Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Voxilaprevir in Adults With Chronic Hepatitis C Virus Infection

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety and tolerability of voxilaprevir (formerly GS-9857) alone or with sofosbuvir (SOF)/velpatasvir (VEL) fixed dose combination (FDC) and antiviral activity of voxilaprevir in adults with genotype 1, 2, 3, 4 hepatitis C virus (HCV) infection. All participants will be monitored for up to 48 weeks after the last dose.

Official Title
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Phase 1b, Randomized, Double-Blind, Multiple-Dose Ranging Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GS-9857 in Subjects With Chronic Hepatitis C Virus Infection

Conditions
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Hepatitis C Virus Infection

Intervention / Treatment
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* Drug: Voxilaprevir
* Drug: Placebo to match voxilaprevir
* Drug: SOF/VEL


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Chronic genotype 1-4 HCV infection For Cohorts 1-9, HCV RNA ≥ 100,000 IU/mL at screening (no HCV RNA restriction for Cohort 10) Screening laboratory values within defined thresholds Use of two effective contraception methods if female of childbearing potential or sexually active male Key Exclusion Criteria: Pregnant or nursing female or male with pregnant female partner Presence of cirrhosis Prior exposure to approved or experimental HCV Protease Inhibitors Co-infection with HIV or hepatitis B virus (HBV) Current or prior history of clinical hepatic decompensation Chronic use of systemic immunosuppressive agents History of clinically significant illness or any other medical disorder that may interfere with participant's treatment, assessment or compliance with the protocol Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (GT 1a, Cohort 1)<br>Participants with genotype (GT) 1a HCV infection will receive placebo once daily for 3 days under fasted conditions. | Drug: Placebo to match voxilaprevir<br>* Placebo to match voxilaprevir tablets administered orally once daily<br>|
| Experimental: Voxilaprevir 50 mg (GT 1a, Cohort 1)<br>Participants with GT 1a HCV infection will receive voxilaprevir 50 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg (GT 1a, Cohort 1)<br>Participants with GT 1a HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 300 mg (GT 1a, Cohort 1)<br>Participants with GT 1a HCV infection will receive voxilaprevir 300 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Placebo Comparator: Placebo (GT 3, Cohort 2)<br>Participants with GT 3 HCV infection will receive placebo once daily for 3 days under fasted conditions. | Drug: Placebo to match voxilaprevir<br>* Placebo to match voxilaprevir tablets administered orally once daily<br>|
| Experimental: Voxilaprevir 50 mg (GT 3, Cohort 2)<br>Participants with GT 3 HCV infection will receive voxilaprevir 50 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg (GT 3, Cohort 2)<br>Participants with GT 3 HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 300 mg (GT 3, Cohort 2)<br>Participants with GT 3 HCV infection will receive voxilaprevir 300 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Placebo Comparator: Placebo (GT 2, Cohort 3)<br>Participants with GT 2 HCV infection will receive placebo once daily for 3 days under fasted conditions. | Drug: Placebo to match voxilaprevir<br>* Placebo to match voxilaprevir tablets administered orally once daily<br>|
| Experimental: Voxilaprevir 100 mg (GT 2, Cohort 3)<br>Participants with GT 2 HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg (GT 4, Cohort 4)<br>Participants with GT 4 HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg (GT 1b, Cohort 5)<br>Participants with GT 1b HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fasted conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg Fed (GT 3a, Cohort 6)<br>Participants with GT 3a HCV infection will receive voxilaprevir 100 mg once daily for 3 days under fed conditions. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 600 mg (Cohorts 7-9)<br>Participants with genotypes 1a, 1b, 2, 3, or 4 HCV infection will receive voxilaprevir up to 600 mg under fasted or fed conditions for 3 days. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;|
| Experimental: Voxilaprevir 100 mg + SOF/VEL 400/100 mg (Group 1, Cohort 10)<br>Participants with any GT HCV infection received voxilaprevir 100 mg on Day 1 after moderate fat meal and voxilaprevir 100 mg plus sofosbuvir (SOF)/velpatasvir (VEL) (400/100 mg) fixed-dose combination (FDC)on Days 2 and 3 after either a light or moderate-fat meal. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;Drug: SOF/VEL<br>* 400 mg/100 mg FDC tablet administered orally once daily<br>|
| Experimental: Voxilaprevir 100 mg + SOF/VEL 400/100 mg (Group 2, Cohort 10)<br>Participants with any GT HCV infection received voxilaprevir 100 mg on Day 1 and voxilaprevir 100 mg plus SOF/VEL (400/100 mg) FDC on Days 2 and 3 after moderate fat meal. | Drug: Voxilaprevir<br>* Voxilaprevir tablets administered orally once daily<br>* Other names: GS-9857;Drug: SOF/VEL<br>* 400 mg/100 mg FDC tablet administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment Emergent Adverse Events |  | First dose date up to Day 3 plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The severity of laboratory abnormalities was assessed as Grade 0, 1 (mild), 2 (moderate), 3 (severe), or 4 (potentially life threatening) using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. The most severe graded abnormality from all tests was counted for each participant. | First dose date up to Day 3 plus 30 days | 
| Antiviral Activity of Voxilaprevir as Measured by Change From Baseline in Plasma HCV RNA | The outcome measure was assessed to evaluate antiviral activity of voxilaprevir only (cohorts 1 through 6). Data are summarized by treatment/cohort and placebo. | Baseline; Days 4, 5, 6, 7, 8, 10, and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiviral Activity of Voxilaprevir as Measured by Absolute HCV RNA Level Through Week 48 | The outcome measure was assessed to evaluate antiviral activity of voxilaprevir only (cohorts 1 through 6). | Baseline (Pre Day 1 Dose); Days 4, 5, 6, 7, 8, 10, and Week 48 | 
| Antiviral Activity of Voxilaprevir as Measured by Number of Participants Achieving Reductions From Baseline in HCV RNA | Categorical declines from baseline were summarized by the number of participants with a < 1, ≥ 1 to <2, ≥ 2 to <3, or ≥ 3 log10 IU/mL decrease in HCV RNA from baseline to each postdose assessment up to Week 48 by treatment/cohort and placebo. The outcome measure was assessed to evaluate antiviral activity of voxilaprevir only (cohorts 1 through 6). | Baseline; Days 4, 5, 6, 7, 8, 10, and Week 48 | 
| Percentage of Participants Who Have HCV RNA < Lower Limit of Quantitation (LLOQ) Detected, and < LLOQ Target Not Detected (TND) | The lower limit of quantitation (LLOQ) detection for HCV RNA levels was 15 IU/mL. HCV detected means calculated HCV RNA level is below LLOQ of the assay. The outcome measure was assessed to evaluate antiviral activity of voxilaprevir only (cohorts 1 through 6). | Days 4, 5, 6, 7, 8, 10, and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, Liver Diseases, Digestive System Diseases, Hepatitis, Viral, Human, Enterovirus Infections, Picornaviridae Infections, RNA Virus Infections, Flaviviridae Infections, Antiviral Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions, Antimetabolites, Molecular Mechanisms of Pharmacological Action