Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Velpatasvir in Participants With Chronic HCV Infection

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety, tolerability, and antiviral activity of velpatasvir (formerly GS-5816) in HCV treatment naive participants with genotypes 1-6.

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-5816 in Subjects With Chronic Hepatitis C Virus Infection

Conditions
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Chronic Hepatitis C Virus

Intervention / Treatment
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* Drug: Velpatasvir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: HCV treatment-naive adult participants (18-65 years of age) with chronic HCV infection and plasma HCV RNA ≥ 5 log10 IU/mL at screening Agree to use protocol defined precautions against pregnancy Key Exclusion Criteria: Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease, α1 antitrypsin deficiency, cholangitis) Evidence of cirrhosis Evidence of current drug abuse Screening laboratory results outside the protocol specified requirements 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Velpatasvir 5 mg (GT 1a)<br>Participants with genotype (GT) 1a HCV infection will receive velpatasvir 5 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 25 mg (GT 1a)<br>Participants with GT 1a HCV infection will receive velpatasvir 25 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 50 mg (GT 1a)<br>Participants with GT 1a HCV infection will receive velpatasvir 50 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 100 mg (GT 1a)<br>Participants with GT 1a HCV infection will receive velpatasvir 100 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 150 mg (GT 1a)<br>Participants with GT 1a HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 150 mg (GT 1b)<br>Participants with GT 1b HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 150 mg (GT 2)<br>Participants with GT 2 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 25 mg (GT 3)<br>Participants with GT 3 HCV infection will receive velpatasvir 25 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 50 mg (GT 3)<br>Participants with GT 3 HCV infection will receive velpatasvir 50 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 150 mg (GT 3)<br>Participants with GT 3 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir 150 mg (GT 4)<br>Participants with GT 4 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Velpatasvir up to 400 mg (GT 2)<br>Participants with GT 2 HCV infection will receive velpatasvir up to 400 mg or placebo once daily for 3 days under fasted conditions. | Drug: Velpatasvir<br>* Tablets administered orally<br>* Other names: GS-5816;Drug: Placebo<br>* Tablets administered orally<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 | Treatment-emergent adverse events were defined as any new or worsening adverse event that began on or after the date of the first dose of study drug until the Day 17 study visit date + 2 (Day 19 if Day 17 visit missing). | First dose date up to Day 17 + 2 (Day 19 if Day 17 visit missing) | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from baseline at any postbaseline visit up to the Day 17 visit date + 2 days (or Day 19 if Day 17 visit was missing). The criteria used to grade laboratory results were as follows: Grade 1 (mild), Grade 2 (moderate), or Grade 3 (severe). Graded laboratory abnormalities were defined using the grading scheme defined in protocol (Gilead Sciences, Inc. Grading Scale for Severity of Adverse Events and Laboratory Abnormalities) for analysis purpose. | First dose date up to Day 17 + 2 (Day 19 if Day 17 visit missing) | 
| Antiviral Activity of Velpatasvir as Measured by Change in Plasma HCV RNA From Baseline | Participants who were genotyped incorrectly but received appropriate treatment for that genotype were included in that treatment group for the efficacy analysis. Data were summarized by treatment and placebo. | Baseline; Days 4, 5, 6, 7, 8, 10, and 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute HCV RNA Level |  | Baseline; Days 4, 5, 6, 7, 8, 10, and 17 | 
| 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 by treatment (velpatasvir dose/HCV genotype) and placebo at each collection time point through Day 17. | Baseline; Days 4, 5, 6, 7, 8, 10, and 17 | 
| Number of Participants Who Have HCV RNA < Lower Limit of Quantitation (LLOQ) Detected | The lower limit of quantitation (LLOQ) detection for HCV RNA levels was 25 IU/mL. HCV detected means calculated HCV RNA level is below LLOQ of the assay. | Days 4, 5, 6, 7, and 8 | 
| Plasma HCV RNA Levels by Treatment and IL28B Genotype |  | Days 4, 5, 6, 7, 8, 10, and 17 | 
| Pharmacokinetic (PK) Parameter of Velpatasvir: AUCinf | AUCinf is defined as the concentration of drug extrapolated to infinite time. | 0 (predose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose at Day 1 | 
| PK Parameter of Velpatasvir: AUCtau | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | 0 (predose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose at Day 3 | 
| PK Parameter of Velpatasvir: Cmax | Cmax is defined as the maximum observed plasma concentration of drug. | 0 (predose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose at Day 1 for single dose and Day 3 for multiple dose. | 
| PK Parameter of Velpatasvir: CL/F | CL/F is defined as the apparent oral clearance following administration of the drug. | 0 (predose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose at Day 1 for single dose and Day 3 for multiple dose | 
| PK Parameter of Velpatasvir: Ctau | Ctau is defined as the observed drug concentration at the end of the dosing interval. | 0 (predose), 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose at Day 3 | 
| Number of Participants With Nonstructural Protein 5A (NS5A) Resistance Associated Variants (RAVs) at Pretreatment or Postbaseline Timepoints | The full-length NS5A coding region was analyzed pretreatment (baseline) by deep sequencing using MiSeq for all 70 participants who received velpatasvir and for 8 of 17 participants who received placebo prior to and up to 2 weeks (Day 17) after dosing with velpatasvir. Participants were categorized by velpatasvir dose/HCV genotype and presence or absence of NS5A RAVs. | First dose date up to Day 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV, Hepatitis C, Genotype 1, Genotype 2, Genotype 3, Genotype 4, Genotype 5, Genotype 6, Liver Disease