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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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HCV Infection

Intervention / Treatment
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* Drug: LDV/SOF
* Drug: RBV
* Drug: Placebo to match LDV/SOF
* Drug: Placebo to match RBV


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: LDV/SOF<br>LDV/SOF FDC tablet plus placebo to match RBV for 24 weeks | Drug: LDV/SOF<br>* LDV/SOF (90/400 mg) FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: Placebo to match RBV<br>* Placebo to match RBV administered orally in a divided daily dose<br>|
| Experimental: LDV/SOF + RBV<br>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<br>* LDV/SOF (90/400 mg) FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* 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)<br>Drug: Placebo to match LDV/SOF<br>* Placebo to match LDV/SOF administered orally once daily<br>Drug: Placebo to match RBV<br>* Placebo to match RBV administered orally in a divided daily dose<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 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), 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. | Baseline to Posttreatment Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV, Hepatitis C, Cirrhosis