Boceprevir (SCH 503034) Plus Peg-Intron, With and Without Added Ribavirin, in Patients With Chronic Hepatitis C, Genotype 1, Who Did Not Respond to Previous Treatment With Peginterferon Alfa Plus Ribavirin (Study P03659AM2)(COMPLETED)

Study Overview
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Brief Summary
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The primary objective of this study is to determine the safe and effective dose range of boceprevir (SCH 503034) in combination with PEG-Intron in adult subjects who have chronic hepatitis C without cirrhosis, and who have failed an adequate course of combination therapy with peginterferon-alfa plus ribavirin. A secondary objective is to explore whether ribavirin provides an additional benefit when combined with PEG-Intron plus boceprevir.

Official Title
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PEG-Intron/REBETOL vs PEG-Intron/ SCH 503034 With and Without Ribavirin in Chronic Hepatitis C Virus Genotype 1 (HCV-1) Peginterferon Alfa/Ribavirin Nonresponders: A SCH 503034 Dose-Finding Phase 2 Study

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Boceprevir (BOC)
* Biological: PegIntron (PEG)
* Drug: Ribavirin (RBV)


Participation Criteria
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Eligibility Criteria
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Key inclusion criteria: Documented infection with chronic hepatitis C (CHC), genotype 1. Documented failure to respond to an adequate course of treatment (minimum 12 weeks) with peginterferon-alfa plus ribavirin (failure defined as <2 log drop in HCV-RNA after 12 weeks of therapy or those who never become Hepatitis C Virus Ribonucleic Acid (HCV)-RNA negative) No evidence of cirrhosis on liver biopsy. Results of physical examination and laboratory tests within specified ranges. Abstinence from use of abused substances. Key exclusion criteria: Women who are pregnant or nursing a child. Patients with cirrhosis, co-infection with Hepatitis B or human immunodeficiency virus (HIV), and African-American patients (by protocol amendment 2, African-American patients can enroll). Previous treatment with any Hepatitis C Virus (HCV) polymerase or protease inhibitor. Patients who relapsed following response to previous treatment. Evidence of advanced liver disease, or liver disease from a cause other than CHC. Pre-existing psychiatric condition.

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 |
| --- | --- |
| Active Comparator: Arm 1A: PegIntron (PEG) + Ribavirin (RBV)<br>A single dose of PEG is given first, followed 1 week later by PEG + RBV for 12 weeks. If HCV-RNA is undetected, PEG + RBV will continue for another 36 weeks. | Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>Drug: Ribavirin (RBV)<br>* 200 mg capsules taken twice daily (BID) (total daily dose of 800-1400 mg/day, depending on weight [weight-based dosing {WBD}])<br>|
| Active Comparator: Arm 1B: PegIntron (PEG)+Ribavirin (RBV)+Boceprevir (BOC) 400<br>A single dose of PEG is given first, followed 1 week later by PEG + RBV for 12 weeks. If HCV-RNA is detectable, BOC 400 mg TID will be added for 36 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>Drug: Ribavirin (RBV)<br>* 200 mg capsules taken twice daily (BID) (total daily dose of 800-1400 mg/day, depending on weight [weight-based dosing {WBD}])<br>|
| Experimental: Arm 2: PegIntron (PEG) + Boceprevir (BOC) 100 (48 weeks)<br>A single dose of PEG is given first, followed 1 week later by PEB + BOC 100 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>|
| Experimental: Arm 3: PegIntron (PEG) + Boceprevir (BOC) 200 (48 Weeks)<br>A single dose of PEG is given first, followed 1 week later by PEG + BOC 200 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>|
| Experimental: Arm 4: PegIntron (PEG) + Boceprevir (BOC) 400 (48 weeks)<br>A single dose of PEG is given first, followed 1 week later by PEG + BOC 400 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>|
| Experimental: Arm 5: PegIntron (PEG)+Ribavirin (RBV)+Boceprevir (BOC) 400<br>A single dose of PEG is given first, followed 1 week later by PEG + RBV + BOC 400 for 48 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>Drug: Ribavirin (RBV)<br>* 200 mg capsules taken twice daily (BID) (total daily dose of 800-1400 mg/day, depending on weight [weight-based dosing {WBD}])<br>|
| Experimental: Arm 6: PegIntron (PEG) + Boceprevir (BOC) 400 (24 Weeks)<br>A single dose of PEG is given first, followed 1 week later by PEG + BOC 400 for 24 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>|
| Experimental: Arm 7: PegIntron (PEG) + Boceprevir (BOC) 800<br>By first protocol amendment to P03659, this non-randomized arm is added. A single dose of PEG is given first, followed 1 week later by PEG + BOC 800 for 24 weeks. By second protocol amendment to P03659, participants will be rolled over into Arm 8 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>|
| Experimental: Arm 8: PegIntron (PEG)+Ribavirin (RBV)+Boceprevir (BOC) 800<br>By second protocol amendment to P03659, participants from all arms except Arm 1A will be rolled over into PEG + RBV + BOC 800 for the remainder of the treatment period. | Drug: Boceprevir (BOC)<br>* 100 or 200 mg capusles taken orally as 100 mg, 200 mg, 400 mg, or 800 mg TID<br>* Other names: SCH 503034;Biological: PegIntron (PEG)<br>* 1.5 mcg/kg weekly subcutaneously<br>Drug: Ribavirin (RBV)<br>* 200 mg capsules taken twice daily (BID) (total daily dose of 800-1400 mg/day, depending on weight [weight-based dosing {WBD}])<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Were Hepatitis C Virus Ribonucleic Acid (HCV-RNA) Negative at the End of Treatment (EoT) | Sustained Viral Response (SVR) was defined as the percentage of participants with HCV-RNA undetectable at the follow-up Week 24. All percentages were based on the total number of participants originally randomized/enrolled to that particular arm. For Arm 1B, the denominator for the percentages was the number who received at least 1 dose of BOC. Arm 1A was not analyzed. | Baseline up to Week 49 | 
| Percent of Participants Who Achieved Sustained Virologic Response (SVR) | SVR was defined as the percentage of participants with Hepatitis C Virus Ribonucleic Acid (HCV-RNA) undetectable at the follow-up Week 24. All percentages were based on the total number of participants originally randomized/enrolled to that particular arm. For Arm 1B, the denominator for the percentages was the number who received at least 1 dose of BOC. Arm 1A was not analyzed. | Baseline up to Week 73 [24 weeks after end of treatment (EoT)] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Achieved Sustained Viral Response (SVR) by Time to First Negative HCV-RNA | Percentage of participants who became HCV-RNA undetectable within the first 13 weeks and subsequently became HCV-RNA positive were not considered negative for this analysis. | Baseline up to Week 73 [24 weeks after EoT] | 
| Percentage of Participants Who Were HCV-RNA Negative at EoT After Receiving 1 Week of Treatment With PegIntron (PEG) by Log Drop | For each log drop category (<0, 0 to 0.5, 0.5 to <1, 1 to <1.5, ≥1.5, and Missing), the percentage of participants receiving combination therapy who were HCV-RNA negative at EoT (Week 49) was calculated as follows: Number of participants in a log category who were HCV-RNA negative divided by the total number of participants in that log drop category (n). Percentages were NOT derived using treatment arm N values. The sum of the n values for all 6 log drop categories within a treatment arm equals the overall N for that treatment group. | Week 1 and Week 49 | 
| Percent of Participants With Virologic Response Prior to Amendment 2 | Virologic response was defined as the percentage of participants with Hepatitis C Virus Ribonucleic Acid (HCV-RNA) ≤10,000 IU/mL. | Week 3, Week 5, Week 13 | 
| Peak Plasma Concentration of Boceprevir (BOC) | All plasma samples were assayed using a validated liquid chromatography with tandem mass spectrometric detection (LCMS/MS) method. | All visits during treatment (baseline to Week 49) except Day 1 of Week 1 | 
| Area Under the Plasma Concentration-time Curve of Boceprevir Plasma Concentration for an 8-hour Dosing Period | All plasma samples were assayed using a validated liquid chromatography with tandem mass spectrometric detection (LCMS/MS) method. The dosing interval of 8 hours is represented as the hr in the unit of measure. | All visits during treatment (baseline to Week 49) except Day 1 of Week 1 | 
| Trough Plasma Concentration Level | All plasma samples were assayed using a validated liquid chromatography with tandem mass spectrometric detection (LCMS/MS) method. | All visits during treatment (baseline to Week 49) except Day 1 of Week 1 | 
| Change in Alanine Aminotransferase (ALT) Levels | Change in ALT levels during initial treatment regimen and after rolling into amendment 2 as compared to baseline. | Baseline up to dosing change (> 25 weeks) | 
| Number of Participants Who Were HCV-RNA Negative During Amendment 2 (AM2) for Those Who Started on Arms 2 (PEG+BOC 100), 3 (PEG+BOC 200), 4 (PEG+BOC 400 [48 Weeks]), 6 (PEG+BOC 400 [24 Weeks]) | Log drop at baseline of dosing change = difference of log viral loads between baseline (closest to the treatment begin date) and dosing change baseline (virology value closest to the dosing change begin date). | From dosing change to end of follow-up (Week 73)(up to 48 weeks) | 
| Number of Participants Who Were HCV-RNA Negative During Amendment 2 (AM2) for Those Who Started on PegIntron (PEG) + Rebetol (RVB) + Boceprevir (BOC) 400 (Arm 5) | Log drop at baseline of dosing change = difference of log viral loads between baseline (closest to the treatment begin date) and dosing change baseline (virology value closest to the dosing change begin date). | From dosing change to end of follow-up (Week 73)(up to 48 weeks) | 
| Number of Participants Who Were HCV-RNA Negative During Amendment 2 (AM2) for Those Who Started on PegIntron (PEG) + Boceprevir (BOC) 800 (Arm 7) | Log drop at baseline of dosing change = difference of log viral loads between baseline (closest to the treatment begin date) and dosing change baseline (virology value closest to the dosing change begin date). | From dosing change to end of follow-up (Week 73) (up to 48 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PEG-Intron, Ribavirin, Protease Inhibitor