exposed skin area. Among patients who received 600 mg b.i.d. BI 207127 in combination with FDV and RBV, all skin reactions were mild. There were no moderate, severe, or serious skin reactions or discontinuation of treatment due to skin events reported. Serious rash and photosensitivity reactions were only reported with higher BI 207127 dose (600 mg tid) and none of the cases were considered life-threatening. There were no cases of Stevens-Johnson, erythema multiforme, toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and systemic symptoms (DRESS) reported in any of the BI 207127-FDV combination trials to date. However, DRESS has been reported in FDV program in combination with PegIFN/RBV at 120 and 240 mg QD doses. Rash and photosensitivity reactions will be carefully monitored and managed with a detailed dermatologic management plan (cf. Appendix 10.2 and ISF). The dermatologic plan includes precautionary measures to restrict exposure to sun and artificial ultraviolet (UV) light and instructions to decrease the dose of BI 207127 in specific cases. Every skin reaction fulfilling the criteria as protocoldefined significant AEs will be reported in an expedited manner similar to SAEs and will be subject to review by a dermatological adjudication committee (cf. Sections 3.1.1.2 and 5.2.2).
GI events such as nausea, vomiting and diarrhoea were reported in BI 207127-FDV combination trials. The highest risk of vomiting in previous trials was observed during the first 2 days of treatment (17% cumulative risk of vomiting during the first 2 days) (U11-3471-01). There was an association between the high BI 207127 exposure at Day 1 and the risk of GI events (U11-3472-01). This may have been due to the administration of an induction dose of BI 207127 (1200 mg, 2 times the individual dose) on the morning of first day of dosing. Since there was no virologic benefit associated with the induction dose (no association between BI 207127 exposure and the initial HCV RNA decay kinetics), this induction dose will not be used in this trial. As such, the risk of vomiting during the first 2 days of treatment in this trial may be lower than in previous trials. PegIFN-free regimens of BI 207127 in Trial 1241.21 Parts 1 and 2 did not cause any relevant changes from baseline in laboratory parameters, except for a continuous drop in alanine aminotransferase (ALT) in all patients, a decrease in haemoglobin (Hb, consistent with RBV treatment) and increase in total bilirubin due primarily to increases in the unconjugated fraction (a known clinically benign effect of FDV treatment). Up to 25% of patients experienced jaundice due to increases in unconjugated bilirubin without concomitant increases in liver function tests (LFTs) or any sign of liver toxicity. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. 5 days of treatment interruption and was re-challenged with BI 207127-FDV-RBV without recurrence of neutropenia. Mean absolute neutrophil count in patients during the course of treatment remains similar to the levels observed at baseline in the completed and ongoing Phase 3 trials with BI 207127+FDV+RBV. At this stage, it is unclear whether these events are related to the study drugs, underlying disease (hepatitis) or other conditions. Of note, only approximately 10% of patients experienced anaemia (defined as Hb > 10g/dL) receiving the oral combination in SOUND-C2 compared to 36% of receiving telaprevir with PegIFN/RBV (R12-0262) or 49% of receiving boceprevir with PegIFN/RBV (R12-0263). This may be explained by the lack of PegIFN and its myelosuppressive effect which enhances the negative effect of RBV in the regimen.
The evaluation of the ECGs in one phase 1b/2 trial in Japan (trial 1241.25) suggested an increase in the QTc of 10 to 20 ms compared to baseline for patients receiving a combination of the three active drugs. However, the trial was not designed to evaluate QT effects, but rather collected the ECG data in a routine manner without controlling for factors known to affect the QT interval and introducing a potential bias in the assessment. Of note, there were no patients in the trial 1241.25 with abnormal QTc interval defined according to current standards as >450 ms for males and >470 ms for females. Based on an extensive phase 1-3 clinical database of subjects receiving faldaprevir (approximately 3355 subjects) and BI 207127 (approximately 600 subjects), there have been no reports of unexplained serious arrhythmias, QT prolongations, torsades de pointes or sudden deaths. A thorough QTc trial with faldaprevir only (trial 1220.16) demonstrated no QT prolongation in a manner that suggested any clinically relevant effects on cardiac repolarization as per the FDA and EMA guidance. Another thorough QTc study with faldaprevir and BI207127 combination therapy is currently planned to further evaluate any potential for QTc prolongation.
Based on the current understanding that cirrhotic patients require longer treatment durations and the lack of substantial clinical data in cirrhotic patients treated for 16 weeks in phase 2, patients with compensated cirrhosis will receive treatment for 24 weeks.
A potential risk with a PegIFN-free regimen is the selection of mutations conferring resistance to both compound classes which may limit future treatments options. However, it is currently not known if HCV resistant variants are archived and persist. Therefore it might be possible to retreat patients that had selected for resistance mutation on a given DAA(s) with the same regiment once the variants are no longer detectable. Additionally, major resistant variants associated with the use of BI 207127, such as P495L, would only confer resistance to another thumb site-1 nonnucleoside NS5B inhibitor. There are currently a number of DAAs with different MOA in development (including: thumb site-2 NS5B inhibitors, NS5A inhibitors, nuclotide NS5B inhibitors, cyclophlin inhibitors, etc.). Future treatment options will be expanded once some of these agents become available to patients in the near future. To maximize the chance to achieve SVR and reduce the chance of emergence of resistance only GT1b patients (which have the highest rate of response to this regimen) will be included.
Patients with decompensated cirrhosis randomised to placebo will not receive benefit from participating in the trial. However, the knowledge gained from this treatment group will be invaluable in understanding the emergence of AEs in decompensated cirrhotic patients during This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. placebo treatment, and thus understanding of the safety profile of the tested regimen in this population. These patients currently have no HCV treatment options and participation in this trial will not compromise future treatment options for these patients. Patients randomised to receive placebo will be given the option of receiving Arm 5 treatment after completion of 24 weeks, if still eligible for treatment (cf. Section 3.1). In addition, an independent Data Monitoring Committee (DMC) will be established (cf. Section 3.1.1.1) and all patients will be frequently monitored. If the risk-benefit ratio changes upon favourable on-treatment clinical data in the active treatment arm 5 of Cohort B, the DMC may recommend that placebo arm patients are offered the option of receiving active treatment prior to completion of 24 weeks of placebo.
Other risks to the patients are the risks inherent to any clinical trial, such as unexpected adverse clinical or laboratory events. Patients will be closely monitored for AEs and rebounds of plasma HCV RNA.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and follow-up of laboratory abnormalities of selected liver laboratory parameters to ensure patients' safety.
Given the good safety profile of this PegIFN-free combination treatment, coupled with rapid and potent antiviral activity observed so far, the sponsor assesses benefit risk relationship in this study as positive, and the knowledge gained will outweigh the potential risk for this patient population with an unmet medical need.

OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre and multi-staged trial. Interim data from Cohort A (open label) will be used to select the BI 207127 dose to be assessed in Cohort B (double-blind, and placebo controlled, randomised with a 1:3 ratio for Arm 4 and Arm 5) CPB patients.     Forty eight patients in Cohort B will be assigned via Interactive Response Tool (IRT) to participate in a PK sub-study (cf. Section 5.5).
"On-treatment" AEs are those AEs that begin during treatment with the trial medications or within 28 days of the End of Treatment (EOT) visit. For more details on safety assessments in this trial, cf. Section 5.2 and Section 7.3.3.
Upon EOT visit patients will complete an additional 96 12 weeks follow-up (FU) period. Individual patient participation is concluded when the patient has completed the last planned visit.
The end of the trial is defined as "last patient out", i.e. last scheduled visit completed by last patient.

Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim.
Boehringer Ingelheim (BI) will appoint a Trial Clinical Monitor (TCM), responsible for coordinating the activities required in order to manage the trial in accordance with applicable regulations and internal standard operating procedures (SOPs), directing the clinical trial team in the preparation, conduct, and reporting of the trial, order the materials as needed for the trial, ensures appropriate training and information of Local Clinical Monitors (CML), Clinical Research Associates (CRAs), and investigators of participating countries.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs. For these activities, a Trial Data Manager and a Trial Statistician will be appointed.

Boehringer Ingelheim Clinical Trial Report BI Trial No.:
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined according to BI SOPs. A list of responsible persons will be given in the Clinical Trial Master File (CTMF) document.
The organisation of the trial in the participating countries will be done by the respective local BI-organisation (Operative Unit (OPU)) or by a Contract Research Organisation (CRO) with which the responsibilities and tasks will have been agreed and a written contract filed before initiation of the clinical trial. In each OPU participating in this study, a CML will be appointed responsible for coordinating the activities required in order to manage the trial in accordance with applicable regulations and internal SOPs in the countries covered by the respective BI OPU.
A Co-ordinating Investigator will be nominated to coordinate investigators at different sites participating in this multicentre trial. Tasks and responsibilities for the Co-ordinating Investigators will be defined in a contract filed before initiation of the trial.
Documents on participating (Principal) investigators and other important study personnel, especially their curricula vitae, will be filed in the CTMF.
Details of the trial supplies including responsible institutions are given in Section 4 of this protocol.
The ISF will be maintained at the sites as required by local regulation and BI-SOP. A copy of the ISF documents will be kept as an electronic CTMF document according to BI SOPs.
A central laboratory service and IRT will be used in this trial.

Data Monitoring Committee (DMC)
The study will have a DMC independent from the sponsor. The purpose of the DMC is to ensure that the welfare of patients participating in this trial is maintained by:  Monitoring the trial for possible untoward harmful effects or unexpected frequency of adverse safety events of study drugs;  Assessing whether the goals of the trial are unlikely to be achieved, based on emerging data.
The DMC will evaluate the unblinded accrued patient data in order to recommend whether the trial or program should continue, be modified or stopped for safety concerns or ethical reasons. The DMC will review pertinent trial data, including deaths, serious adverse events (SAEs) and AEs, laboratory data and efficacy markers (HCV RNA). Unless specified differently in the DMC charter, it is expected that the first DMC meeting will occur approximately 2 months after the first patient has entered the trial and then every 3-4 months thereafter, with more frequent reviews as deemed necessary by the DMC or the sponsor. The DMC will review Cohort A Week 4 data prior to the start of Cohort B. All materials provided to the DMC are confidential. The tasks and responsibilities of the DMC will be filed in a charter before initiation of the trial and will contain written operating procedures.
The DMC will maintain written records of all its meetings. Sponsor will remain blinded to these ongoing data reviews.

Rash and Photosensitivity Adjudication Committee (RPAC)
The study will include an independent committee of dermatology experts responsible for evaluation of protocol-defined significant skin AEs (cf. Section 5.2.2.1). The tasks and responsibilities for this committee will be established by contract before initiation of the trial and will contain written operating procedures.

Internal independent data review committee
The study will include a committee of sponsor members that are independent from the trial team. This committee will evaluate interim analysis data, including PK data, to select the BI 207127 dose for Cohort B. Refer to Section 7.3.4 for interim analysis plan and dose selection criteria.
The first interim analysis will be performed on Arm 1 and Arm 2 data up to Week 4 for submission to the committee. The BI 207127 dose for Cohort B will be selected or it will be determined that it is necessary to conduct Arm 3. If Arm 3 is needed, a second interim analysis will be performed on Arm 1 and Arm 3 data up to Week 4 for submission to the committee for Cohort B dose evaluation. Thus, randomisation in Cohort B will begin based on the Week 4 interim data of Cohort A.
The tasks and responsibilities for the Internal Independent Data Review Committee will be established before initiation of the trial and will contain written operating procedures.

DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF CONTROL GROUPS
The CPB patient population was selected because these patients, despite having the highest urgency for treatment, currently have no HCV treatment options and therefore have a high unmet medical need. Patients with poorly controlled ascites are excluded due to common fluctuations in ascites i.e. the distribution volume which could interfere with the PK analysis of both compounds.
The CPA control group was chosen because there is limited PK data in CPA patients in the phase II program for BI 207127.
Due to the low SVR rate seen in phase 2 studies in GT1a patients (cf. Table 1.2: 1), these patients are excluded from the program until a more effective treatment regimen has been identified.
The study is double-blind in order to eliminate the reporter/observer bias for the assessment of safety and of the treatment duration on efficacy between treatment Arm 4 and Arm 5.
The Arm 4 placebo group will allow comparison of safety between active treatment and placebo. It will be informative to assist in the identification of AEs related to active triple therapy versus symptoms associated with the underlying diseases and co-morbidities in CPB patients. The CPB placebo group is ethically acceptable since this population currently does not have an antiviral treatment option and their participation will be closely monitored by the DMC. The duration of the 24 week placebo treatment may be potentially shortened and active treatment offered, if results from ongoing trial change the risk benefit ratio as evaluated by the DMC.
The smaller sample size of the PBO group was selected as a compromise between the expectation of spontaneous symptoms and (S)AE of patients due to underlying severe liver disease and the withholding of active treatment from such patients with high treatment need. It is recognised that double-blinding of such a treatment group will be challenging because of multiple laboratory test changes, specifically viral load, bilirubin, liver enzymes and hematologic changes that are related to the administration of active triple therapy vs. no such changes in patients in Arm 4. Nevertheless, extensive efforts will be made to overcome these difficulties through blinding selected laboratory tests for Arm 4 and Arm 5 to investigator, patient and sponsor (cf. Section 4.1.5.1).
PegIFN is not used in the trial and therefore, contraindications to use of PegIFN do not apply as exclusions in the eligibility criteria. Patients with retinopathies, history of psychiatric diseases, autoimmune diseases, thrombocytopenia and other conditions that contraindicate the use of PegIFN, may be entered in the study as long as their co-morbidities are considered clinically stable and with appropriate treatment, if necessary. This will ensure that the trial population is as representative as possible of the patient population seen in clinical practice.
Extended 96 12-week FU period will allow assessment of the persistence of the virological response, assessment of the progression of the liver disease and resistance profile of HCV over time. In case of re-detection of HCV RNA during the FU period, assessment will be made whether this represents a relapse or a subsequent re-infection.

SELECTION OF TRIAL POPULATION
A sufficient number of patients will be screened for the trial to ensure that approximately 165 30 patients are randomised to trial treatment (15 patients in each treatment Arm 1, Arm 2, and Arm 3; 30 patients in Arm 4, and 90 patients in Arm 5).
Demographic information, including patient gender, race and ethnicity, will be collected at screening.
Treatment Arm 1, and Arm 2 and Arm 3 will be stratified by gender with a minimum of 8 females per arm (cf. Section 7.5).
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all centres when such a number of patients has been screened that it is anticipated that a sufficient number of patients will be randomised to trial treatment. This process of competitive screening will be carried out independently for each screening stage (cf. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. For Cohort A, patient replacement will be permitted (i.e. those patients who were assigned to a treatment group but did not receive any study drug will be replaced and those that discontinued study drug prior to Week 4 may be replaced as needed to ensure sufficient PK sample size).
For Cohort B, patients assigned to a treatment group who discontinue from the trial after start of treatment will not be replaced (i.e. those patients who were assigned to a treatment group but did not receive any study drug will be replaced to ensure that patients will receive study drug in each treatment group).
Re-screening of patients will not be permitted.
A log of all patients included into the study (i.e. having given informed consent) will be maintained in the ISF at the investigational site irrespective of whether they have been treated with investigational drug or not.

Main diagnosis for study entry
This study will be performed in treatment naïve and experienced patients (see inclusion criteria 4 for definitions) with chronic HCV infection of GT1, sub-GT1b virus only.

Inclusion criteria
1. Chronic HCV infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening in addition to at least one of the following: a) positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening b) liver biopsy consistent with chronic HCV infection c) history of elevated ALT levels at least 6 months prior to screening 2. HCV infection, confirmed by genotypic testing at screening, of GT1, sub-GT1b virus. 3. HCV viral load ≥ 1,000 IU/ml at screening 4. Previous treatment status must be one of the following: a) Treatment naïve: defined as patients who have never been previously treated with any interferon, with an investigational/approved DAA or any other HCV treatment regimen. b) Treatment experienced to an approved PegIFN/RBV regimen with prior relapse: defined as HCV RNA level > 25 IU/mL during the post-treatment period in patients who had plasma HCV RNA level undetected at end of all treatment c) Treatment experienced interferon intolerant: defined as patients who had to stop a previous PegIFN/RBV regimen before week 12 of treatment due to safety or tolerability issues.

Boehringer Ingelheim Clinical Trial Report BI Trial No.:
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. d) (Allowed in Cohort A only) Treatment experienced to an approved PegIFN/RBV regimen with prior partial response: defined as HCV RNA level > 25 IU/mL at end of treatment in patients who had HCV RNA drop by ≥2 log10 from baseline at Week 12. e) Treatment experienced to interferon not as part of an approved PegIFN/RBV regimen. 5. Liver cirrhosis defined as at least one of the following: f) Metavir Grade =4 or Ishak Grade ≥5 on liver biopsy g) liver stiffness of ≥13 kPa on fibroscan 6. No evidence of liver cancer in an appropriate imaging study (e.g., ultrasound, CT scan, or magnetic resonance imaging [MRI]) within last 3 months prior to randomisation. 7. No active variceal bleeding or large varices in an upper GI endoscopy, as part of standard of care in patients with liver cirrhosis, performed within 12 months prior to randomization. Note: Patients may be included if they have a history of variceal bleeding or a history of large varices, if properly treated and monitored. 8. Age 18 to 75 years (inclusive) 9. Female patients with a negative urine pregnancy test (dipstick) at Visit 2 prior to randomization: a) with documented hysterectomy, b) who have had both ovaries removed, c) with documented tubal ligation, d) who are post-menopausal with last menstrual period at least 12 months prior to screening, or e) of childbearing potential with a negative serum pregnancy test at screening and Day 1, who, if sexually active, agree to use two non-hormonal methods of birth control from the date of screening until 7 months after the last dose of RBV. Patients must agree not to breast-feed at any time from the date of screening until 7 months after the last dose of RBV. Accepted methods of contraception in the study include diaphragm with spermicidal substance, cervical caps, intrauterine devices and condoms. Note: Systemic hormonal contraceptives may not be as effective in women taking BI 207127/FDV combination therapy and are not accepted methods of contraception in the study. Male patients: a) who are documented to be sterile, or b) who are without pregnant female partner(s) and consistently and correctly use a condom while their female partner(s) (if of child-bearing potential) use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of RBV. It is in the responsibility of the male patient to ensure that his partner(s) is not pregnant prior to screening into the study or becomes pregnant during the treatment and the observation phase. Female partners of childbearing potential should 20. Received silymarin (milk thistle), glycyrrhizin, Sho-saiko-to (SST) or any medication listed in a restricted medication list provided in ISF within 28 days prior to randomisation, with the exception of parenteral analgesics used during liver biopsy procedure. 21. Known hypersensitivity to any ingredient of the study drugs 22. Hb < 11 g/dL for women and men 23. Absolute neutrophil count < 1,000 cells/mm 3 24. Creatinine clearance ≤ 50 ml/min 26. MELD score > 20 27. Platelet count < 40,000 cells/mm 3 28. Patients who have been previously treated with an investigational or approved DAA. 29. Patients classified as Child Pugh C (score 10-15 points)

3.3.4
Removal of patients from therapy or assessments

Removal of individual patients
Patients have the right to withdraw from the study at any time without the need to justify the decision. The investigator has the right to remove patients from the study for non-adherence. Furthermore, patients' treatment should be discontinued early due to lack of viral response or other reasons (as described below). The sponsor reserves the right to terminate a patient from the trial for non-adherence. It is understood that an excessive rate of withdrawals can render the study results uninterpretable; therefore unnecessary withdrawal of patients should be avoided. Patients who discontinue their treatment early will be followed throughout the course of the study and undergo all study required procedures as defined in Section 6.2.3.
If a patient is suspected to be, or becomes, pregnant during treatment (including rescue treatment), the patient must inform the investigator immediately and stop taking all study drugs. For the reporting, follow up and documentation of pregnancy cases refer to Section 5.2.2.2. These patients will be followed throughout the course of the study as defined in Section 6.2.3. If a female partner of a male patient becomes pregnant during treatment (including rescue treatment), the patient should inform the investigator immediately and investigator must inform the sponsor. If a male subject reports the pregnancy of his female partner to the investigator, the pregnancy must be reported to the sponsor AND followed up. Part B of the pregnancy monitoring form should be submitted upon outcome of the pregnancy. The decision on whether to discontinue the patient treatment must be made by physician investigator based on the local RBV label and his clinical judgment. The details of female partner's pregnancy will neither be tracked nor recorded in the trial documentation.

Identity of BI investigational products and comparator products
The following tables summarise the information about the investigational, non-investigational medicinal products, and comparator products as used in this trial.

Method of assigning patients to treatment groups
After assessment of all entry criteria, the investigator or designee at the site will follow the process outlined in the ISF to assign the patient to a treatment group at visit 2. This will involve the use of an IRT system which will assign eligible patients to a treatment arm according to current screening stage of the trial (cf. Figure 3.1: 2). Treatment group assignment will be recorded on the eCRF and source document. For statistical features of the treatment allocation process refer to Section 7.5.

Selection of doses in the trial
The doses selected to be evaluated in this trial are BI 201727 400 mg b.i.d. or BI 201727 600 mg b.i.d. along with FDV 120 mg q.d. and weight-based RBV.
In SOUND-C2, the doses of BI 207127 600 mg b.i.d. in combination with FDV 120 mg q.d. and RBV demonstrated a favourable safety profile with a low rate of discontinuations due to AEs, and the absence of moderate or severe skin events or discontinuations due to skin events (rash or photosensitivity).
Safety and efficacy results from SOUND-C2 in patients with compensated liver cirrhosis were favourable (cf. Section 2.3). However, a 2-fold increase in exposure of both FDV and BI 207127 in cirrhotic patients compared to non-cirrhotic patients was observed. As such, it is expected that FDV and BI 207127 exposure in CPB patients will be at least 2-fold higher than that of non-cirrhotic patients. Therefore, a 400 mg b.i.d. dose of BI 207127 in combination with 120 mg FDV q.d. and RBV in CPB cirrhotic patients is expected to achieve similar or higher exposure than 600 mg b.i.d. dose group in non-cirrhotic patients. If this is not the case and exposure is lower, Arm 3 will be conducted to test the 600 mg b.i.d. dose in CPB patients before the start of Cohort B. The dose for Cohort B will be selected and released by the internal data review committee.
PK / pharmacodynamic (PD) analyses performed in SOUND-C1 and 2 indicate that a PK exposure higher than the one achieved with BI 207127 600 mg b.i.d. does not provide an efficacy benefit in target patient population but rather negatively affects the safety profile. In particular, PK trough levels achieved with the 600 mg b.i.d. dose of BI 207127 were already beyond the exposure-response threshold for GT1b virus. BI 207127 doses higher than 600 mg b.i.d. did not increase viral response but impacted negatively on the safety profile (more severe skin and GI events).
No BI 207127 induction dose will be used (cf. Section 2.3).
Based on the current understanding that cirrhotic patients require longer treatment durations and the lack of substantial clinical data in cirrhotic patients treated for 16 weeks in phase 2, patients in this trial are planned to receive treatment for 24 weeks only.

Drug assignment and administration of doses for each patient
For Cohort A (Arm 2 and Arm 3 only), once an investigator establishes that a CPB patient meets all entry criteria, the investigator will send electronically to the TCM a written request for assignment of the treatment visit date. The investigator will be required to receive written approval from the sponsor before confirming the appointment for the treatment visit with the patient (cf. ISF for request/approval form to be used).
The investigator will make a randomisation call to IRT to randomise/assign an eligible patient. Dispensing of study drugs will begin at Visit 2.
IRT will assign the medication number(s). The assigned medication number(s) must be entered in the eCRF, and the corresponding medication unit(s) must be given to the patient. Each medication unit will have a unique medication number and more than one medication unit may be assigned by IRT dependent on the visit schedule. The visits at which medication is dispensed to patients are specified in the Flow Chart. For details please refer to the ISF.
FDV (or matching placebo) loading dose on Day 1 will include an additional 120 mg capsule for a total of 240 mg for the first active dose. FDV (or matching placebo) should be taken q.d. in the morning together with the morning doses of BI 207127 and RBV (or matching placebo), and together with food. The evening doses of BI 207127 and RBV (or matching placebo) should be taken together with food 12 hours after the morning dose.
Patients in all groups are planned to receive study drugs (active or placebo) for a total of 24 weeks. Early treatment discontinuation rules for lack of viral response or other reasons are defined for all groups (cf. Section 3.3.4.1).
If either of FDV or BI 207127 needs to be discontinued early all three trial medications need to be discontinued. Dose reductions of FDV or BI 207127 are not allowed in this trial. The dose of RBV may be reduced or RBV may be temporarily discontinued due to anaemia (cf. Section 4.2.1) while still continuing FDV and BI 207127 treatment. However, RBV should be reintroduced even at a reduced dose as soon as clinically possible.
Treatment interruptions must be avoided as much as possible. If the combination therapy is interrupted due to an unavoidable reason, it should restart no later than 3 days after the treatment was interrupted. Treatment interruptions for more than 3 days are not allowed and in these cases, treatment has to be stopped permanently and an EOT visit should be performed (cf. Section 6.2.3).

Blinding
Cohort A Treatment Arm 1, and Arm 2, and Arm 3 will be open-label.

Cohort B
Study medications will be administered double blinded in treatment Arm 4 and Arm 5.
It is recognised that this blinding will be challenging because of multiple laboratory test changes, specifically viral load, bilirubin, liver enzymes and hematologic changes that are related to the administration of active triple therapy vs. no such changes in patients with placebo. However, it is important to maintain the blinding through the blinding of specific laboratory assessments (cf. In order to mitigate the risk of indirect unblinding and to maintain the integrity of the blinded assessments, Arm 4 and Arm 5 results of plasma HCV RNA levels and a series of safety laboratory tests after start of the treatment will be blinded to investigators, patients and sponsor for up to Week 24 visit (non-inclusive, i.e., Week 24 results will be reported to investigators) (cf. Central laboratory service will disclose the results of safety laboratory parameters when the unblinding criteria for those laboratory tests are met. If any of ALT or AST meets the criteria for unblinding, results for both laboratory tests will be disclosed from that time-point forward. If Hb meets the criteria for unblinding results for RBC count, Hb, hematocrit will be disclosed from that time point forward. If for the patient care management the investigator needs to know the blinded laboratory results even prior meeting the criteria established in Table 4.1.5.1: 1, the investigator will be able to request these laboratory tests (except HCV RNA) from central laboratory service after consultation with BI Clinical Monitor.
Central laboratory service will inform the investigator whether the patient meets lack of on treatment viral response criteria based on HCV RNA, without disclosing the actual results of HCV RNA. If any of these stopping rules are met, the investigator will receive a notification for repeat testing or treatment discontinuation.
Note that treatment code will be only broken upon investigator's request as per procedures described in Section 4.1.5.2. According to BI's SOPs, suspected unexpected serious adverse reactions (SUSARs) will be unblinded for reporting to competent authorities. In such cases, access to the code will only be permitted by authorized drug safety representatives via IRT.

Not applicable.
An emergency code break will be available to the investigator/pharmacist/investigational drug storage manager via IRT. Details are included in the ISF. This code break may only be used in emergency situations when the identity of the trial drug must be known to the investigator in order to provide appropriate medical treatment or if required to assure safety of trial participants.
If the code break for a patient is used, the sponsor must be informed immediately. The reason for using the code break, the date when the code was broken and initials of person who broke the code must be documented on the appropriate electronic case report form (eCRF) page.

4.1.6
Packaging, labelling, and re-supply Supply and re-supply will be managed by IRT.
For details of packaging and the description of the label, refer to the ISF.

Storage conditions
Drug supplies will be kept in their original packaging under the recommended storage conditions indicated on the label. Storage temperature should be monitored and documented.
The trial medication must be stored securely, e.g. in a locked cupboard or at a pharmacy. It may only be dispensed to trial patients according to the protocol by authorised personnel as documented in the form "Investigator's Trial Staff".
All unused medication must be returned to the sponsor. Receipt, usage and return must be documented on the respective forms. Account must be given for any discrepancies.
All dose adjustments of RBV, discontinuations and rescue medications must be documented in the patient source documentation and corresponding eCRF.
Management of drug-related skin events: In case of drug-related skin events, the investigator should follow the dermatologic management plan, as specified in Appendix 10.2.

Management of gastrointestinal (GI) events:
GI AEs such as nausea, vomiting or diarrhoea have been reported during treatment with BI 207127 and FDV. The highest onset rate of these AEs was during the first week of treatment, particularly Day 1 and 2, followed by a significant decrease over time.
The following general measures are strongly recommended in order to prevent and manage these AEs and maintain adequate hydration:  BI 207127 doses should be taken along with food avoiding intake in fasting conditions. Patients should be instructed to take their medications with food, preferably during breakfast and dinner.
 Early symptomatic treatment is recommended particularly during the first days of treatment and should be initiated for GI AEs as early as possible.
 Antiemetic treatments such as metoclopramide 10 mg tablets (orally dissolved) one tablet b.i.d. or q8h are recommended for nausea and vomiting. These agents may be taken approximately 30 minutes before BI 207127 intake if needed, and continued depending upon response. An antiemetic should be applied as soon as the first symptoms of nausea appear, even if mild. Re-taking study medications after vomiting is not recommended; patients should follow their regular schedule.
 Antimotility agents such as loperamide 2 mg caplets (or capsules) are recommended for non-infectious diarrhea; starting with 4 mg dose (2 caplets) and continue with 2 mg after each subsequent loose stool but no more than 4 caplets in 24 hours.   1 If the abnormality is reversed, Ribavirin should be restarted at 600 mg daily, and further increased to 800 mg daily at the discretion of the treating physician. However, a return to higher doses is not recommended.
Of note, other ribavirin dosage modification guidelines due to anaemia may apply according to local approved Copegus ® label.
The use of eyrthropoiesis stimulating agents (ESA), is permitted at the discretion of the investigator. If ESA are being prescribed, the following guidelines have to be followed:  ESA should not be initiated until haemoglobin levels falls below 10g/dL  Iron studies should be obtained prior to and during ESA treatment  Iron supplementation should be initiated for deficient patients and to maintain transferring saturation at levels supporting erythropoiesis  Once an ESA is initiated, haemoglobin levels and blood pressure must be monitored weekly until stabilisation of haemoglobin  Treatment should target a haemoglobin level sufficient to avoid transfusion  ESA dose should be titrated to treatment response  ESA dose should be reduced if the haemoglobin rises by more than 1 g/dL in a 2-week period  ESA dose should not exceed those recommended for currently approved indications  ESA should not be used in patients at increased risk for thromboembolic events, cardiovascular events, including those with inadequately controlled hypertension, and patients with diagnosed malignancies  Patients must be informed about the risks associated with ESA use, as described in the patient information  Dose and duration of treatment must be documented in the eCRF The use of silibinin or other medications extracted from the milk thistle is not allowed during the treatment period of this trial.
The co-administration of drugs which may cause photosensitivity reactions should be avoided throughout the treatment duration and up until 28 days after all treatment discontinuation, unless the benefit outweighs the risk based on the investigators' clinical judgment. The restriction of drugs with photosensitivity potential includes and is not limited to tetracyclines (e.g. tetracycline, doxycycline), fluoroquinolones (e.g. ciprofloxacin, ofloxacine), sulfonamides, sulfonylureas (e.g. glipizide), psoralens, oral retinoids (e.g. isotretinoin, acitretin), phenothiazines and amiodarone.
All concomitant and/or rescue therapies will be recorded on the appropriate pages of the eCRFs.

Restrictions on diet and life style
Patients must be willing to protect any uncovered skin area (including hands, face and lips) from sun-or UV-light exposure using sun-blocker cream with an SPF ≥50 providing UV-A and -B protection during treatment period on a daily basis. Lip balm with the highest SPF locally available should be used. Patients should avoid unnecessary or prolonged exposure to sunlight and wear protective clothing, sunglasses and hats in addition to sun-block. It is recommended to avoid direct sun exposure as much as possible. Tanning booths must be avoided during treatment period. No alcohol consumption during screening, treatment, and follow-up periods of the trial.

TREATMENT COMPLIANCE
Study medication will be dispensed to the patient at the study site by responsible site personnel. Details regarding dispensing of the study medication to each participating patient, including patient identification, the amount of study drug dispensed, the date the drug was dispensed, and the numbers of capsules/tablets/vials returned to the site will be recorded in the drug dispensing log. All dispensed study drug should be recorded in the drug-dispensing log in the ISF.
Patients must return to the site drug packaging including unused or empty medication packages at each visit. Study medication usage and return must be documented on the respective form and account must be given for any discrepancies.
Treatment compliance for all three drugs will be strictly monitored and assessed at each relevant visit through pill-count by Investigator (or designated site personnel) according to worksheets provided in ISF. For more information regarding FDV pill-count procedure, please cf. ISF. Compliance worksheets must be kept as a source documents. BI Clinical Monitor should be contacted for cases of suspected non-compliance.
Compliance will be calculated according to the formula: This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
 Compliance (%) = Number of medications actually taken since last count / Number of medications which should have been taken in the same period ×100% Planned interruptions and dose reductions in treatment (applicable for RBV) in accordance with the protocol and prescribed by the investigator should be taken into account when calculating compliance.
If the treatment compliance cannot be assessed in a specific visit (e.g., bottle is lost or forgotten), the eCRF compliance page at that visit should be left blank.
Compliance to the BI 207127, FDV, RBV and matching placebos should be between 80% and 120%. Patients who are non-compliant according to this definition will be treated as protocol violations. The identification, handling and inclusion/exclusion of these and other protocol violations will be discussed in the trial statistical analysis plan (TSAP).
Patients who are non-compliant (e.g., have low treatment compliance, do not attend trial visits or violate the restrictions) may be withdrawn from the trial and the eCRF will be completed accordingly (for further procedures cf. Section 3.3.4), following discussion with BI Clinical Monitor.
Patients should take their medication regularly at the same time every day (BI 207127 and RBV every 12-hour and FDV every 24-hour). Excursions ± 1 hour outside from the regular times of intake should be avoided since this may lead to viral resistance and treatment failure.
If a patient misses a scheduled BI 207127 dose, and discovers this error:  Less than 6 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit.
 6 hours or more after the scheduled dose time, the patient must: take the next scheduled dose at the next scheduled time; not take the missed dose; and, report the error at the next study visit.
If a patient misses a scheduled FDV dose, and discovers this error:  Less than 12 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit.
 12 hours or more after the scheduled dose time, the patient must: take the next scheduled dose at the next scheduled time; not take the missed dose; and, report the error at the next study visit.
If a patient misses a scheduled RBV dose, and discovers this error:  Less than 6 hours after the scheduled dose time, the patient must: take the missed dose; take all remaining doses at scheduled time; and, report the error at the next study visit. An SAE is defined as any AE which results in death, is immediately life-threatening, results in persistent or significant disability / incapacity, requires or prolongs patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for any other reason if it is an important medical event when based upon appropriate medical judgement which may jeopardise the patient and may require medical or surgical intervention to prevent one of the other outcomes listed in the above definitions.

Intensity of adverse event
All AEs with the exception of photosensitivity reaction will be graded according to DAIDS grading scale (see DAIDS grading scale in ISF (R10-1332)). Photosensitivity reactions will be graded according to a scale provided in the Dermatology Management Plan in Appendix 10.2.
The intensity of the AE should be judged based on the DAIDS Grading Scale: Yes: There is a reasonable causal relationship between the investigational product administered and the AE. No: There is no reasonable causal relationship between the investigational product administered and the AE.
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. any active comparator or placebo according to the trial design).
Worsening of the underlying disease or other pre-existing conditions Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the eCRF.

Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
As described in Section 4.1.5.1 selected laboratory tests results in Arm 4 and 5 will be blinded to investigator, patients and sponsor. Therefore, it is understood that by design investigator will not be able to report laboratory related AEs, unless they are in the range that require unbinding of the investigator to the results (cf. Table 4.1.5.1: 1). The blinding ranges were set to exclude values that may be clinically relevant to avoid an effect on the AE reporting rates. In the Clinical Trial Report (CTR), all laboratory tests will be analyzed and presented to demonstrate any potential effect of laboratory test blinding on AE reporting rates.
Protocol-specified significant events The following are considered as protocol-specified significant events:  Skin rash cases of Grade ≥2 severity or photosensitivity reactions of moderate or greater severity.
Protocol-specified significant events are to be reported in an expedited manner similar to SAEs, even if they do not meet any of the seriousness criteria. For details please see Section 5.2.2.2.

Adverse event and serious adverse event reporting
All AEs, serious and non-serious, with onset date from signing the informed consent until 28 days after all treatment discontinuation (FU1 visit), and all SAEs with onset date after FU1 visit up to EOO will be collected, documented and reported to the sponsor by the investigator on the appropriate eCRFs/SAE reporting forms. The period from EOT to 28 days after after EOT is called "residual effect period". Reporting will be done according to the specific definitions and instructions detailed in the 'Adverse Event Reporting' section of the ISF.
For each AE, the investigator will provide the onset date, end date, intensity, treatment required, outcome, seriousness, and action taken with the investigational drug. The investigator will determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1. For details refer to the subsections of this Section.
If not stipulated differently in the ISF, the investigator must report the following events 1) if using paper process SAE form via telephone/fax or 2) if available for the trial, using the electronic submission process (RDC) immediately (within 24 hours to the sponsor: SAEs and non-serious AEs which are relevant for a reported SAE(s), and protocol-specified significant events.
BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these "always serious adverse events", if a non serious AE is identified to be serious per BI definition, a query will be raised. The investigator must verify the description and seriousness of the event. If the event description is correct, the item "serious" needs to be ticked and an SAE has to be reported in expedited fashion This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
following the same procedure as above. The list of these AEs can be found via the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU (country-specific contact details will be provided in the ISF) or by using the electronic submission process. This immediate report is required irrespective of whether the investigational product has been administered or not and irrespective of causal relationship. It also applies if new information to existing SAEs or protocol-specified significant events becomes available.
Reporting AEs occurring up to 28 days after all treatment discontinuation (FU1 visit): The investigator has the responsibility to report all AEs occurring up to 28 days after all treatment discontinuation (FU1 visit), regardless whether they are serious, non-serious, related or not-related to the trial medication. Any AEs persisting after FU1 visit must be followed until they have resolved, or as deemed reasonable by the investigator in consultation with BI Clinical Monitor. These AEs will be considered "on-treatment", except if the onset date was after the start of the active treatment option (for Arm 4 patients only).
Reporting AEs occurring later than 28 days after all treatment discontinuation (FU1 visit): AEs that occur after FU1 visit will be reported only if serious. These events will be attributed to the "post-treatment period." The investigator does not need to actively monitor patients for adverse events once the clinical trial has ended (after EOO). However, if the investigator becomes aware of an SAE(s) that occurred after the patient has completed the clinical trial, it should be reported by the investigator to the sponsor if considered relevant by the investigator. These events will be attributed to the "post-study period."

Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been enrolled into the clinical trial, after having taken study medication, the investigator must report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 hours) to the defined unique entry point for SAE forms of the respective BI OPU (country-specific contact details will be provided in the ISF). The outcome of the pregnancy associated with the drug exposure during pregnancy must be followed up. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. AE eCRF page and the skin eCRF page. Please note, the event should NOT be reported as serious on the SAE form unless it meets the regulatory definitions of a SAE defined in the "Adverse Event Reporting" section of the ISF. It is recommended that all patients with protocol-defined significant AEs should see be referred to a local dermatologist for diagnosis, confirmation of severity, and treatment advice. All patients with protocol-defined significant AEs should have a photo-documentation of their lesions. For instructions on photodocumentation, please refer to the ISF. For specific management and grading guidelines for patients developing rash and photosensitivity reactions, please cf. Appendix 10.2 and Dermatologic Operations Manual in the ISF.
Grade 1/mild skin AEs are not considered "protocol-defined significant AEs" and should be reported in the AE eCRF and skin eCRF. Skin AEs with a known etiology (e.g. viral exanthema, collagen vascular disease, neoplasia, bacterial infection, psoriasis, fungal skin infection, or autoimmune blistering disease) deemed not related to the trial medications are not considered "protocol-defined significant AEs" and should be reported in the AE eCRF page only. A skin eCRF page is not required.
Protocol-defined significant AEs will be subject to review by the dermatological adjudication committee.
BI has set up a list of AEs which are defined to be always serious. In order to support the investigator with the identification of these "always serious adverse events", if a non serious AE is identified to be serious per BI definition, a query will be raised. The investigator must verify the description and seriousness of the event. If the event description is correct, the item "serious" needs to be ticked and an SAE has to be reported in expedited fashion following the same procedure as above. The list of these AEs can be found via the RDC-system.

Assessment of safety laboratory parameters
The safety laboratory will be performed at the central laboratory service provider. Reference ranges and instructions on sample collection, handling/processing, and shipping will be provided in the ISF.
Patients should be fasting for at least 6 hours prior to the blood sample being taken (except screening visit). For time points of sampling refer to the Clinically relevant laboratory values should be commented on lab report print-outs. A clinically relevant value may be either in-or outside the reference range. Clinically relevant abnormal laboratory test results must be confirmed using an unscheduled visit lab kit and should be repeated until normalisation or stabilisation or until an alternative explanation has been found.
The following laboratory results will be flagged by the central laboratory for further assessment of potential DILI cases, if observed at same time point:  ALT or AST 2x baseline that is at least 100 IU/L higher than baseline, AND This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Serum pregnancy tests will be performed at screening (Visit 1) and at every visit up to 24week follow-up for all female patients of childbearing potential. In addition to serum pregnancy test, a urine (dipstick) pregnancy test will be performed for all females before receiving the study drugs at Day 1 (Visit 2). Only female patients with negative urine pregnancy test will receive study medication at Day 1 (Visit 2). Urine (dipstick) pregnancy tests will not be captured in the database.
When visits are more than 4 weeks apart and/or due to early treatment termination, female patients of childbearing potential will be provided with urine pregnancy tests to perform monthly pregnancy tests at home between visits until 7 months after EOT. It is strongly recommended that female partners of childbearing potential of male patients also perform This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. monthly pregnancy test at home and the sponsor will provide urine (dipstick) pregnancy tests for this purpose.

Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
It will be recorded after the patients have rested for at least 5 minutes in supine position at Visit 1. Six limb leads, as specified by Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and six pre-cordial leads (V1-V6), according to Wilson, will be used. The investigator or a designate will evaluate whether the ECG is normal or abnormal and, if abnormal, whether it is clinically significant. Additionally, any occurrence of re-or depolarization disorders, arrhythmic disorders or other abnormalities will be assessed.
The electronic version of the ECG is regarded as source data. Dated and signed printouts will be stored in the patient's medical file.
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs may be collected by the investigator for safety reasons, included but not limited to follow up of patients who experience palpitations, fainting, sudden loss of consciousness or syncope. Clinically relevant abnormal findings will be reported as AEs. The ECGs may be sent to the ECG laboratory to undergo central assessment.

Physical examination
Complete and target physical examinations will be carried out as described in the Flow Chart.
A complete physical exam consists of an evaluation of organ systems with vital signs (including respiratory rate, temperature, pulse rate, and systolic/diastolic blood pressure). Respiratory rate, temperature, pulse rate, and blood pressure will be measured after patients have been sitting comfortably for at least five minutes.
A targeted physical examination includes an evaluation of organ systems only associated with an AE symptom(s) (as needed,and particularly focused on hepatic-related events) and evaluation of vital signs.
Clinically relevant abnormal findings will be reported as AEs.

FibroSURE TM
Non-invasive method for lived fibrosis assessment, FibroSURE TM , will be assessed at the time-points specified in the Flow Chart. FibroSURE TM is an algorithm based on a composite of five serum biochemical markers (alpha-2-macroglobulin, apolipoprotein A1, haptoglobin, GGT and bilirubin) that is used to assess liver fibrosis with its different degrees. The algorithm generates a score that correlates with the level of fibrosis and the presence of cirrhosis. For the purpose of a separate health economic analysis (such as cost-utility analysis), HCRU data will be collected throughout the study. Resource use data collected for calculating direct costs will include unscheduled hospitalisations, healthcare provider visits, and emergency room/ICU use. Information on work productivity will also be collected.
The economic evaluation of the HCRU data will not be part of the CTR but reported separately.

EQ-5D
Health related quality of life will be assessed using the EQ-5D at the visits indicated on the Flow Chart. EQ-5D is a standardized instrument for use as a measure of health outcome. It is a generic measure, rather than disease-specific, and is therefore applicable to a wide range of health conditions and treatments. It provides a simple descriptive profile and a single index value for health status. EQ-5D is designed for self completion by patients.
The EQ-5D self-report questionnaire (EQ-5D) essentially consists of 2 pages comprising:  The descriptive system (five dimensions of health; namely mobility, self care, usual activities, pain/discomfort, anxiety/depression). Each dimension comprises three levels (no problems, some/moderate problems, extreme problems).
 The EQ-VAS (visual analogue scale) which records the patient's self-rated health status on a vertical graduated (0 -100) VAS.
The paper-and-pen version in the required native language of the patient will be used. If the required language is not available then the patient is not required to complete the questionnaire.
A patient can self-administer the EQ-5D in a few minutes, and the Investigator (or designated site-personnel) should ensure that the patient has access to a quiet area at the site where he can be left alone to record a response to the descriptive system and VAS. In instances where a patient cannot give or decide upon a response, no response should be recorded. In this study of FDV and BI 207127 combination therapy, genotypic resistance monitoring (sequencing) will focus on the NS3/4A and NS5B genomic segments. Samples for genotyping the HCV NS3/4A protease and NS5B polymerase will be collected at screening (Visit 1) and at all patient visits. Viral genotyping will be performed for patients who discontinue study treatment. HCV RNA plasma viral load data will guide which additional samples are examined; genotyping will be performed on samples in which the HCV RNA plateaus above the lower limit of quantification or in which the HCV RNA rebounds during trial period (before or at EOO visit) and compared to baseline sequence. These include FU isolates (as detailed in Flow Chart) from individuals whose on-and post-treatment viral samples are genotyped to assess the persistence of resistance mutations during the outgrowth of wild-type virus.
The viral RNA will be extracted, cDNA synthesized and amplified using reverse transcriptase-PCR. The length of amplified product potentially limits the detection to samples with HCV RNA >10 3 IU/mL. The NS3/4A protease and NS5B polymerase nucleotide sequences will be obtained by direct DNA sequencing of the amplified product that allows for the detection of variants present at approximately ≥30%.

Phenotypic Resistance
The virology samples obtained for genotypic resistance monitoring are also suitable for phenotyping. NS3 protease or NS5B polymerase replicon-based phenotyping will be performed on samples in which the HCV RNA plateaus above the limit of quantification or in which the HCV RNA rebounds during trial period (before or at EOO visit) and which are associated with unique resistant mutants that have not been previously phenotyped. Representatives of the most common and well characterized pathways in assays will be included as references. In addition to patient-derived NS3 or NS5B samples, novel amino acid substitutions will also be characterized phenotypically using site-directed mutagenesis if they are observed repeatedly in genotyped subjects.

Methods and timing of sample collection
At least 4 mL of plasma from 8 mL of blood sample will be collected for virology samples (genotyping and phenotyping analyses) at each visit. These will be divided into two 2 mL aliquots: one primary and one back-up. Samples will be shipped to the central laboratory on dry ice. The central laboratory will store samples at -80°C until processing. Detailed instructions for obtaining, handling, and shipping virology samples are provided in ISF.

Assessment of liver disease progression
Markers of liver disease progression will be collected as occurrence of any of the following clinical outcomes and assessed at the time points specified in the Flow Chart: This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Pharmacogenomic evaluation The first sample, a mandatory part of the protocol, collected at Visit 2 will be used for DNA extraction and subsequent genotyping of genotyping of IL-28b rs12979860, as well as other genes involved in the activity and/or efficacy of the drug within the context of the clinical trial. In addition, genes influencing assimilation and/or metabolism like UGT1A1, HLA class I and II molecules, CYP450 enzyme and drug transporter genes, like OATPs, genes influencing the therapeutic outcome like interferon signalling pathway genes and/or interferon stimulated genes may be evaluated. After successful analysis, the remaining material will be destroyed.
The second sample collected at Visit 2 sample is voluntary and will be taken and processed or stored only after informed consent is given in accordance with local ethical and regulatory requirements. This sample will be completely anonymised. The anonymization procedure will guarantee a very high level of data protection for the donor. Once the anonymization has been carried out, there will be no way to trace back to the identity of the donor through the coding keys. The anonymised DNA may be analysed at a later time to identify whether there are genetic factors that could contribute to a better therapeutic outcome or a higher risk of developing treatment-related adverse drug reactions. These analyses may include genes related to efficacy, safety and PK. After anonymization, the third sample (or the DNA derived thereof) will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests.

Methods and timing of sample collection
One mandatory and one optional 8.5mL blood sample will be taken at Visit 2 for pharmacogenetic testing with PaxGene DNA blood sampling tubes. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular genetics methods and analyzed by TaqMan or other standard genotyping technologies.

APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements in HCV treatment trials and will be performed in order to monitor safety aspects or assess treatment response in an appropriate way.
The scheduled measurements are appropriate to see drug induced changes in vital signs, standard laboratory values and ECG. These primary and secondary endpoints are standard and accepted for evaluation of safety and tolerability of an oral drug, and they are widely used in this kind of studies.
Therefore, the appropriateness of all measurements applied in this trial is given.

Pharmacokinetic endpoints
The following primary PK parameters will be calculated for patients participated in Cohort A:  Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
 CL/F (apparent clearance of the analyte in the plasma after extravascular administration)  V z /F (apparent volume of distribution during the terminal phase  z ) In addition plasma protein binding of BI 207127 & metabolites and FDV will be determined in Cohort A only.

Methods of sample collection
The date and clock time of the most recent drug intakes, and date and clock time of the blood sample collection will be entered in the eCRF. Further details on collection, preparation, and shipping will be included in ISF. For all patients in Cohort A and Cohort B, pre-dose PK blood samples will be collected according to the Flow Chart. If patient is subjected to intensive PK on same visit day, only collect intensive PK samples. Patients should not take study medication the mornings of treatment period visits. Administration of the study drug will be done under the supervision of the investigator or his designee after the pre-dose sample has been collected. The time elapsed since the last dose of FDV should be as close to 24 hours as possible and the last dose of BI 207127 should be as close to 12 hours as possible.
For quantification of FDV and RBV plasma concentration, 2.0 mL of blood will be drawn from a forearm vein in an EDTA-anticoagulant blood drawing tube. For quantification of BI 207127, CD 6168, BI 208333 (BI 207127 acylglucuride) and CD 6168-acylglucuronide, 4.5 mL of blood will be drawn from a forearm vein in a blood drawing tube containing citrate or citrate and citric acid. Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
For determination of protein binding of BI 207127 & metabolites and FDV (Arm 1, 2 and 3 in Cohort A only), two 10 mL blood samples will be drawn from a forearm vein in EDTA-anticoagulant blood drawing tubes at 2.5 h post dose at Day 1,8 and Week 4 and 16. Due to the resource capacity, only samples collected at Day 8 will be first used for protein binding assay. Remaining samples will be analyzed only if needed.

Pharmacokinetics
All analytes will be determined by a validated HPLC-MS/MS assay (high performance liquid chromatography, tandem mass spectrometry). Bioanalytical determinations for all the analytes will be performed by Tandem Labs (Salt Lake City, UT 84124).
FDV ZW: The concentration of FDV ZW in EDTA plasma will be determined by a validated HPLC/MS/MS (high performance liquid chromatography, tanden mass spectrometry) method.
BI 207127: The concentrations of BI 207127 and its metabolites in citrated/citric acid plasma will be determined by a validated HPLC/MS/MS (high performance liquid chromatography, tandem mass spectrometry) method.
RBV: The concentrations of RBV in EDTA plasma will be determined by a validated HPLC/MS/MS (high performance liquid chromatography, tandem mass spectrometry) method.

Boehringer Ingelheim
Clinical Trial Report BI Trial No.: Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Protocol and amendments
Administration of the morning dose of study drug will be done under the supervision of the investigator or his designee after the pre-dose PK sample has been collected. Note that the routine laboratory samples are to be collected in fasted condition and only afterwards patients must take their medication with food.

Randomization/treatment assignment visit (Visit 2)
Patients will begin treatment as assigned by the IRT at Visit 2 with the first dose administered in the office (Day 1) including an additional 120 mg loading dose of FDV (or placebo) (cf. Section 4.1.4).
For Cohort B, IRT will assign mandatory PK sub-study participation (cf. Section 5.5).

Visit 3 to Visit 12
For Cohort B, results of plasma HCV RNA levels and a series of safety laboratory tests after start of the treatment will be blinded to investigators, patients and sponsor (cf. Section 4.1.5.1). The Investigator will be informed by the central laboratory when a criteria for treatment discontinuation due to lack of virologic response (cf. Section 3.3.4.1) are met for a given patient during this period.

EOT Visit
Planned EOT visit will occur at Week 24 according to the planned treatment duration. These patients should be registered as completed in IRT.
Patients who discontinue treatment early due to either lack of efficacy or safety reasons will be required to have an EOT visit (if the patient is at the research site), or have EOT visit scheduled within 2 weeks from the last intake of study medication. These patients should be registered in IRT as early discontinuation of trial medication. Please note that if either BI 207127 or FDV is permanently discontinued, all study medication including RBV must be discontinued immediately (cf. Section 4.2.1).
For Cohort B, the sponsor, patient, and investigator will be unblinded to all laboratory values and treatment (active or placebo) for each patient at their EOT visit.

End of trial and follow-up period
Termination of trial medication and trial completion must be recorded on the corresponding eCRFs for all randomised/treatment assigned patients.

Follow-up (FU)
If HCV RNA is detected during a FU visit, a subsequent confirmatory testing should be performed.
If a patient receives any other HCV treatment outside this protocol during the FU period the patient will need to be discontinued from the trial and have EOO visit prior to the start of that Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. treatment. Efficacy data collected after the start of such treatment will not be attributed to the trial treatment. Any subsequent end-points will be considered as not achieving treatment response.

Patients with EOT at Week 24
Patients who successfully complete the 24-week treatment period should return to the clinic for FU visits according to the Flow Chart. FU1 visit will occur 4 weeks after the discontinuation of trial treatment. This is the last at which the investigator has the responsibility to report every AE. During the next FU visits, only SAEs will be reported. Refer to Flow Chart and Section 5.2.2.

Patient with early treatment termination
Patients who stop study treatment prior to completion of the treatment period should return to the clinic for all FU visits per the Flow Chart starting with a FU1 visit 4 weeks after EOT.
It is understood that a patient may withdraw consent at any time and decide not to complete FU, but such FU is to be encouraged.

End of Observation
EOO will be performed for all patients at 96 12 weeks after EOT.
Patients who discontinue the FU period early will be required to have an EOO visit (if the patient is at the research site), or have EOO visit scheduled within 3 weeks from discontinuation of the FU.

Treatment Option for Arm 4
For patients that participated in Arm 4, an option to received trial treatment according to Arm 5 may be offered, if patient is still eligible for treatment (cf. Section 3.1). The trial Flow Chart will not be followed; instead these patients will follow the treatment visit schedule and procedures as listed in Table 4

Protocol and amendments
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA) coding dictionary. All events with an onset after the first dose of study medication up to a period of 28 days after the last dose of study medication will be assigned to the treatment phase for evaluation. Other AEs will be assigned either to the screening or FU phase as appropriate. Frequency tables of patients who experience AEs leading to discontinuation will be provided. Kaplan-Meier curves might be used to investigate the time to an event for considerations of special interest, for example rash event. More details of these analyses will be included in the TSAP.
Laboratory values taken after the first dose of randomised treatment up to a period of 7 days after the last intake of treatment will be assigned to the treatment phase for evaluation. Frequency tables with abnormal laboratory values defined by DAIDS grades (R10-1332) and, if necessary, the proportion exceeding multiples (2*, 3* …) of the upper normal range limit will be provided. Changes in bilirubin (direct, indirect, total) values will be described in the context of being associated with clinical events. The absolute value and the change from baseline in laboratory values will be summarized by treatment group. Baseline is defined as the last observed measurement prior to administration of any randomised study medication.
A DMC will be set up with primary responsibility to review the safety database on an ongoing basis. Refer to Section 3.1.1 for more details.

Interim analyses
For safety monitoring, trough plasma concentrations of BI 207127 and FDV up to Week 4 will be analysed for Arm 1 and Arm 2 patients after all patients have completed visit 6 and, as needed, until all patients have completed EOT. Geometric mean of difference, sd, 90% CI will be calculated between treatment arms. For Cohort A, PK parameters AUC 0-12 , Cmax, C 12 of BI 207127 and AUC 0-24 , Cmax, C 24 of FDV will be calculated and provided to evaluate the systemic exposure of BI 207127 and FDV in CPB patients after receiving 400 mg BI 207127 compared to BI 207127 and FDV in CPA patients after receiving 600 mg BI 207127. Geometric mean of difference, sd, 90% CI will be calculated for these parameters between treatment arms. The results will be presented descriptively and no statistical testing will be performed. The lower bound of the 90% CI for the geometric mean test arm (Arm 1): control arm (Arm 2) of C 12 will be compared to 0.5 while the upper bound will be compared to 2. The boundaries were derived based on SOUND-C2 results. Whether the lower BI 207127 dose treatment in Arm 1 will provide proper exposure to CPB patients will be decided by assessment of the descriptive statistics listed above along with the efficacy and safety profile of the patients by an independent internal review committee (cf. Section 3.1.1). This committee will either select a dose for Cohort B or determine that Arm 3 should be conducted and the same analysis performed comparing Arm 1 to Arm 3.

Boehringer Ingelheim
Clinical Trial Report BI Trial No.: Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.

Pharmacokinetic analyses
Cohort A: Refer to Section 5.5.1 7.3.4.
Cohort B: The PK parameters AUC 0-12 , C max , C 12 of BI 207127 and AUC 0-24 , C max , C 24 of FDV will be calculated after Day 1, 8, Week 4 and 16 of intensive PK sample collection.

Other analyses
Ninety-five percent CIs will be reported for the differences in response rates between treatment groups for W4U TND , W4U, W12U TND , and ETR TND .
Time to achieving HCV RNA undetected and time to virologic failure will be analyzed using Cox model.
The relationship between patient response and exposure will be investigated. HCV RNA change from baseline over time will be regressed on corresponding BI 201335 and BI 207127 concentrations to assess saturation of the exposure-response relationship.
Biochemical response and liver disease progression will be presented descriptively.

HANDLING OF MISSING DATA
All randomised patients who discontinue from the trial without reaching the SVR time points will be counted as treatment failures. Patients with missing SVR4 will be imputed by SVR12, if available. Patients with missing SVR12 will be imputed by SVR24, if available. Likewise, patients with missing SVR24 will be left as missing at the time of the interim database lock. Sensitivity analyses for missing SVR12 values due to early discontinued patients will be described in the TSAP.
It is not planned to impute missing values for safety data with the exception that missing AE start and end dates will be estimated (details to be written up in the TSAP).

RANDOMISATION
Cohort A: Eligible patients will be assigned to a treatment arm according the patient's Child Pugh score and the current screening stage of the trial. No randomisation is needed. All treatment arms will require a minimum of 8 females per arm. Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission. Eligible patients will be randomly assigned to one of the two treatment regimens to avoid possible biases due to subjective patient selection. An allocation ratio of 1:3 for Arm 4 and Arm 5 is planned.
The randomisation list will be generated using a validated system, which involves a pseudorandom number generator to guarantee the reproducibility of the assignments. This randomisation list will be checked by an independent statistician and used by a third-party IRT system to assign randomisation numbers to eligible patients.

DETERMINATION OF SAMPLE SIZE
Cohort A: Aiming at equal trough between Arms 1 and 2, 15 patients per arm will provide reasonable power to detect differences when alpha = 0.1 and the lower equivalence bound of the trough ratio is set at 0.5 and upper bound set at 2 (Table 7.6: 1). Computed with proc power of SAS version 9.2 (assuming log normal and using exact method) Cohort B: Thirty patients will be recruited for the placebo group and 90 will be recruited for the active treatment group. The response rate for the placebo group is expected to be zero. For calculation purpose, it is set to 1%. The reference response rate for the active treatment group has not been set yet because no such treatment combination was tested on such patient population. The trial will have a power of 81% to detect, with a 2-sided alpha=0.05, an SVR12 incidence rate of 20% on active treatment group using Fisher's exact test. If the incidence rate reaches 30%, the power will be greater than 99% (Table 7.6: 2). Proprietary confidential information.  2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
Severe (Grade III): Diffuse macular, maculopapular, or morbilliform rash with vesicles; limited number of bullae; or, superficial ulcerations of mucous membrane limited to one site.
Potentially Life-Threatening (Grade IV): Extensive or generalized bullous lesions; SJS; ulceration of mucous membrane involving two or more distinct mucosal sites; or, TEN. Note that DRESS is not listed in DAIDs grading table but is considered potentially life threatening.
If a severe or potentially life-threatening cutaneous event is suspected, it is important that a dermatologist who is experienced in these reactions should be promptly consulted to assist in the diagnosis and management of the patient.

Management guidelines of skin rash
Mild: Medium to high potency topical corticosteroids (potentially combined with oral antihistamines) should be prescribed as early as possible. Other non-prescription remedies such as oatmeal baths may be used to provide temporary relief of skin sensitivity and pruritus.
The need for UV light protection should be reinforced (Section 10.2.2).
Treatment with study medication may be continued without interruption.

Moderate:
The patient should have a detailed photo-documentation of the skin, preferably prior to the administration of any therapy. The subject should be seen by a dermatologist as soon as possible, but no later than 72 hours for diagnosis, confirmation of severity and treatment. A non-progressive moderate skin rash, confirmed by the dermatologist should be closely and frequently monitored at the investigator's discretion taking into account recommendation by dermatologist.
Medium to high potency topical corticosteroids combined with oral antihistamines should be prescribed as early as possible, but preferably after detailed photo-documentation of the skin lesions. Other non-prescription remedies such as oatmeal baths may be used to provide temporary relief of skin sensitivity and pruritus. Systemic corticosteroids may be applied if deemed clinically necessary.
The need for UV light protection should be reinforced (Section 10.2.2).
These reactions do not require discontinuation of study treatment. This document may not -in full or in part -be passed on, reproduced, published or otherwise used without prior written permission.
Medium to high potency topical corticosteroids combined with oral antihistamines should be prescribed as early as possible. Systemic corticosteroids may be applied if deemed clinically necessary. Subjects should have a detailed photo-documentation of the skin and referred to a dermatologist immediately but no later than 24 hours for diagnosis, confirmation of severity, treatment and skin biopsy. These patients must be closely monitored.
The decision to stop or continue the study treatment should be based on the clinical judgement of the investigator taking into account the recommendation by the dermatologist.

Potentially Life-Threatening
Patients with potentially life-threatening skin reactions such as DRESS or SJS/TEN should be referred immediately for emergency care. Subjects should stop all study medications. Patients should be seen by a dermatologist for diagnosis, confirmation of severity, treatment and skin biopsy. The patient should be followed up as appropriate.

Photosensitivity reactions
Photosensitivity reactions typically resemble exaggerated sunburn with erythema and edema often occurring within minutes to hours of sun exposure, and may involve vesiculation and desquamation in some cases. These photosensitivity reactions affect exclusively the sun-exposed skin areas; therefore, a clear delimitation of the erythema by garments is typically observed.

Definition of severity of photosensitivity reactions
Mild: Any localized superficial 1st degree burn: erythema and edema, peeling.
Severe: Extensive or full face 2 nd degree sunburn with blistering, serous exudates.

Management guidelines for photosensitivity reactions
Symptomatic management of photosensitivity reaction of any severity includes cool compresses, soothing lotions, topical corticosteroids and/or systemic non-steroidal antiinflammatory drugs (NSAID) or antipruritics. The need for UV light protection should be reinforced (Section 10.2.2).

Mild:
Treatment with study medication may be continued without interruption. Moderate: The patient should have a detailed photo-documentation of the skin and should be seen by a dermatologist as soon as possible but no later than 72 hours for diagnosis, confirmation of