A Study of TMC435 Plus Pegylated Interferon Alfa-2a and Ribavirin in Participants With Chronic HCV Infection

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, tolerability, and safety of 12-weeks of treatment with TMC435 plus pegylated interferon alfa-2a (PegIFNα-2a) and ribavirin (RBV) in previously untreated adult participants with genotype 1 or genotype 4 chronic Hepatitis C Virus (HCV) infection.

Detailed Description
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This is a multicenter, international study where all participants will receive triple therapy with the following 3 medications: TMC435 also referred to as simeprevir (formerly known as TMC435350) which is an investigational medication in development for the treatment of chronic hepatitis C virus (HCV) infection, pegylated interferon alfa-2a (PegIFNα-2a), and ribavirin (RBV). PegIFNα-2a and RBV are commercially available therapies for HCV infection. Participants will receive treatment with TMC435, PegIFNα-2a, and RBV for 12 weeks. If blood levels of HCV ribonucleic acid (RNA) monitored at Weeks 2, 4, and 8 are below 25 IU/mL, all treatment will be stopped at Week 12. If HCV RNA values are above 25 IU/mL at Weeks 2, 4, or 8, treatment with PegIFNα-2a and RBV will continue for an additional 12 weeks (up to Week 24) unless protocol-specified stopping criteria are met at Week 4 or 12, at which time all treatment will be discontinued. The study will be conducted in 3 phases: a screening phase of maximum 6 weeks, a treatment phase extending from Day 1 (baseline) up to 12 or 24 weeks depending on the response to treatment, and a posttreatment follow-up period of 24 weeks after the participant's last planned dose of study drug. The duration of the participation (excluding screening phase) for each participant will vary between 36 and 48 weeks, depending on the response to treatment. Blood samples for laboratory analysis will be obtained from participants at protocol-specified time points during the study and participant safety will be monitored throughout the study.

Official Title
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A Phase 3, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of TMC435 Plus Pegylated Interferon Alfa-2a and Ribavirin Administered for 12 Weeks in Treatment-Naïve Subjects With Chronic Genotype 1 or Genotype 4 HCV Infection

Conditions
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Hepatitis C, Chronic, Infection

Intervention / Treatment
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* Drug: TMC435
* Drug: Pegylated interferon alfa-2a (PegIFNα-2a)
* Drug: Ribavirin (RBV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: treatment-naïve with confirmed chronic Hepatitis C Virus (HCV) infection liver biopsy performed within 2 years prior to screening or non-invasive confirmation of the liver disease stage (by transient elastography) performed within 6 months prior to screening liver disease stage equivalent to Metavir Score F0-F2 (no fibrosis, or portal fibrosis without or with few septa) Exclusion Criteria: -Participants with advanced liver disease equivalent to Metavir score F3-F4 (bridging fibrosis or cirrhosis), with hepatic decompensation, with any liver disease of non-HCV etiology, and/or with a non-genotype 1 or non-genotype 4 hepatitis C, hepatitis B or HIV co-infection will be excluded from the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMC435 + PegIFNα-2a + RBV<br>TMC435 will be administered as triple therapy with pegylated interferon alfa-2a (PegIFNα-2a) and ribavirin (RBV). | Drug: TMC435<br>* 150 mg taken orally (by mouth) as a capsule with food once daily for 12 weeks.<br>Drug: Pegylated interferon alfa-2a (PegIFNα-2a)<br>* 180 mcg administered according to the manufacturer's prescribing information as a 0.5 mL subcutaneous (under the skin) (SC) injection once a week in the morning or evening for up to 24 weeks.<br>* Other names: Pegasys;Drug: Ribavirin (RBV)<br>* 1000 mg or 1200 mg administered according to the manufacturer's prescribing information for up to 24 weeks. If the participant's baseline body weight is < 75 kg, the total daily dose of RBV will be 1000 mg, administered orally (by mouth) as 400 mg (2 tablets of 200 mg, intake with food) in the morning and 600 mg (3 tablets of 200 mg, intake with food) in the evening. If the baseline body weight is > or = 75 kg, the total daily dose will be 1200 mg, administered as 600 mg in the morning and evening (3 tablets of 200 mg per intake, with food).<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion (percentage) of participants infected wtih genotype 1 HCV with a sustained virologic response 12 weeks after planned end of treatment (SVR12) | Participants are considered to have reached SVR12 if at the actual end of treatment hepatitis C virus (HCV) ribonucleic acid (RNA) levels < 25 IU/mL undetectable, AND at the time point of SVR12 (i.e., 12 weeks after the planned end of treatment [EOT]), HCV RNA levels < 25 IU/mL undetectable. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion (percentage) of participants infected wtih genotype 4 HCV with a sustained virologic response 12 weeks after planned end of treatment (SVR12) | See SVR12 defined above. | Week 24 | 
| The proportion (percentage) of participants who achieve rapid virologic response (RVR) | Rapid virologic response (RVR) defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < 25 IU/mL undetectable measured 4 weeks after start of treatment. RVR will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Week 4 | 
| The proportion (percentage) of participants who achieve virologic response at Week 2 (W2VR) | Virologic response at Week 2 (W2VR) defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < 25 IU/mL (detectable or undetectable) measured 2 weeks after start of treatment. W2VR will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Week 2 | 
| The proportion (percentage) of participants with sustained virologic response 24 weeks after planned end of treatment (SVR24) | Participants are considered to have reached SVR24 if at the actual end of treatment hepatitis C virus (HCV) ribonucleic acid (RNA) levels < 25 IU/mL undetectable, AND at the time point of SVR24 (i.e., 24 weeks after the planned end of treatment [EOT]) HCV RNA levels < 25 IU/mL undetectable. SVR24 will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Week 48 | 
| The proportion (percentage) of participants with sustained virologic response 12 weeks after planned end of treatment (SVR12) | SVR12 (defined above) will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Week 24 | 
| The proportion (percentage) of participants with > or = 2 log decrease in hepatitis C virus (HCV) RNA at each time point | To be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Up to Week 48 | 
| The proportion (percentage) of participants with hepatitis C virus (HCV) RNA < 25 IU/mL undetectable at each time point | To be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Up to Week 48 | 
| The proportion (percentage) of participants with viral breakthrough | Viral breakthrough is a confirmed increase of > 1 log10 IU/mL in hepatitis C virus (HCV) ribonucleic acid (RNA) level from the lowest level reached, or a confirmed HCV RNA level of > 100 IU/mL in participants whose HCV RNA levels had previously been below the limit of quantification (< 25 IU/mL detectable) or undetectable (< 25 IU/mL undetectable) while on study treatment. Viral breakthrough will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Up to Week 48 | 
| The proportion (percentage) of participants with viral relapse | Participants are considered to have a viral relapse if at actual end of treatment hepatitis C virus (HCV) ribonucleic acid (RNA) levels < 25 IU/mL undetectable, AND during the follow-up period HCV RNA levels > or = 25 IU/mL. Viral relapse will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately). | Up to Week 48 | 
| Change from Baseline in the Hepatitis C Treatment Symptom & Impact Questionnaire (HCV SIQ) symptom and impact scores | The HCV SIQ asks participants to rate 26 symptoms associated with HCV or its treatment and how symptoms impacted the participants' life during the prior week. This questionnaire provides a simple tool for monitoring symptoms during HCV treatment and follow-up. To be assessed in participants with genotype 1 or genotype 4 HCV infection for both genotypes combined (subanalyses for each genotype separately will also be done). | Day 1 and at each study visit up to Week 48 | 
| Change from Baseline in The Fatigue Severity Scale (FSS) total score | The FSS will be used to document fatigue severity and impact of fatigue on participants' daily lives. To be assessed in participants with genotype 1 or genotype 4 HCV infection for both genotypes combined (subanalyses for each genotype separately will also be done). | Day 1 and at each study visit up to Week 48 | 
| Change from Baseline in The Center for Epidemiologic Studies Depression Scale (CES-D) score | The CES-D is a brief assessment that asks participants to rate how often in the past week they experienced 20 symptoms associated with depressive illness, will be used to assess depressive symptom severity. To be assessed in participants with genotype 1 or genotype 4 HCV infection for both genotypes combined (subanalyses for each genotype separately will also be done). | Day 1 and at each study visit up to Week 48 | 
| Change from Baseline in The Work Productivity and Activity Index (WPAI) for Hepatitis C missed work time, daily activity impairment, and productivity scores | The (WPAI) will be used to measure the impact of HCV on time missed from work (absenteeism), reduced performance while at work (productivity impairment), and impairment in daily activities without regard to employment status. To be assessed in participants with genotype 1 or genotype 4 HCV infection for both genotypes combined (subanalyses for each genotype separately will also be done). | Day 1 and at each study visit up to Week 48 | 
| Change from Baseline in The EuroQol 5 Dimension (EQ5D) Visual Analog Scale (VAS) valuation index, and Descriptive System scores | The EQ-5D questionnaire is an instrument designed to assess overall health status using 5 health dimension scores (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a thermometer visual analog scale (VAS) ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). To be assessed in participants with genotype 1 or genotype 4 HCV infection for both genotypes combined (subanalyses for each genotype separately will also be done). | Day 1 and at each study visit up to Week 48 | 
| The proportion (percentage) of participants with normalized alanine aminotransferase (ALT) levels | To be assessed in participants with genotype 1 or genotype 4 HCV infection (separately by genotype) | Up to Week 48 | 
| Change from Screening in liver disease stage assessment | To be assessed in participants with genotype 1 or genotype 4 HCV infection (separately by genotype). | Week -6; Week 48 | 
| The number of participants reporting adverse events as a measure of safety and tolerability | All participants will be monitored throughout the study for the occurrence of adverse events including psychiatric symptoms, anemia, hyperglycemia (elevated glucose levels), disturbances in serum creatinine levels (a measure of renal [kidney] safety), decreased White Blood Cell (WBC) Count, decreased Platelet Count (ability of the blood to clot), and thyroid abnormalities. | Up to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C, Chronic, Infection, Triple therapy, TMC435, simeprevir, Pegylated interferon alfa-2a (PegIFNα-2a), ribavirin (RBV), PEGASYS, COPEGUS