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

Study Overview
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Brief Summary
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This study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir/sofosbuvir fixed dose combination (FDC) with or without ribavirin (RBV) administered for 12 or 24 weeks in treatment-experienced subjects with chronic genotype 1 hepatitis C virus (HCV) infection.

Official Title
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A Phase 3, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/GS-5885 Fixed-Dose Combination ± Ribavirin for 12 and 24 Weeks in Treatment-Experienced Subjects With Chronic Genotype 1 HCV Infection

Conditions
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Chronic Hepatitis C Virus

Intervention / Treatment
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* Drug: LDV/SOF
* Drug: RBV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18, with chronic genotype 1 HCV infection HCV treatment-experienced, including patients who have previously failed a nonstructural protein (NS)3/4A protease inhibitor plus pegylated interferon (PEG)/RBV regimen HCV RNA > 10,000 IU/mL at screening Cirrhosis determination; a liver biopsy may be required 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 Coinfection with HIV or hepatitis B virus Current or prior history of clinical hepatic decompensation 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDV/SOF 12 Weeks<br>Participants will receive LDV/SOF FDC for 12 weeks. | Drug: LDV/SOF<br>* Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: GS-5885/GS-7997;|
| Experimental: LDV/SOF+RBV 12 Weeks<br>Participants will receive LDV/SOF FDC plus RBV for 12 weeks. | Drug: LDV/SOF<br>* Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: GS-5885/GS-7997;Drug: RBV<br>* Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)<br>|
| Experimental: LDV/SOF 24 Weeks<br>Participants will receive LDV/SOF FDC for 24 weeks. | Drug: LDV/SOF<br>* Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: GS-5885/GS-7997;|
| Experimental: LDV/SOF+RBV 24 Weeks<br>Participants will receive LDV/SOF FDC plus RBV for 24 weeks. | Drug: LDV/SOF<br>* Ledipasvir (LDV) 90 mg/sofosbuvir (SOF) 400 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: GS-5885/GS-7997;Drug: RBV<br>* Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)<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. | Posttreatment Week 12 | 
| Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized. | Up to 24 weeks | 

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 at Week 1 |  | Week 1 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 2 |  | Week 2 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 4 |  | Week 4 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 8 |  | Week 8 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 12 |  | Week 12 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 24 |  | Week 24 | 
| Change From Baseline in HCV RNA at Week 1 |  | Baseline; Week 1 | 
| Change From Baseline in HCV RNA at Week 2 |  | Baseline; Week 2 | 
| Change From Baseline in HCV RNA at Week 4 |  | Baseline; Week 4 | 
| Change From Baseline in HCV RNA at Week 8 |  | Baseline; Week 8 | 
| Percentage of Participants With Virologic Failure | Virologic failure was defined as on-treatment virologic failure or virologic relapse. On-Treatment Virologic Failure was defined as 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 was defined as 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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GS-7977, HCV genotype 1 (GT-1), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, GS-5885, Ribavirin, Open Label, Sofosbuvir, Additional relevant MeSH terms:, Hepatitis, Hepatitis, Chronic, Hepatitis C, Hepatitis C, Chronic, Liver Diseases, Digestive System Diseases, Hepatitis, Viral, Human, Virus Diseases, Enterovirus Infections, Picornaviridae Infections, RNA Virus Infections, Flaviviridae Infections, Antiviral Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions, Antimetabolites, Molecular Mechanisms of Pharmacological Action