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

• ClinicalTrials.gov Identifier: NCT01965535
• Recruitment Status: Completed
• First Posted: October 18, 2013
• Results First Posted: September 28, 2015
• Last Update Posted: November 16, 2018
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
HCV Infection	Drug: LDV/SOF; Drug: RBV; Drug: Placebo to match LDV/SOF; Drug: Placebo to match RBV	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2013
• Actual Primary Completion Date: August 2014
• Actual Study Completion Date: November 2014

Arms and Interventions

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: 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; Drug: Placebo to match RBV; Placebo to match RBV administered orally in a divided daily dose

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [ Time Frame: Posttreatment Week 12 ]

   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).

Secondary Outcome Measures :

1. Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) [ Time Frame: Posttreatment Weeks 4 and 24 ]
   SVR4 and SVR24 were defined as HCV RNA < LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.
2. Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 [ Time Frame: Weeks 1, 2, 4, 8, 12, and 24 ]
3. Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 [ Time Frame: Baseline; Weeks 1, 2, 4, 8, and 12 ]
4. Percentage of Participants With Virologic Failure [ Time Frame: Baseline to Posttreatment Week 24 ]

   Virologic failure is defined as

   • On-treatment virologic failure:

     • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or
     • Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or
     • Non-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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

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, 75012

Paris, France, 75013

Paris, France, 75014

Paris, France, 75020

Pessac, France, 33604

Rennes, France, 35033

Strasbourg, France, 67091

Toulouse, France, 31059

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Robert H Hyland, DPhil; Gilead Sciences

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bourlière M, Bronowicki JP, de Ledinghen V, Hézode 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, Grangé 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.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01965535
• Other Study ID Numbers: GS-US-337-0121; 2013-002296-17 ( EudraCT Number )
• First Posted: October 18, 2013
• Results First Posted: September 28, 2015
• Last Update Posted: November 16, 2018
• Last Verified: June 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: http://www.gilead.com/research/disclosure-and-transparency

Keywords provided by Gilead Sciences:

Hepatitis C; HCV; Cirrhosis

Additional relevant MeSH terms:

Infections; Communicable Diseases; Hepatitis C; Disease Attributes; Pathologic Processes; Blood-Borne Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases; Sofosbuvir; Ledipasvir, sofosbuvir drug combination; Ledipasvir; Antiviral Agents; Anti-Infective Agents