A Study of TMC435 in Combination With PSI-7977 (GS7977) in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders To Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Patients

An Exploratory Phase IIa, Randomized, Open-Label Trial to Investigate the Efficacy and Safety of 12 Weeks or 24 Weeks of TMC435 in Combination With PSI-7977 (GS7977) With Or Without Ribavirin in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders To Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Subjects

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01466790

Acronym

COSMOS

Enrollment

168

Registered

2011-11-08

Start date

2012-01-31

Completion date

2014-01-31

Last updated

2015-02-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hepatitis C

Keywords

Hepatitis C, TMC435, PSI-7977, GS7977, Ribavirin, HCV, Hep C, Genotype 1

Brief summary

The purpose of this study is to investigate the efficacy and safety of TMC435 plus PSI-7977 (GS7977) with or without ribavirin in patients who are chronically infected with genotype 1 hepatitis C virus (HCV) and who did not respond to prior peginterferon/ribavirin therapy or are HCV treatment-naive (patients who never received treatment for HCV infection).

Detailed description

This is a Phase IIa, randomized (the study medications are assigned by chance), open label (all people know the identity of the intervention) study of TMC435 plus PSI-7977 (GS7977) with or without ribavirin. The study consists of a screening phase (6 weeks); a treatment phase (12 or 24 week period); and a posttreatment phase (follow-up period up to Week 48). Approximately 180 patients will be enrolled in this study. Patients will be sequentially enrolled into two cohorts in this study. Cohort 1 (90 patients) will include patients without advanced hepatic fibrosis who did not respond to previous PegIFN/ribavirin therapy and Cohort 2 (90 patients) will include only patients with advanced hepatic fibrosis who did not respond to previous PegIFN/ribavirin therapy or are HCV treatment-naive. Safety will be evaluated throughout the study and will include evaluations of adverse events, clinical laboratory tests, electrocardiogram, vital signs, and physical examination. The entire study duration for each participant will be approximately 48 weeks.

Interventions

DRUGTMC435

TMC435 will be administered as one oral capsule of 150 mg once a day.

DRUGPSI-7977 (GS7977)

PSI-7977 (GS7977) will be administered as oral tablets (2 tablets of 200 mg for Cohort 1 and 1 tablet of 400 mg for Cohort 2) once a day.

DRUGRibavirin

Ribavirin will be administered according to body weight. For patients with body weight less than 75 kg daily dose (1000 mg) will be administered as 400 mg (2 oral tablets of 200 mg) in the morning and 600 mg (3 oral tablets of 200 mg) in the evening. Body weight more than or equal to 75 kg daily dose (1200 mg) will be administered as 600 mg twice a day (3 tablets of 200 mg per intake, morning and evening).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Chronic genotype 1 hepatitis C virus (HCV) infection * Plasma HCV RNA of more than 10,000 IU/mL at screening * Patients in Cohort 1 must be null responders to PegIFN/ribavirin with at least 1 documented previous course of PegIFN/ribavirin therapy for at least 12 consecutive weeks * Patients in Cohort 2 must be null responders to PegIFN/ribavirin with at least 1 documented previous course of PegIFN/ribavirin therapy for at least 12 consecutive weeks and could also be HCV treatment-naive, meaning never received treatment with any approved or investigational drug for the treatment of HCV * Null responders patients in Cohort 1 and Cohort 2 must meet the defined criterion for a null responder, defined as on-treatment less than 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 of the most recent PegIFN/ribavirin therapy * Patient must have had a liver biopsy within 3 years before screening (or between screening and baseline visit) or patient must have had a liver biopsy at any time in the past which showed Metavir F3 or F4 fibrosis * Must agree to use 2 forms of effective contraception throughout the study (male and female)

Exclusion criteria

* Has evidence of hepatic decompensation * Has any liver disease of non-HCV etiology * Has an infection/co-infection with non-genotype 1 HCV * Has a co-infection with Human immunodeficiency virus (HIV) type 1 or type 2 (HIV-1 or HIV-2) (positive HIV-1 or HIV-2 antibody test at screening) * Has a co-infection with hepatitis B virus (hepatitis B surface antigen \[HBsAg\] positive) * Has a history of malignancy within 5 years of the screening visit

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With a Sustained Virologic Response (SVR) 12 Weeks After the Planned End of Treatment (EOT)	Week 12 and 24 (for the arms treated for 12 weeks) or Week 24 and 36 (for the arms treated for 24 weeks)	Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) undetectable at end of treatment and HCV RNA less than (\<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 12 weeks after the planned end of treatment.

Secondary

Measure	Time frame	Description
Number of Participants With a Sustained Virologic Response (SVR) 4 Weeks After the Planned End of Treatment (EOT)	Week 12 and 16 (for the arms treated for 12 weeks) or Week 24 and 28 (for the arms treated for 24 weeks)	Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) undetectable at end of treatment and HCV RNA less than (\<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 4 weeks after the planned end of treatment.
Number of Participants With a Sustained Virologic Response (SVR) 24 Weeks After the Planned End of Treatment (EOT)	Week 12 and 36 (for the arms treated for 12 weeks) or Week 24 and 48 (for the arms treated for 24 weeks)	Participants with HCV RNA undetectable at end of treatment and HCV RNA less than (\<) 25 IU/mL (detectable or undetectable) at 24 weeks after the planned end of treatment.
Number of Participants With a Sustained Virologic Response (SVR) at Week 48	Week 48	Participants with HCV RNA undetectable at end of treatment and HCV RNA less than (\<) 25 IU/mL (detectable or undetectable) at week 48.
Number of Participants With Viral Breakthrough	Up to End of Treatment [Week 12 (for the arms treated for 12 weeks) or Week 24 (for the arms treated for 24 weeks)]	Viral breakthrough was defined as confirmed quantifiable HCV RNA after becoming less than (\<) lower limit of quantification (LLOQ) or confirmed greater than (\>) 1 log10 HCV RNA increase from the lowest level reached on 2 consecutive occasions.
Number of Participants With Inadequate Virologic Response	Week 8 and End of Treatment [Week 12 (for the arms treated for 12 weeks) or Week 24 (for the arms treated for 24 weeks)]	Inadequate Virologic Response was defined as confirmed detectable HCV RNA at or after Week 8 and not meeting the viral breakthrough definition.
Number of Participants With Viral Relapse	During the Follow-up [Week 36 (for the arms treated for 12 weeks) or Week 24 (for the arms treated for 24 weeks)]	Viral relapse was defined as undetectable HCV RNA at the actual EOT and confirmed quantifiable HCV RNA (\>= 25 IU/mL) during follow-up period.

Countries

Puerto Rico, United States

Participant flow

Pre-assignment details

A total of 168 participants enrolled to study. 1 participant who was randomized to Cohort 1: TMC435, PSI-7977 and Ribavirin for 24 Weeks group, but never received treatment.

Participants by arm

Arm	Count
Cohort 1: TMC435, PSI-7977 and Ribavirin for 24 Weeks Cohort 1 participants (without advanced hepatic fibrosis, who did not respond to previous pegylated interferon \[PegIFN\]/ribavirin therapy) received TMC435 150 milligram (mg) capsule along with PSI-7977 (GS7977) 400 mg tablet and ribavirin 1000-1200 mg tablet (1000 mg for participants with body weight less than 75 kilogram \[kg\] and 1200 mg for participants with body weight more than or equal to 75 kg) orally once daily for 24 weeks followed by a 24-week follow-up phase.	24
Cohort 1: TMC435 and PSI-7977 for 24 Weeks Cohort 1 participants received TMC435 150 mg capsule along with PSI-7977 (GS7977) 400 mg tablet orally once daily for 24 weeks followed by a 24-week follow-up phase.	15
Cohort 1: TMC435, PSI-7977 and Ribavirin for 12 Weeks Cohort 1 participants received TMC435 150 mg capsule along with PSI-7977 (GS7977) 400 mg tablet and ribavirin 1000-1200 mg tablet (1000 mg for participants with body weight less than 75 kg and 1200 mg for participants with body weight more than or equal to 75 kg) orally once daily for 12 weeks followed by a 36-week follow-up phase.	27
Cohort 1: TMC435 and PSI-7977 for 12 Weeks Cohort 1 participants received TMC435 150 mg capsule along with PSI-7977 (GS7977) 400 mg tablet orally once daily for 12 weeks followed by a 36-week follow-up phase.	14
Cohort 2: TMC435, PSI-7977 and Ribavirin for 24 Weeks Cohort 2 participants (with advanced hepatic fibrosis, who did not respond to previous PegIFN/ribavirin therapy or who never received treatment for HCV infection) received TMC435 150 mg capsule along with PSI-7977 400 mg tablet and ribavirin 1000-1200 mg tablet (1000 mg for participants with body weight less than 75 kg and 1200 mg for participants with body weight more than or equal to 75 kg) orally once daily for 24 weeks followed by a 24-week follow-up phase.	30
Cohort 2: TMC435 and PSI-7977 for 24 Weeks Cohort 2 participants received TMC435 150 mg capsule along with PSI-7977 400 mg tablet orally once daily for 24 weeks followed by a 24-week follow-up phase.	16
Cohort 2: TMC435, PSI-7977 and Ribavirin for 12 Weeks Cohort 2 participants received TMC435 150 mg capsule along with PSI-7977 400 mg tablet and ribavirin 1000-1200 mg tablet (1000 mg for participants with body weight less than 75 kg and 1200 mg for participants with body weight more than or equal to 75 kg) orally once daily for 12 weeks followed by a 36-week follow-up phase.	27
Cohort 2: TMC435 and PSI-7977 for 12 Weeks Cohort 2 participants received TMC435 150 mg capsule along with PSI-7977 400 mg tablet orally once daily for 12 weeks followed by a 36-week follow-up phase.	14
Total	167

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG004	FG006	FG007
Overall Study	Adverse Event	1	0	2	0	0
Overall Study	Lost to Follow-up	2	0	0	0	0
Overall Study	Withdrawal by Subject	1	1	1	1	1

Baseline characteristics

Characteristic	Cohort 1: TMC435, PSI-7977 and Ribavirin for 24 Weeks	Cohort 1: TMC435 and PSI-7977 for 24 Weeks	Cohort 1: TMC435, PSI-7977 and Ribavirin for 12 Weeks	Cohort 1: TMC435 and PSI-7977 for 12 Weeks	Cohort 2: TMC435, PSI-7977 and Ribavirin for 24 Weeks	Cohort 2: TMC435 and PSI-7977 for 24 Weeks	Cohort 2: TMC435, PSI-7977 and Ribavirin for 12 Weeks	Cohort 2: TMC435 and PSI-7977 for 12 Weeks	Total
Age, Continuous	56 years	56 years	55 years	55.5 years	58 years	57.5 years	57 years	57.5 years	57 years
Sex: Female, Male Female	9 Participants	9 Participants	7 Participants	6 Participants	9 Participants	9 Participants	7 Participants	4 Participants	60 Participants
Sex: Female, Male Male	15 Participants	6 Participants	20 Participants	8 Participants	21 Participants	7 Participants	20 Participants	10 Participants	107 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	48 / 54	25 / 31	42 / 54	17 / 28
serious Total, serious adverse events	3 / 54	1 / 31	0 / 54	0 / 28

Outcome results

Primary

Number of Participants With a Sustained Virologic Response (SVR) 12 Weeks After the Planned End of Treatment (EOT)

Participants with hepatitis C virus (HCV) ribonucleic acid (RNA) undetectable at end of treatment and HCV RNA less than (\<) 25 international unit per milliliter (IU/mL) (detectable or undetectable) at 12 weeks after the planned end of treatment.

Time frame: Week 12 and 24 (for the arms treated for 12 weeks) or Week 24 and 36 (for the arms treated for 24 weeks)