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

Sponsor

Janssen-Cilag International NV (Industry)

Overall Status

Completed

CT.gov ID

NCT01846832

Collaborator

(none)

232

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic Infection	Drug: TMC435 Drug: Pegylated interferon alfa-2a (PegIFNα-2a) Drug: Ribavirin (RBV)	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

232 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2013

Actual Primary Completion Date :

Aug 1, 2015

Actual Study Completion Date :

Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMC435 + PegIFNα-2a + RBV TMC435 will be administered as triple therapy with pegylated interferon alfa-2a (PegIFNα-2a) and ribavirin (RBV).	Drug: TMC435 150 mg taken orally (by mouth) as a capsule with food once daily for 12 weeks. Drug: Pegylated interferon alfa-2a (PegIFNα-2a) 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. Other Names: Pegasys Drug: Ribavirin (RBV) 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). Other Names: Copegus

Arm

Intervention/Treatment

Experimental: TMC435 + PegIFNα-2a + RBV

TMC435 will be administered as triple therapy with pegylated interferon alfa-2a (PegIFNα-2a) and ribavirin (RBV).

Drug: TMC435

150 mg taken orally (by mouth) as a capsule with food once daily for 12 weeks.

Drug: Pegylated interferon alfa-2a (PegIFNα-2a)

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.

Other Names:

Pegasys

Drug: Ribavirin (RBV)

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).

Other Names:

Copegus

Outcome Measures

Primary Outcome Measures

The proportion (percentage) of participants infected wtih genotype 1 HCV with a sustained virologic response 12 weeks after planned end of treatment (SVR12) [Week 24]
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.

Secondary Outcome Measures

The proportion (percentage) of participants infected wtih genotype 4 HCV with a sustained virologic response 12 weeks after planned end of treatment (SVR12) [Week 24]
See SVR12 defined above.
The proportion (percentage) of participants who achieve rapid virologic response (RVR) [Week 4]
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).
The proportion (percentage) of participants who achieve virologic response at Week 2 (W2VR) [Week 2]
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).
The proportion (percentage) of participants with sustained virologic response 24 weeks after planned end of treatment (SVR24) [Week 48]
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).
The proportion (percentage) of participants with sustained virologic response 12 weeks after planned end of treatment (SVR12) [Week 24]
SVR12 (defined above) will be assessed for all participants per assigned total treatment duration and per HCV genotype (separately).
The proportion (percentage) of participants with > or = 2 log decrease in hepatitis C virus (HCV) RNA at each time point [Up to Week 48]
To be assessed for all participants per assigned total treatment duration and per HCV genotype (separately).
The proportion (percentage) of participants with hepatitis C virus (HCV) RNA < 25 IU/mL undetectable at each time point [Up to Week 48]
To be assessed for all participants per assigned total treatment duration and per HCV genotype (separately).
The proportion (percentage) of participants with viral breakthrough [Up to Week 48]
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).
The proportion (percentage) of participants with viral relapse [Up to Week 48]
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).
Change from Baseline in the Hepatitis C Treatment Symptom & Impact Questionnaire (HCV SIQ) symptom and impact scores [Day 1 and at each study visit up to Week 48]
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).
Change from Baseline in The Fatigue Severity Scale (FSS) total score [Day 1 and at each study visit up to Week 48]
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).
Change from Baseline in The Center for Epidemiologic Studies Depression Scale (CES-D) score [Day 1 and at each study visit up to Week 48]
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).
Change from Baseline in The Work Productivity and Activity Index (WPAI) for Hepatitis C missed work time, daily activity impairment, and productivity scores [Day 1 and at each study visit up to Week 48]
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).
Change from Baseline in The EuroQol 5 Dimension (EQ5D) Visual Analog Scale (VAS) valuation index, and Descriptive System scores [Day 1 and at each study visit up to Week 48]
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).
The proportion (percentage) of participants with normalized alanine aminotransferase (ALT) levels [Up to Week 48]
To be assessed in participants with genotype 1 or genotype 4 HCV infection (separately by genotype)
Change from Screening in liver disease stage assessment [Week -6; Week 48]
To be assessed in participants with genotype 1 or genotype 4 HCV infection (separately by genotype).
The number of participants reporting adverse events as a measure of safety and tolerability [Up to Week 48]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	City	Country
1	Linz	Austria
2	Wien	Austria
3	Brussels	Belgium
4	Brussel	Belgium
5	Edegem	Belgium
6	Clichy	France
7	Limoges Cedex	France
8	Orleans	France
9	St Laurent Du Var	France
10	Berlin	Germany
11	Düsseldorf	Germany
12	Frankfurt	Germany
13	Hamburg	Germany
14	Würzburg	Germany
15	Riyadh	Saudi Arabia
16	Barcelona	Spain
17	Madrid	Spain
18	Valencia	Spain
19	Valme	Spain
20	Glasgow	United Kingdom
21	London	United Kingdom