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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C Virus
• Intervention / Treatment: Drug: Velpatasvir; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 1

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundacion De Investigacion de Diego
• United States
  • California
    • Costa Mesa, California, United States, 92626
      • West Coast Clinical Trials, Llc
  • Florida
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research, LLC
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Gastroenterology and Hepatology
  • New Jersey
    • Marlton, New Jersey, United States, 08053
      • CRI Worldwide, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19139
      • CRI Worldwide, LLC
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • New Orleans Center For Clinical Research-Knoxville
  • Texas
    • San Antonio, Texas, United States, 78215
      • Alamo Medical Research
  • Washington
    • Tacoma, Washington, United States, 98418
      • Charles River Clinical Services Northwest, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Velpatasvir 5 mg (GT 1a); Participants with genotype (GT) 1a HCV infection will receive velpatasvir 5 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 25 mg (GT 1a); Participants with GT 1a HCV infection will receive velpatasvir 25 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 50 mg (GT 1a); Participants with GT 1a HCV infection will receive velpatasvir 50 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 100 mg (GT 1a); Participants with GT 1a HCV infection will receive velpatasvir 100 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 150 mg (GT 1a); Participants with GT 1a HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 150 mg (GT 1b); Participants with GT 1b HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 150 mg (GT 2); Participants with GT 2 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 25 mg (GT 3); Participants with GT 3 HCV infection will receive velpatasvir 25 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 50 mg (GT 3); Participants with GT 3 HCV infection will receive velpatasvir 50 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 150 mg (GT 3); Participants with GT 3 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir 150 mg (GT 4); Participants with GT 4 HCV infection will receive velpatasvir 150 mg or placebo once daily for 3 days under fasted conditions.	Drug: Velpatasvir; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally
Experimental: Velpatasvir up to 400 mg (GT 2); 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; Tablets administered orally; Other Names: GS-5816; Drug: Placebo; Tablets administered orally

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Hebner C, Gontcharova V, Chodavarapu RK, Rodriguez-Torres M, Lawitz E, Yang C, et al. Deep Sequencing of HCV NS5A From a 3-Day Study of GS-5816 Monotherapy Confirms the Potency of GS-5816 Against Pre-Existing Genotype 1-3 NS5A Resistance-Associated Variants [Abstract 470]. The Liver Meeting The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2013 November 1-5; Washington, D.C.
• Lawitz E, Glass SJ, Gruener D, Freilich B, Hill JM, Link JO, et al. GS-5816, a Once-Daily NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients with Genotype 1, 2, 3, or 4 HCV Infection in a 3-Day Monotherapy Study [Abstract 1082]. The Liver Meeting The 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2013 November 1-5; Washington, D.C.
• Lawitz EJ, Dvory-Sobol H, Doehle BP, Worth AS, McNally J, Brainard DM, Link JO, Miller MD, Mo H. Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5368-78. doi: 10.1128/AAC.00763-16. Print 2016 Sep.
• Lawitz E, Freilich B, Link J, German P, Mo H, Han L, Brainard DM, McNally J, Marbury T, Rodriguez-Torres M. A phase 1, randomized, dose-ranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat. 2015 Dec;22(12):1011-9. doi: 10.1111/jvh.12435. Epub 2015 Jul 16.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2012
• Primary Completion (Actual): March 15, 2013
• Study Completion (Actual): January 24, 2014

Study Registration Dates

• First Submitted: November 26, 2012
• First Submitted That Met QC Criteria: November 30, 2012
• First Posted (Estimate): December 4, 2012

Study Record Updates

• Last Update Posted (Actual): December 16, 2020
• Last Update Submitted That Met QC Criteria: December 11, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: HCV; Hepatitis C; Liver Disease; Genotype 1; Genotype 2; Genotype 3; Genotype 4; Genotype 5; Genotype 6
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Anti-Infective Agents; Antiviral Agents; Velpatasvir
• Other Study ID Numbers: GS-US-281-0102

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No