Antiviral Effect, Safety, and Pharmacokinetics of BI201335 +PegIFN/RBV in HCV-GT1 (SILEN-C1&2)

Study Overview
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Brief Summary
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The objective was to investigate the antiviral effect, safety, and pharmacokinetics of BI 201335 (Faldaprevir), given as a soft gelatine capsule, in patients with hepatitis C virus (HCV) genotype 1 infection. Combination therapy of BI 201335 (Faldaprevir) with pegylated interferon α-2a (PegIFN) and ribavirin (RBV), with or without a 3-day lead-in, was assessed in treatment-naïve (TN) and treatment experienced (TE) patients.

Official Title
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Antiviral Effect, Safety and Pharmacokinetics of BI 201335 NA in Hepatitis C Virus Genotype 1 Infected Treatment-naïve and Treatment-experienced Patients for 24 Weeks as Combination Therapy With Pegylated Interferon-alpha 2a and Ribavirin (Double-blinded, Randomised, Placebo-controlled, Phase II)

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: BI 201335 NA 240 mg QD / LI
* Drug: PegIFN/RBV
* Drug: BI 201335 NA 120mg QD / LI
* Drug: PegIFN/RBV
* Drug: BI 201335 NA 240 mg QD
* Drug: PegIFN/RBV
* Drug: BI 201335 NA 240 mg QD
* Drug: PegIFN/RBV
* Drug: BI 201335 NA 240 mg BID
* Drug: PegIFN/RBV
* Drug: PegIFN/RBV
* Drug: BI 201335 NA 240 mg QD
* Drug: PegIFN/RBV
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: chronic HCV GT1; therapy-naive to IFN, PegIFN, or RBV; HCV VL >=100,000 IU/mL Liver biopsy within 2 years prior to study enrolment showing necroinflammatory activity or presence of fibrosis Normal retinal finding on fundoscopy within 6 months prior to Day 1 age 18-65 years Females and males with adequate contraception Exclusion criteria: Mixed genotype (1/2, 1/3, or 1/4), diagnosed by genotypic testing at screening Previous treatment with protease inhibitor Evidence of liver disease due to causes other than chronic HCV infection HIV-1 or HIV-2 positive HBV positive Decompensated liver disease, or history of decompensated liver disease Active or suspected malignancy or history of malignancy within the last 5 years History of alcohol or drug abuse within the past 12 months. Usage of any investigational drug within 30 days prior to enrolment, or 5 half-lives, whichever is longer Known hypersensitivity to any ingredient of the study drugs Condition that is defined as one which in the opinion of the investigator may put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study Alpha-fetoprotein value > 100ng/mL at screening; if >20ng/mL and <=100ng/mL, patients can be included if there is no evidence of liver cancer in two congruent imaging studies Total bilirubin > 1.5x ULN wiht ratio of direct/indirect >1. ALT or AST levels > 5x ULN INR prolonged to >1.5x ULN Exclusion criteria related to PegIFN and/or RBV restrictions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 240 mg QD TN<br>240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients | Drug: BI 201335 NA 240 mg QD<br>* 240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks<br>* Other names: Faldaprevir;Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks<br>|
| Experimental: 240 mg QD / LI-TN<br>240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients | Drug: BI 201335 NA 240 mg QD / LI<br>* 240mg BI 201335 NA (Faldaprevir) once daily with a 3 days lead-in phase of PegIFN/RB, 24 weeks<br>* Other names: Faldaprevir;Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo once daily combined with PegIFN/RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients | Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: 120 mg QD / LI-TN<br>120 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in (LI) phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), followed by an additional 24 weeks of PegIFN/RBV in treatment naive (TN) patients | Drug: BI 201335 NA 120mg QD / LI<br>* 120mg BI 201335 NA (Faldaprevir) once daily, for 24 weeks<br>* Other names: Faldaprevir;Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks<br>|
| Experimental: 240 mg QD TE<br>240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV in treatment experienced (TE) patients | Drug: BI 201335 NA 240 mg QD<br>* 240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks<br>* Other names: Faldaprevir;Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks<br>|
| Experimental: 240 mg QD / LI-TE<br>240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-experienced (TE) patients | Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks<br>Drug: BI 201335 NA 240 mg QD<br>* 240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks<br>* Other names: Faldaprevir;|
| Experimental: 240 mg BID / LI-TE<br>240mg BI 201335 NA (Faldaprevir) twice daily combined with PegIFN/RBV for 24 or 48 weeks, with 3-day lead-in phase of PegIFN/RBV, in treatment-experienced patients | Drug: BI 201335 NA 240 mg BID<br>* 240mg BI 201335 NA (Faldaprevir) twice, 24 weeks<br>* Other names: Faldaprevir;Drug: PegIFN/RBV<br>* PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Response 4 Weeks After the End of Treatment With BI 201335 or Placebo | An achieved virological response is defined as the plasma Hepatitis C Virus RiboNucleic Acid (HCV RNA) level below the lower limit of detection (BLD). This data was only collected for patients, who stopped trial participation at Week 24 and did not continue with PegIFN/RBV until Week 48. The lower limit of quantification (BLQ) of this assay was 25 IU/mL and the lower limit of detection (BLD) was 10 IU/mL at the time of the protocol finalisation. During the course of the trial, the manufacturer defined BLD as '< 25 IU/mL, not detectable' and BLQ as '< 25 IU/mL, detectable'. | Week 28 | 
| Sustained Virological Response 24 Weeks (SVR24) After Completion of All Therapy | Virological (VL) response was defined as the plasma HCV RNA level below the lower limit of detection. The first VL measurement that occurred in the time window ≥ Day 155 (from End Of Treatment on) was selected for the determination of SVR24. Therefore, patients with virological load BLD 24 weeks after completion of therapy, who had a rebound after this time point (outside the defined time window of 155 days after end of all treatments) were identified as SVR24 achieved. | Day 155 after the end of all treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological Response at Week 2 | Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 2 (< 25 IU/ml, detectable or undetectable) | Week 2 | 
| Virological Response at Week 4 | Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 4 (< 25 IU/ml, detectable or undetectable) | Week 4 | 
| Early Virological Response (EVR) | Early Virological Response (EVR) is defined as ≥ 2 log 10 reduction in plasma HCV RNA level from baseline at Week 12 | Baseline and Week 12 | 
| Extended Rapid Virological Response (eRVR) | Extended Rapid Virological Response (eRVR) is defined as plasma HCV RNA levels below the lower limit of quantification at Week 4 and below the lower limit of detection at Week 12 | Week 4 and Week 12 | 
| Complete Early Virological Response (cEVR) | Complete Early Virological Response (cEVR) is defined as plasma HCV RNA level below the lower limit of detection at Week 12 | Week 12 | 
| End of Treatment Response at Week 24 | End of Treatment Response of BI 201335 or placebo (ETR BI 201335/placebo ) is defined as plasma HCV RNA level below the lower limit of detection at Week 24. | Week 24 | 
| End of Treatment Response at End of All Therapy | End of Treatment Response (ETR) is defined as plasma HCV RNA level below the lower limit of detection at end of all therapy, i.e. at Week 24 or Week 48 | Week 24 or Week 48 | 
| Sustained Virological Response 12 Weeks (SVR12) After Completion of All Therapy | Sustained Virological Response 12 Weeks (SVR12) after completion of all therapy is defined as plasma HCV RNA level below the lower limit of detection at 12 weeks after completion of all therapy, i.e. at Week 36 or 60 | Week 36 or Week 60 | 
| Time to Reach a Plasma HCV RNA Level Below the Lower Limit of Detection | Summary of time (i.e Median number of days) to reach a plasma HCV RNA level below limit of detection (BLD) | On or after day 155 post end of all treatment | 
| Time to Loss of Virological Response | Time to loss of virological response, defined as the last value below the lower limit of detection in a patient who subsequently had 2 consecutive plasma HCV RNA level measurements ≥100 IU/mL. Patients that did not achieve suppression of plasma HCV RNA levels below the lower limit of detection until Week 24 were defined as having a time to failure of zero. Time is expressed in Median number of days. | Week 24 | 
| Virological Rebound | Virological rebound is defined as increase of ≥ 1 log 10 in plasma HCV RNA level from a quantifiable nadir, or to ≥ 250 IU/mL after previous nadir < 25 IU/mL (detectable), or to ≥ 100 IU/mL after a previous viral load below the lower limit of detection. Note that this is numerical rebound, not requiring confirmation with a re-measurement. | Week 24 or Week 48 | 
| Breakthrough on BI 201335/Placebo (Rebound While All 3 Treatments Were Still Ongoing) | Number of patients with Unconfirmed rebound ( ≥ 1log10 increase in HCV mRNA) while on BI201335/placebo + 5 days washout. | Up to Week 24 | 
| Breakthrough on PegIFN/RBV (Rebound While Only PegIFN/RBV Treatment Alone Was Still Ongoing) | Number of patients with Unconfirmed rebound (≥ 1log10 increase in HCV mRNA) while on PegIFN/RBV treatment + 5 days washout. | Week 24 through Week 48 | 
| Relapse | Relapse was rebound after the viral load at end of all treatment had been below the lower limit of detection, or, if the value at end of all treatment was missing, after both the last value before End of Treatment (EOT) and the first value after End of Treatment were below the lower limit of detection. Patients could experience relapse at any point post-treatment. | post-End of treatment (i.e. post 48 weeks) | 
| Change From Baseline to Week 24 in Diastolic Blood Pressure and Systolic Blood Pressure | Baseline is defined as the last value before the initial drug administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Pulse Rate | Baseline is defined as the last value before the administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Weight of the Patients | Baseline is defined as the last value before the administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Global Assessment of Tolerability | The investigator was to assess the tolerability of trial medication based on adverse events (AEs) and the laboratory evaluation. Tolerability was assessed by the investigator according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'. | Week 24 | 
| Change From Baseline to Week 24 in Haemoglobin of the Patients | Baseline is defined as the last value before the administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Haemoglobin | Number of patients with normal or high baseline moved to low . | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Absolute Neutrophils of the Patients | Baseline is defined as the last value before the administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Absolute Neutrophils | Number of patients with normal or high baseline moved to low . | Baseline and Week 24 | 
| Change From Baseline to Week 24 in ALT/GPT,SGPT of the Patients | Baseline is defined as the last value before the drug administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter ALT/GPT,SGPT | Number of patients with normal or low baseline moved to high . | Baseline and Week 24 | 
| Change From Baseline to Week 24 in Total Bilirubin of the Patients | Baseline is defined as the last value before the administration of BI 201335 or placebo. | Baseline and Week 24 | 
| Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Total Bilirubin | Number of patients with normal or low baseline moved to high . | Baseline and Week 24 | 
| Trough Concentration (Cpre,ss) of Faldaprevir at Steady State | C(pre,ss) is defined as pre-dose (trough) concentration of Faldaprevir in plasma at steady state immediately before administration of the next dose. | Week 8, week 10, week 12, week 24 | 
| Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1000 mg/Day RBV) | C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose. | Week 8, week 10, week 12, week 24 | 
| Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1200 mg/Day RBV) | C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose. | Week 8, week 10, week 12, week 24 | 
| Trough Concentration (Cpre,ss) of PegIFN at Steady State | C(pre,ss) is defined as pre-dose (trough) concentration of PegIFN in plasma at steady state immediately before administration of the next dose. | Week 8, week 10, week 12, week 24 |