HCV Infection, Hepatitis C, HIV Infections
Conditions
Keywords
coinfection, protease inhibitor, HIV
Brief summary
The primary objective of this trial is to compare the efficacy of boceprevir (SCH 503034) 800 mg three times a day (TID) orally (PO) in combination with peginterferon alfa-2b (PegIFN-2b) 1.5 µg/kg weekly (QW) subcutaneously (SC) plus weight-based dosing (WBD) of ribavirin (RBV) (600 mg/day to 1400 mg/day) PO to therapy with PegIFN-2b + RBV alone in adult participants coinfected with human immunodeficiency virus (HIV) and previously untreated chronic hepatitis C virus (HCV) genotype 1. Boceprevir is a potent, orally administered, novel serine protease inhibitor, specifically designed to inhibit the HCV nonstructural protein 3 (NS3) protease and, thereby, inhibit viral replication in HCV-infected host cells. The mechanism of inhibition represents a new mechanism of action compared to both interferon alfa and ribavirin. Based on previous experience with PegIFN-2b and RBV in combination with boceprevir in the HCV-monoinfected population, this combination treatment is expected to provide significant benefit to the HIV/HCV coinfected population. Given the high unmet medical need of these participants and the benefit of the addition of boceprevir to PegIFN-2b/RBV, it is important to demonstrate the safety and efficacy of boceprevir in combination with PegIFN-2b/RBV in participants coinfected with HIV/HCV. This is a randomized, multi-center trial, double-blinded for boceprevir or placebo in combination with open-label PegIFN-2b/RBV in participants coinfected with HIV and previously untreated chronic HCV (genotype 1), to be conducted in conformance with Good Clinical Practice (GCP). This trial consists of two arms, one control arm (Arm 1) and one experimental arm (Arm 2). Participants in the control arm (Arm 1) may receive boceprevir/PegIFN-2b/RBV via a crossover arm.
Interventions
DRUGPegIFN-2b
PegIFN-2b (1.5 μg/kg/week subcutaneously)
DRUGRBV
Ribavirin (600-1400 mg/day, orally, divided into two daily doses)
Placebo to boceprevir (orally, three times per day)
DRUGBoceprevir
Boceprevir (800 mg, orally, three times per day)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* \>=18 and \<=65 years of age * Body weight \>=40 and \<=125 kg * Documented history of HIV infection for greater than 6 months prior to Day 1 * On an optimized anti-retroviral treatment regimen (OTR) with stable HIV disease with CD4 \>=200 cells/µL and HIV-1 RNA viral load \<50 copies/mL * Documented chronic hepatitis C (CHC) genotype 1 infection (greater than 6 months prior to Day 1) * Use of acceptable methods of contraception 2 weeks prior to Day 1 and at least 6 months or longer after treatment * Liver biopsy with histology consistent with CHC and no other etiology
Exclusion criteria
* Participants who received prior treatment for hepatitis C other than herbal remedies except those with known hepatotoxicity * Coinfected with hepatitis B virus (Hepatitis B surface antigen (HBsAg) positive) and/or demonstrating signs and symptoms consistent with concomitant infection * Evidence of decompensated liver disease * Participants who have changed their anti-retroviral regimen within the last 3 months prior to Day 1 or had first initiated anti-retroviral therapy within the last 6 months prior to Day 1 * Use of certain HIV medications will not be allowed. Medications will be reviewed by the Investigator * History of clinically significant opportunistic infections (except oral thrush) within the last year prior to Day 1 * Current evidence of substance abuse within 3 years of the Screening Visit * History of a clinical diagnosis within the past 6 months of substance abuse prior to Day 1 * Participants receiving opiate agonist substitution therapy but not enrolled in an opiate substitution maintenance program * History of marijuana use deemed excessive by the Investigator * Infected with HIV-2 * Use of any HIV protease inhibitor without the coadministration of ritonavir within one month of Day 1 and throughout the period of the trial * Participants receiving any of the following medication(s) within 2 weeks prior to the Day 1 visit: alfuzosin, antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, and quinidine), ergot derivatives, cisapride, lovastatin, simvastatin, pimozide, triazolam, and orally administered midazolam. Key Laboratory
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Viral Response (SVR) at Follow-up Week 24 (FW24) Among Randomized Participants Who Received At Least One Dose of Trial Medication | Up to Week 72 | SVR24 is defined as undetectable plasma hepatitis C virus ribonucleic acid (HCV-RNA) at 24 weeks after the end of all study treatment. If there was no value in the FW24 visit window, the closest value available chronologically after this window was used; if a value was still missing after that, the value from Follow-up Week 12 (FW12) was used. HCV-RNA is detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR24 Among Randomized Participants Who Received At Least One Dose of Boceprevir (Experimental) or Placebo (Control) | Up to Week 72 | SVR24 is defined as undetectable plasma HCV-RNA 24 weeks after the end of all study treatment. If there was no value in the FW24 visit window, the closest value available chronologically after this window was used; if a value was still missing after that, the value from FW12 was used. HCV-RNA is detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
| Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | Up to Week 12 | EVR was defined as undetectable HCV-RNA at Treatment Week (TW) 2, 4, 8, or 12. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
| Percentage of Participants With Undetectable HCV-RNA at Follow-up Week 12 (FW12) | Up to Week 60 | The virologic response at FW12 was considered SVR12 with an additional rule for handling missing data: participants with missing HCV-RNA assessment at FW12 but having non-missing, undetectable HCV-RNA assessments at both FW4 and FW24, were assumed to be responders for SVR12. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
| Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Baseline and Week 4 | This is a measure of the change in the amount of HCV-RNA in the plasma at the end of 4 weeks of treatment. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
| Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound | Up to Week 72 | Virologic breakthrough is defined as achieving undetectable HCV-RNA and subsequently having an HCV-RNA level of \>1000 IU/mL. Incomplete Virologic Response/Rebound is defined as having a one log10 increase in HCV-RNA from the participant's nadir, with an HCV-RNA \>1000 IU/mL. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL. |
Participant flow
Pre-assignment details
One participant in the pegylated interferon alfa-2b (PegIFN-2b) + ribavirin (RBV) + boceprevir group withdrew from the study after randomization but prior to administration of any study treatment.
Participants by arm
| Arm | Count |
|---|---|
| PegIFN-2b + RBV PegIFN-2b (1.5 µg/kg/week subcutaneously) plus RBV (600-1400 mg/day, orally, divided into two daily doses) for 4 weeks followed by placebo to boceprevir plus PegIFN-2b/RBV for 44 weeks with 24 weeks post-treatment follow-up (Control Arm). Participants who do not achieve HCV-RNA \<9.3 IU/mL by Treatment Week 24 (TW24) are eligible to cross-over and receive boceprevir along with the PegIFN-2b and RBV for up to 44 weeks. | 34 |
| PegIFN-2b + RBV + Boceprevir PegIFN-2b (1.5 µg/kg/week subcutaneously) plus RBV (600- 1400 mg/day, orally, divided into two daily doses) for 4 weeks followed by boceprevir (800 mg, orally, 3 times per day) plus PegIFN-2b/RBV for 44 weeks with 24 weeks post-treatment follow-up. | 64 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Lost to Follow-up | 3 | 2 |
| Follow-up Period | Withdrawal by Subject | 3 | 4 |
| Treatment Period | Adverse Event | 3 | 13 |
| Treatment Period | Did not receive treatment | 0 | 1 |
| Treatment Period | Futility/crossover to boceprevir | 4 | 0 |
| Treatment Period | Lack of Efficacy | 15 | 6 |
| Treatment Period | Lost to Follow-up | 0 | 1 |
| Treatment Period | Non-Compliance with Protocol | 0 | 1 |
| Treatment Period | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | PegIFN-2b + RBV | PegIFN-2b + RBV + Boceprevir | Total |
|---|---|---|---|
| Age, Continuous | 45.1 years STANDARD_DEVIATION 9.8 | 42.9 years STANDARD_DEVIATION 8.3 | 43.6 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 12 Participants | 18 Participants | 30 Participants |
| Sex: Female, Male Male | 22 Participants | 46 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 33 / 34 | 62 / 64 | 4 / 4 |
| serious Total, serious adverse events | 7 / 34 | 11 / 64 | 0 / 4 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Viral Response (SVR) at Follow-up Week 24 (FW24) Among Randomized Participants Who Received At Least One Dose of Trial Medication
SVR24 is defined as undetectable plasma hepatitis C virus ribonucleic acid (HCV-RNA) at 24 weeks after the end of all study treatment. If there was no value in the FW24 visit window, the closest value available chronologically after this window was used; if a value was still missing after that, the value from Follow-up Week 12 (FW12) was used. HCV-RNA is detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Up to Week 72
Population: All randomized participants receiving at least one dose of any study medication (Full Analysis Set); this includes 3 participants who did not enter the Follow-Up Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PegIFN-2b + RBV | Percentage of Participants Achieving Sustained Viral Response (SVR) at Follow-up Week 24 (FW24) Among Randomized Participants Who Received At Least One Dose of Trial Medication | 29.4 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants Achieving Sustained Viral Response (SVR) at Follow-up Week 24 (FW24) Among Randomized Participants Who Received At Least One Dose of Trial Medication | 62.5 percentage of participants |
Comparison: The methodology for 95% Confidence Interval (CI) is based on a Modified Koch approach which adjusted for Randomization Strata of Cirrhosis/Fibrosis (Yes or No). The adjustment of randomization strata of HCV-RNA (\< or \>= 800,000 IU/mL) was not possible due to sparse data.p-value: 0.000895% CI: [14.1, 53.3]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4)
This is a measure of the change in the amount of HCV-RNA in the plasma at the end of 4 weeks of treatment. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Baseline and Week 4
Population: All randomized participants receiving at least one dose of any study medication (Full Analysis Set); this includes 3 participants who did not enter the Follow-Up Period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PegIFN-2b + RBV | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with <1 positive log drop | 15 participants |
| PegIFN-2b + RBV | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with >= 1 positive log drop | 16 participants |
| PegIFN-2b + RBV | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with undetectable HCV-RNA | 3 participants |
| PegIFN-2b + RBV | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with missing data | 0 participants |
| PegIFN-2b + RBV + Boceprevir | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with missing data | 1 participants |
| PegIFN-2b + RBV + Boceprevir | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with <1 positive log drop | 28 participants |
| PegIFN-2b + RBV + Boceprevir | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with undetectable HCV-RNA | 3 participants |
| PegIFN-2b + RBV + Boceprevir | Change From Baseline in log10 HCV-RNA at Treatment Week 4 (TW4) | Participants with >= 1 positive log drop | 32 participants |
Secondary
Percentage of Participants Achieving SVR24 Among Randomized Participants Who Received At Least One Dose of Boceprevir (Experimental) or Placebo (Control)
SVR24 is defined as undetectable plasma HCV-RNA 24 weeks after the end of all study treatment. If there was no value in the FW24 visit window, the closest value available chronologically after this window was used; if a value was still missing after that, the value from FW12 was used. HCV-RNA is detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Up to Week 72
Population: All randomized participants receiving one dose of boceprevir (PegIFN-2b + RBV + Boceprevir group) or placebo to boceprevir (PegIFN-2b + RBV group), defined as the Modified Intent-to-Treat Population; this includes 2 participants who did not enter the Follow-up Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PegIFN-2b + RBV | Percentage of Participants Achieving SVR24 Among Randomized Participants Who Received At Least One Dose of Boceprevir (Experimental) or Placebo (Control) | 30.3 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants Achieving SVR24 Among Randomized Participants Who Received At Least One Dose of Boceprevir (Experimental) or Placebo (Control) | 64.5 percentage of participants |
Comparison: The methodology for 95% CI is based on the asymptotic normal approximation to the binomial distributionp-value: 0.000795% CI: [14.5, 53.9]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24
EVR was defined as undetectable HCV-RNA at Treatment Week (TW) 2, 4, 8, or 12. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Up to Week 12
Population: All randomized participants receiving at least one dose of any study medication (Full Analysis Set); this includes 3 participants who did not enter the Follow-Up Period. No participants had undetectable HCV-RNA at Week 2; the n value in the table below represents the number of participants with EVR at that time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PegIFN-2b + RBV | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 2 (n=0, 0) | 0 percentage of participants |
| PegIFN-2b + RBV | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 4 (n=3, 3) | 100 percentage of participants |
| PegIFN-2b + RBV | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 8 (n=5, 27) | 100 percentage of participants |
| PegIFN-2b + RBV | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 12 (n=8, 38) | 87.5 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 12 (n=8, 38) | 92.1 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 2 (n=0, 0) | 0 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 8 (n=5, 27) | 92.6 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With Early Virologic Response (EVR) Who Achieved SVR24 | HCV-RNA undetectable at Week 4 (n=3, 3) | 100 percentage of participants |
Secondary
Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound
Virologic breakthrough is defined as achieving undetectable HCV-RNA and subsequently having an HCV-RNA level of \>1000 IU/mL. Incomplete Virologic Response/Rebound is defined as having a one log10 increase in HCV-RNA from the participant's nadir, with an HCV-RNA \>1000 IU/mL. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Up to Week 72
Population: All randomized participants receiving at least one dose of any study medication (Full Analysis Set); this includes 3 participants who did not enter the Follow-Up Period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PegIFN-2b + RBV | Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound | Virologic breakthrough | 0 percentage of participants |
| PegIFN-2b + RBV | Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound | Incomplete response | 17.6 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound | Virologic breakthrough | 6.3 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With HCV Virologic Breakthrough or Incomplete Virologic Response/Rebound | Incomplete response | 9.4 percentage of participants |
Secondary
Percentage of Participants With Undetectable HCV-RNA at Follow-up Week 12 (FW12)
The virologic response at FW12 was considered SVR12 with an additional rule for handling missing data: participants with missing HCV-RNA assessment at FW12 but having non-missing, undetectable HCV-RNA assessments at both FW4 and FW24, were assumed to be responders for SVR12. HCV-RNA was detected by a nucleic acid amplification test and the lower limit of detection for this assay is 9.3 IU/mL.
Time frame: Up to Week 60
Population: All randomized participants receiving at least one dose of any study medication (Full Analysis Set); this includes 3 participants who did not enter the Follow-Up Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PegIFN-2b + RBV | Percentage of Participants With Undetectable HCV-RNA at Follow-up Week 12 (FW12) | 26.5 percentage of participants |
| PegIFN-2b + RBV + Boceprevir | Percentage of Participants With Undetectable HCV-RNA at Follow-up Week 12 (FW12) | 62.5 percentage of participants |