Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

Study Overview
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Brief Summary
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The substances BI 201335 and BI 207127 are being developed for the treatment of chronic hepatitis C virus infection. BI 201335 and BI 207127 work by preventing the virus from replicating. The currently available medications pegylated interferon alfa and ribavirin for hepatitis C ca have considerable adverse events in patients and in many cases are not sufficiently effective. This is particularly the case in treatment of patients infected with genotype 1 of HCV. A combination therapy of these new substances without pegylated interferon alfa may be associated with fewer adverse events that currently available (pegylated interferon-alfa-based) medication and may also provide a treatment option to the large number of patients with contraindications or intolerance to pegylated interferon alfa. This clinical trial (1241.21) currently consists of 3 distinct studies: Part 1, Part 2 and Part 3. Part 1 (SOUND-C1) is a 2 armed study as described in experimental arms 1 and 2 below (actual enrollment: 56 patients; randomized and treated: 32) Part 2 (SOUND-C2) is a 5 armed study as described in experimental arms 3 to 7 below (actual enrollment: 465; randomized and treated: 362) Part 3 (SOUND-C3) includes 3 arms as described in experimental arms 8 to 10 below (83 patients randomized and treated)

Official Title
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Safety, Antiviral Effect and Pharmacokinetics of BI 207127 in Combination With BI 201335 and With or Without Ribavirin for 4, 16, 24, 28 or 40 Weeks in Patients With Chronic HCV Genotype 1 Infection (Randomized Phase Ib/II)

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: BI 207127
* Drug: BI 201335
* Drug: BI 207127
* Drug: BI 201335
* Drug: Ribavirin
* Drug: Ribavirin
* Drug: Ribavirin
* Drug: BI 207127
* Drug: BI 207127
* Drug: BI 207127
* Drug: BI 201335
* Drug: Ribavirin
* Drug: Ribavirin
* Drug: BI 207127
* Drug: BI 207127
* Drug: BI 201335
* Drug: BI 201335
* Drug: Ribavirin
* Drug: BI 201335
* Drug: BI 201335
* Drug: BI 207127
* Drug: BI 201335
* Drug: BI 201335
* Drug: BI 207127
* Drug: BI 201335
* Drug: Ribavirin
* Drug: Ribavirin
* Drug: BI 207217
* Drug: BI 201335
* Drug: BI 207127
* Drug: Ribavirin
* Drug: BI 207127
* Drug: BI 201335
* Drug: Ribavirin
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Chronic hepatitis C virus (HCV) infection of genotype (GT) 1 Parts 1-3:Treatment naive to Interferon -alfa (IFN), Pegylated interferon -alfa (PegIFN), ribavirin (RBV), and any direct acting antiviral agent for chronic hepatitis C Part 4: Treatment experienced with confirmed prior virological failure to an approved dose of PegIFN/RBV (null-response) HCV RNA >=10,000 IU/mL at screening Liver biopsy within two years or fibroscan within six months prior to baseline Liver biopsy within two years or fibroscan within 6 months prior to screening Age 18-75 years Exclusion criteria: Hepatitis C virus (HCV) infection of mixed genotype Evidence of liver disease due to causes other than chronic HCV infection Positive ELISA for human immunodeficiency virus (HIV) Hepatitis B virus (HBV) infection Decompensated liver disease or history of decompensated liver disease Active or suspected malignancy within the last 5 years Ongoing or historical photosensitivity or recurrent rash History of alcohol or drug abuse (except cannabis) within the past 12 months Body mass index (BMI)I <18 or > 35 kg/m2 Usage of any investigational drugs within 30 days prior to enrolment, or 5 half-lives, whichever is longer; o the planned usage of an investigational drug during the course of the current study Known hypersensitivity to any ingredient of the study drugs A condition that is defined as one which in the opinion of the investigator may interfere with the patient's capability for participation in the trial or may influence the results of the trial Alpha fetoprotein >100ng/mL at screening; if >20ng/mL and <=100ng/mL, patients can be included if there is no evidence of liver cancer in an appropriate imaging study within 6 months prior to randomisation Total bilirubin > 2 mg/dL with ratio of direct/indirect > 1 AST or ALT >5xULN INR prolonged to >1.7xULN Requirement for chronic systemic corticosteroids Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 30 days prior to enrolment or 5 half-lives, whichever is longer Received silymarin or glycyrrhizin or Sho-saiko-to within 30 days prior to enrolment Contraindications pertaining to PegIFN or RBV

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2<br>4 weeks of high dose TID BI 207127 and QD BI 201335 in combination with RBV, Part 1 | Drug: Ribavirin<br>* 48 weeks, according to label<br>Drug: BI 201335<br>* 24 weeks, QD<br>Drug: BI 207127<br>* 4 weeks, high dose, TID<br>|
| Experimental: 1<br>4 weeks of low dose three times per day (TID) BI 207127 and once daily (QD) BI 201335 in combination with RBV, Part 1 | Drug: BI 207127<br>* 4 weeks, low dose TID<br>Drug: BI 201335<br>* 24 weeks, QD<br>Drug: Ribavirin<br>* 48 weeks, according to label<br>|
| Experimental: 3<br>16 weeks of TID BI 207127 and QD BI 201335 in combination with RBV, Part 2 | Drug: BI 207127<br>* 16 weeks, high dose, TID<br>Drug: BI 201335<br>* 16 weeks, QD<br>Drug: Ribavirin<br>* 16 weeks, according to label<br>|
| Experimental: 4<br>28 weeks of TID BI 207127 and QD BI 201335 in combination with RBV, Part 2 | Drug: BI 207127<br>* 28 weeks, high dose, TID<br>Drug: Ribavirin<br>* 28 weeks, according to label<br>Drug: BI 201335<br>* 28 weeks, QD<br>|
| Experimental: 5<br>40 weeks of TID BI 207127 and QD BI 201335 in combination with RBV, Part 2 | Drug: BI 201335<br>* 40 weeks, QD<br>Drug: BI 207127<br>* 40 weeks, high dose, TID<br>Drug: Ribavirin<br>* 40 weeks, according to label<br>|
| Experimental: 6<br>28 weeks of BID BI 207127 and QD BI 201335 in combination with RBV, Part 2 | Drug: Ribavirin<br>* 28 weeks, according to label<br>Drug: BI 201335<br>* 28 weeks, QD<br>Drug: BI 207217<br>* 28 weeks, high dose BID<br>|
| Experimental: 7<br>28 weeks of TID BI 207127 and QD BI 201335 without RBV, Part 2 | Drug: BI 207127<br>* 28 weeks, high dose, TID<br>Drug: BI 201335<br>* 28 weeks, QD<br>|
| Experimental: 8<br>16 weeks of BID BI 207127 and QD BI 201335 in combination with RBV, Part 3 | Drug: BI 207127<br>* 16 weeks, high dose, BID<br>Drug: Ribavirin<br>* 16 weeks, according to label<br>Drug: BI 201335<br>* 16 weeks, QD<br>|
| Experimental: 9<br>24 weeks of BID BI 207127 and QD BI 201335 in combination with RBV, Part 3 | Drug: BI 207127<br>* 24 weeks, very high dose, BID<br>Drug: BI 201335<br>* 24 weeks, QD<br>Drug: Ribavirin<br>* 24 weeks, according to label<br>|
| Experimental: 10<br>24 weeks of TID BI 207127 and QD BI 201335 in combination with RBV, Part 3 | Drug: BI 201335<br>* 24 weeks, QD<br>Drug: BI 207127<br>* 24 weeks, high dose, TID<br>Drug: Ribavirin<br>* 24 weeks, according to label<br>|
| Experimental: 11<br>16 weeks of BID BI 207127 and QD BI 201335 in combination with RBV, Part 4 | Drug: Ribavirin<br>* 16 weeks, according to label<br>Drug: BI 207127<br>* 16 weeks, standard dose, BID<br>Drug: BI 201335<br>* 16 weeks, QD<br>|
| Experimental: 12<br>24 weeks of BID BI 207127 and QD BI 201335 in combination with RBV, Part 4 | Drug: Ribavirin<br>* 24 weeks, according to label<br>Drug: BI 201335<br>* 24 weeks, QD<br>Drug: BI 207127<br>* 24 weeks, standard dose, BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Rapid Virological Response (RVR) | Part 1: Rapid virological response (RVR), defined as Hepatitis C Virus Ribonucleic acid (HCV RNA) <25IU/mL at Week 4 of treatment | 4 weeks | 
| Part 2: Sustained Virological Response (SVR) | Part 2: Sustained virological response (SVR), defined as HCV RNA <25 IU/mL and undetectable at 12 weeks after end of treatment | From drug administration until 12 weeks after end of treatment, up to 52 weeks | 
| Part 3 and 4: Sustained Virological Response (SVR) | Part 3 and 4: Sustained virological response (SVR) defined as HCV RNA <25IU/mL and undetectable at 12 weeks after end of treatment | From drug administration until 12 weeks after end of treatment, up to 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Time to Virological Response | Part 1: Time to virological response, defined as the timepoint of the first measurement of plasma HCV RNA level <25 IU/mL. The percentage of participants who achieved virological response within each time period are displayed for this outcome measure. | From drug administration until end of drug administration, up to 4 weeks | 
| Part 2: Time to Virological Response | Part 2: Time to virological response, defined as the timepoint of the first measurement of plasma HCV RNA level <25 IU/mL. The percentage of participants who achieved virological response within each time period are displayed for this outcome measure. | From drug administration until end of drug administration, up to 40 weeks | 
| Part 1 and 2: Plasma HCV RNA Level Not Detectable at Week 4 | Part 1 and 2: Plasma Hepatitis C Virus Ribonucleic acid (HCV RNA) level not detectable at Week 4 | 4 weeks | 
| Part 2: Sustained Virological Response at 4 and 24 Weeks After End of Treatment | Part 2: Sustained virological response at 4 and 24 weeks after end of treatment | 4 weeks and 24 weeks after the end of treatment, up to 64 weeks | 
| Part 3 and 4: Plasma HCV RNA Level <25 IU/mL at Week 4 and 12 of Treatment | Part 3 and 4: Plasma Hepatitis C Virus Ribonucleic acid (HCV RNA) level <25 IU/mL at week 4 and 12 of treatment | Week 4 and 12 | 
| Part 3 and 4: Sustained Virological Response (SVR) at 4 Weeks After End of Treatment | Part 3 and 4: Sustained virological response (SVR) at 4 weeks after end of treatment | up to 28 weeks |