Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination ± Ribavirin in Cirrhotic Subjects With Chronic Genotype 1 HCV Infection

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination for 12 Weeks With Ribavirin or for 24 Weeks Without Ribavirin in Treatment-Experienced Cirrhotic Subjects With Chronic Genotype 1 HCV Infection

This study is to determine the antiviral efficacy of sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) with and without ribavirin (RBV), and to evaluate the safety and tolerability of each regimen as assessed by review of the accumulated safety data. Approximately 150 participants with genotype 1 HCV infection, who have previously received treatment for HCV, and who have a diagnosis for cirrhosis will be enrolled. Participants will be randomized to 1 of 2 groups.

Group 1: SOF/LDV FDC tablet plus placebo to match RBV for 24 weeks

Group 2: Delayed treatment group: placebo to match SOF/LDV FDC plus placebo to match RBV for 12 weeks, followed by SOF/LDV FDC once daily plus RBV in a divided daily dose for 12 weeks

Randomization will 1:1 to the two groups and will be stratified by HCV genotype (1a, 1b; mixed or other genotype 1 results will be stratified as genotype 1a), and prior HCV therapy treatment response (never achieved HCV RNA < the lower limit of quantitation (LLOQ), or achieved HCV RNA < LLOQ).

Study Overview

• Status: Completed
• Conditions: HCV Infection
• Intervention / Treatment: Drug: LDV/SOF; Drug: Placebo to match RBV; Drug: RBV; Drug: Placebo to match LDV/SOF

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clermont Ferrand, France, 63003
  • Clichy, France, 92110
  • Creteil, France, 94000
  • Grenoble, France, 38043
  • Lille, France, 57037
  • Limoges, France, 87042
  • Lyon, France, 69317
  • Marseille, France, 13285
  • Montpelier, France, 34295
  • Nancy, France, 54500
  • Nice, France, 06202
  • Paris, France, 75013
  • Paris, France, 75014
  • Paris, France, 75012
  • Paris, France, 75020
  • Pessac, France, 33604
  • Rennes, France, 35033
  • Strasbourg, France, 67091
  • Toulouse, France, 31059

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age equal to or greater than 18 years, with chronic genotype 1 HCV infection
• HCV RNA ≥ 10,000 IU/mL at screening
• Prior virological failure after treatment with pegylated interferon (PEG-IFN), RBV and a protease inhibitor following documented prior virology failure after treatment with a PEG-IFN + RBV regimen
• Evidence of cirrhosis
• Screening laboratory values within defined thresholds
• Use of two effective contraception methods if female of childbearing potential or sexually active male

Exclusion Criteria:

• Pregnant or nursing female or male with pregnant female partner
• Current or prior history of clinical hepatic decompensation
• Prior exposure to approved or experimental HCV specific direct-acting antivirals other than a nonstructural protein (NS)3/4A protease inhibitor
• History of solid organ transplantation, including liver transplant
• Hepatocellular carcinoma or other malignancy (with exception of certain resolved skin cancers)
• Chronic use of systemic immunosuppressive agents
• History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LDV/SOF; LDV/SOF FDC tablet plus placebo to match RBV for 24 weeks	Drug: LDV/SOF; LDV/SOF (90/400 mg) FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: Placebo to match RBV; Placebo to match RBV administered orally in a divided daily dose
EXPERIMENTAL: LDV/SOF + RBV; Placebo to match SOF/LDV FDC plus placebo to match RBV for 12 weeks, followed by LDV/SOF FDC plus RBV for 12 weeks.	Drug: LDV/SOF; LDV/SOF (90/400 mg) FDC tablet administered orally once daily; Other Names: Harvoni®; GS-5885/GS-7977; Drug: Placebo to match RBV; Placebo to match RBV administered orally in a divided daily dose; Drug: RBV; RBV (200 mg tablets) administered orally in a divided daily dose based on weight (1000 mg per day for participants weighing < 75 kg; 1200 mg per day for participants weighing ≥ 75 kg); Drug: Placebo to match LDV/SOF; Placebo to match LDV/SOF administered orally once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)	SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, < 25 IU/mL) 12 weeks following the last dose of study drug.; 1 participant who was randomized to the LDV/SOF + RBV group who received placebo discontinued prior to receiving LDV/SOF + RBV and is excluded from the Full Analysis Set.; 1 participant who was randomized to the LDV/SOF + RBV group received LDV/SOF + placebo, and is counted in the LDV/SOF group for the safety analysis, and in the LDV/SOF+RBV group for the efficacy analysis (ie, in the Full Analysis Set).	Posttreatment Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12		Baseline; Weeks 1, 2, 4, 8, and 12
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)	SVR4 and SVR24 were defined as HCV RNA < LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.	Posttreatment Weeks 4 and 24
Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24		Weeks 1, 2, 4, 8, 12, and 24
Percentage of Participants With Virologic Failure	Virologic failure is defined as; On-treatment virologic failure:Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), orRebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), orNon-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment); Virologic relapse:Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit.	Baseline to Posttreatment Week 24

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Bourliere M, Bronowicki JP, de Ledinghen V, Hezode C, Zoulim F, Mathurin P, Tran A, Larrey DG, Ratziu V, Alric L, Hyland RH, Jiang D, Doehle B, Pang PS, Symonds WT, Subramanian GM, McHutchison JG, Marcellin P, Habersetzer F, Guyader D, Grange JD, Loustaud-Ratti V, Serfaty L, Metivier S, Leroy V, Abergel A, Pol S. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015 Apr;15(4):397-404. doi: 10.1016/S1473-3099(15)70050-2. Epub 2015 Mar 13. Erratum In: Lancet Infect Dis. 2015 Jul;15(7):761.

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): November 1, 2014

Study Registration Dates

• First Submitted: October 16, 2013
• First Submitted That Met QC Criteria: October 16, 2013
• First Posted (ESTIMATE): October 18, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 16, 2018
• Last Update Submitted That Met QC Criteria: October 19, 2018
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: HCV; Cirrhosis; Hepatitis C
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Infections; Communicable Diseases; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir
• Other Study ID Numbers: GS-US-337-0121; 2013-002296-17 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP