A Triple Combination Therapy Study of Boceprevir, Pegasys and Copegus in Previously Untreated Patients With Genotype 1 Chronic Hepatitis C

Study Overview
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Brief Summary
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This open-label, multicenter, treatment response guided study will evaluate the sustained virological response and safety of the triple combination therapy boceprevir, Pegasys (peginterferon alfa-2a) and Copegus (Ribavirin) in previously untreated patients with genotype 1 chronic hepatitis C. In the lead-in phase, patients will receive a dual combination therapy of Pegasys and Copegus for 4 weeks. In the following triple combination therapy phase, 800 mg boceprevir, 180 mcg Pegasys and 1000-1200 mg Copegus will be administered for 24, 32 or 44 weeks; the duration depending on the patient's treatment response. The anticipated time on study treatment is up to 48 weeks.

Official Title
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An International, Multicenter, Open-Label Study Evaluating Sustained Virological Response and Safety With Boceprevir in Triple Combination Therapy With Peginterferon Alfa-2a (40KD) and Ribavirin in Treatment-Naïve Patients With Genotype 1 Chronic Hepatitis C

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: boceprevir
* Drug: peginterferon alfa-2a [Pegasys]
* Drug: peginterferon alfa-2a [Pegasys]
* Drug: ribavirin (Copegus]
* Drug: ribavirin (Copegus]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients >/=18 years of age Chronic liver disease consistent with chronic hepatitis C, genotype 1 infection Serum HCV RNA quantifiable at screening Patients who have not been previously treated with pegylated interferon (IFN), standard IFN, RBV or any direct acting anti-viral agent Compensated liver disease (Child-Pugh Grade A clinical classification for patients with cirrhosis: total score </=6) Negative urine or blood pregnancy test (for women of childbearing potential) Exclusion Criteria: Women with ongoing pregnancy or breast feeding Male partners of women who are pregnant Therapy with any systemic anti-viral, anti-neoplastic or immunomodulatory treatment </=6 months prior to the first dose of study drug Any investigational drug </=6 weeks prior to the first dose of study drug History or other evidence of decompensated liver disease History or other evidence of a medical condition associated with chronic liver disease other than chronic hepatitis C Signs or symptoms of hepatocellular carcinoma Co-infection with HCV genotypes other than genotype 1 Co-infection with hepatitis A, hepatitis B, and/or human immunodeficiency virus (HIV) Any patient with an increased risk for anemia History of severe psychiatric disease History of immunologically mediated, chronic pulmonary, or severe cardiac disease Current diseases that are not adequately controlled

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dual Combination Therapy<br> | Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg subcutaneously once a week for 4 weeks<br>Drug: ribavirin (Copegus]<br>* 1000 mg or 1200 mg orally once a day for 4 weeks<br>|
| Experimental: Triple Combination Therapy<br> | Drug: boceprevir<br>* 800 mg three times daily for 24, 32 or 44 weeks<br>Drug: peginterferon alfa-2a [Pegasys]<br>* 180 mcg subcutaneously once a week for 24, 32 or 44 weeks<br>Drug: ribavirin (Copegus]<br>* 1000 mg or 1200 mg orally once a day for 24, 32 or 44 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virological Response (SVR) at 12 Weeks After End of Treatment (EOT) | SVR at 12 weeks after EOT was defined as an undetectable HCV RNA viral load obtained 12 weeks following completion of treatment. HCV RNA viral load was measured using the Roche COBAS TaqMan 2.0 HCV Test, with a lower limit of detection (LOD) of 10 to 15 international units per milliliter (IU/mL). The percentage of participants with SVR was calculated as [number of participants with undetectable HCV RNA at 12 weeks after EOT divided by the number of participants analyzed] multiplied by 100. | At 12 weeks after EOT (up to 60 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With SVR at 24 Weeks After EOT | SVR at 24 weeks after EOT was defined as an undetectable HCV RNA viral load obtained 24 weeks following completion of treatment. HCV RNA viral load was measured using the Roche COBAS TaqMan 2.0 HCV Test, with a lower LOD of 10 to 15 IU/mL. The percentage of participants with SVR was calculated as [number of participants with undetectable HCV RNA at 24 weeks after EOT divided by the number of participants analyzed] multiplied by 100. | At 24 weeks after EOT (up to 72 weeks) | 
| HCV RNA Levels | HCV RNA levels were obtained routinely during and after treatment. Mean HCV RNA levels were calculated by averaging the HCV RNA levels among all participants analyzed at each collection timepoint and expressed in log10 IU/mL. | At Baseline; Weeks 2, 4, 6, 8, 12, 16, 24, 28, and 36; EOT; and 12 and 24 weeks after EOT (up to 72 weeks) | 
| Percentage of Participants With Virological Response | HCV RNA levels were obtained routinely during and after treatment. The percentage of participants with undetectable HCV RNA viral load (ie, virological response) was calculated as [number of participants with undetectable HCV RNA at each timepoint divided by the number of participants analyzed] multiplied by 100. | At Weeks 2, 4, 6, 8, 12, 16, 24, 28, and 36; and EOT (up to 48 weeks) | 
| Percentage of Participants With at Least a 1-Log, 2-Log, or 3-Log Reduction in HCV RNA | HCV RNA levels were obtained routinely during and after treatment. Reductions in HCV RNA viral load by 1-log, 2-log, or 3-log increments were determined relative to Baseline HCV RNA. Each increment represents a reduction greater than or equal to (≥) the specified log value, including results for which HCV RNA was below the limit of quantification (25 IU/mL). The percentage of participants with each log reduction in HCV RNA was calculated as [number of participants with log reduction divided by the number of participants analyzed] multiplied by 100. | At Weeks 2, 4, 6, 8, 12, 16, 24, and 28 | 
| Percentage of Participants With Virological Relapse Following EOT Response | Virological relapse was defined as a detectable post-treatment HCV RNA viral load following a previously undetectable EOT level (ie, virological response). The percentage of participants with virological relapse was calculated as [number of participants meeting the above criteria divided by the number of participants analyzed] multiplied by 100. | Up to 72 weeks (at 12 and 24 weeks after EOT) | 
| Percentage of Participants With Virological Breakthrough Following On-Treatment Response | Virological breakthrough was defined as an HCV RNA viral load greater than (>) 1000 IU/mL following a previously undetectable level at any time during treatment (ie, virological response). Participants who ultimately achieved an EOT response were not considered for virological breakthrough. The percentage of participants with virological breakthrough was calculated as [number of participants meeting the above criteria divided by the number of participants analyzed] multiplied by 100. | Up to 48 weeks (at Baseline; Weeks 2, 4, 6, 8, 12, 16, 24, 28, and 36; and EOT) | 
| Percentage of Participants With Virological Rebound Following On-Treatment Decline in HCV RNA | Virological rebound was defined as an HCV RNA viral load >1000 IU/mL and a ≥1-log increase from nadir following a decline in HCV RNA from Baseline at any time during treatment (ie, on-treatment decline). Participants who ultimately achieved an EOT response were not considered for virological rebound. The percentage of participants with virological rebound was calculated as [number of participants meeting the above criteria divided by the number of participants analyzed] multiplied by 100. | Up to 48 weeks (at Baseline; Weeks 2, 4, 6, 8, 12, 16, 24, 28, and 36; and EOT) | 
| Percentage of Participants With Treatment Discontinued Based Upon Elevated (Week 12) or Detectable (Week 24) HCV RNA | Treatment was to be discontinued for participants who met prespecified criteria, termed the futility rule, after 12 or 24 weeks of treatment. Participants were discontinued from treatment for one of the following reasons: HCV RNA viral load ≥100 IU/mL (Week 12) or a detectable HCV RNA viral load (Week 24). HCV RNA viral load was measured using the Roche COBAS TaqMan 2.0 HCV Test, with a lower LOD of 10 to 15 IU/mL. The percentage of participants with treatment discontinued for each reason was calculated as [number of participants meeting one of the above criteria divided by the number of participants analyzed] multiplied by 100. | At 12 and 24 weeks | 
| Duration of Treatment With PEG-IFN, RBV, and Boceprevir | The duration of treatment with each study drug was determined as the time from treatment start until the last dose of PEG-IFN, RBV, or boceprevir. Median duration of treatment was determined using the actual duration of treatment among individual participants and expressed in weeks. | Up to 48 weeks (from Baseline until EOT) | 
| Percentage of Participants With a Dose Modification of PEG-IFN, RBV, or Boceprevir By Reason | Dose modifications for each study drug included any dose reduction, treatment interruption, or premature withdrawal. Adverse event (AE)-related reasons were documented, as well as reasons related to insufficient efficacy ('Poor efficacy') or other safety-related reasons ('Safety/other'). The percentage of participants with a dose modification documented for each reason was calculated as [number of participants with dose modification divided by the number of participants analyzed] multiplied by 100. | Up to 48 weeks (from Baseline until EOT) | 
| Percentage of Participants Receiving Target Administrations of PEG-IFN, RBV, and Boceprevir | The frequency of missed treatments was examined using the number of administrations received as a percentage of target administrations for each study drug. The maximum number of possible administrations was considered in terms of once-weekly injections with PEG-IFN and in terms of treatment days with RBV and boceprevir. The percentage of target administrations each participant received was separated into ranges of <60%, 60 to <80%, 80 to <95%, and ≥95% for each study drug. The percentage of participants who received each range of target administrations was calculated as [number of participants in each range divided by the number of participants analyzed] multiplied by 100. | Up to 48 weeks (from Baseline until EOT) | 
| Number of Participants With a Safety-Related Dose Modification | Dose modifications for each study drug included any dose reduction, treatment interruption, or premature withdrawal. The percentage of participants with a safety-related dose modification (eg, modification due to adverse event or laboratory abnormality) of any study drug was calculated as [number of participants with dose modification divided by the number of participants analyzed] multiplied by 100. | Up to 48 weeks (from Baseline until EOT) | 
| Time to Safety-Related Dose Modification | Dose modifications for each study drug included any dose reduction, treatment interruption, or premature withdrawal. Median time to safety-related dose modification (eg, modification due to adverse event or laboratory abnormality) of any study drug was estimated using Kaplan-Meier and expressed in weeks. | Up to 48 weeks (from Baseline until EOT) | 
| Percentage of Participants Using Concomitant Hematopoietic Stimulants During Treatment and Follow-Up | Use of concomitant hematopoietic stimulants (such as epoetin) during the 48-week treatment period and/or within 24 weeks of follow-up was documented. The percentage of participants using concomitant hematopoietic stimulants was calculated as [number of participants reporting concomitant use divided by the number of participants analyzed] multiplied by 100. | Up to 72 weeks (from Baseline until 24 weeks after EOT) | 
| Percentage of Participants With a Concomitant Disease Prior to or During the Study | The prevalence of concomitant disease at any time from Screening through the end of follow-up was documented. The percentage of participants with a concomitant disease was calculated as [number of participants reporting or diagnosed with concomitant disease divided by the number of participants analyzed] multiplied by 100. Diseases documented for ≥5% of participants included hypertension, diabetes mellitus, hypothyroidism, and vitamin D deficiency as reported here. | Up to 76 weeks (from Screening until 24 weeks after EOT) | 
| Percentage of Participants Using Concomitant Medications During Treatment and Follow-Up | Use of concomitant prescription or nonprescription medications during the 48-week treatment period and/or within 24 weeks of follow-up was documented. The percentage of participants using concomitant medications was calculated as [number of participants reporting concomitant use divided by the number of participants analyzed] multiplied by 100. Medication classes reported by >10% of participants included analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, corticosteroids, proton pump inhibitors, vitamins and minerals, and beta-adrenoceptor blocking agents as reported here. | Up to 72 weeks (from Baseline until 24 weeks after EOT) |