Ledipasvir/Sofosbuvir Fixed-Dose Combination Plus Ribavirin in Participants With Chronic HCV With Advanced Liver Disease or Post-Liver Transplant

Study Overview
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Brief Summary
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This study will evaluate ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) plus ribavirin (RBV) in participants with advanced liver disease or posttransplant and chronic genotype 1 or 4 hepatitis C virus (HCV) infection. Cohort A: decompensated cirrhosis (advanced liver disease), no prior liver transplant; Cohort B: post-liver transplant, with or without cirrhosis; Group assignment within cohorts is based on severity of liver impairment at screening (Child-Pugh-Turcotte (CPT) score for participants with cirrhosis; fibrosis; or presence of disease for fibrosing cholestatic hepatitis (FCH) groups) Randomization is 1:1 within groups to 12 or 24 weeks of LDV/SOF+RBV treatment.

Official Title
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A Phase 2, Multicenter, Open-Label Study to Investigate the Safety and Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination + Ribavirin Administered in Subjects Infected With Chronic HCV Who Have Advanced Liver Disease or Are Post-Liver Transplant

Conditions
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Chronic HCV Infection

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: Able to provide written informed consent Chronic genotype 1 and/or 4 HCV infection Normal ECG Negative serum pregnancy test for female subjects Male subjects and female subjects of childbearing potential must agree to use contraception Able to comply with the dosing instructions for study drug and able to complete the study schedule of assessments, including all required post treatment visits Exclusion Criteria: Serious or active medical or psychiatric illness HIV or hepatitis B viral (HBV) infection Stomach disorder that could interfere with the absorption of the study drug Treated with an anti-HCV medication in the last 30 days Any prior exposure to an HCV nonstructural protein (NS)5a-specific inhibitor Use of human granulocyte-macrophage colony-stimulating factor (GM-CSF), epoetin alfa or other therapeutic hematopoietic agents within 2 weeks of screening History of clinically significant medical condition associated with other chronic liver disease Active spontaneous bacterial peritonitis at screening Females who are breastfeeding Infection requiring systemic antibiotics Participated in a clinical study with an investigational drug or biologic within the last 30 days Active or history (last 6 months) of drug or alcohol abuse History of organ transplant other than liver, kidney, or corneal.

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: Cohort A, Group 1 (12 wk): CPT Class B (7-9)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class B (CPT score 7-9) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort A, Group 1 (24 wk): CPT Class B (7-9)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class B (CPT score 7-9) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort A, Group 2 (12 wk): CPT Class C (10-12)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class C (CPT score 10-12) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort A, Group 2 (24 wk): CPT Class C (10-12)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class C (CPT score 10-12) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 3 (12 wk): F0-F3 Fibrosis<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with Fibrosis Stage F0-F3 | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 3 (24 wk): F0-F3 Fibrosis<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with Fibrosis Stage F0-F3 | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 4 (12 wk): CPT Class A (5-6)<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with CPT Class A (CPT score 5-6) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 4 (24 wk): CPT Class A (5-6)<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with CPT Class A (CPT score 5-6) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 5 (12 wk): CPT Class B (7-9)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class B (CPT score 7-9) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 5 (24 wk): CPT Class B (7-9)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class B (CPT score 7-9) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 6 (12 wk): CPT Class C (10-12)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 12 weeks in participants with CPT Class C (CPT score 10-12) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 6 (24 wk): CPT Class C (10-12)<br>LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability [weight-based maximum: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg]) for 24 weeks in participants with CPT Class C (CPT score 10-12) | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 7 (12 wk): FCH<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with FCH | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets administered orally in a divided daily dose<br>|
| Experimental: Cohort B, Group 7 (24 wk): FCH<br>LDV/SOF (90/400 mg) plus RBV (weight-based: < 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with FCH | Drug: LDV/SOF<br>* LDV/SOF FDC tablet administered orally once daily<br>* Other names: GS-5885/GS-7977;Drug: RBV<br>* RBV tablets 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, 15 IU/mL) at 12 weeks after stopping study treatment. | Posttreatment Week 12 | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event |  | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With SVR 2 Weeks After Discontinuation of Therapy (SVR2) | SVR2 was defined as HCV RNA < LLOQ at 2 weeks after stopping study treatment. | Posttreatment Week 2 | 
| Percentage of Participants With SVR 4 Weeks After Discontinuation of Therapy (SVR4) | SVR4 was defined as HCV RNA < LLOQ at 4 weeks after stopping study treatment. | Posttreatment Week 4 | 
| Percentage of Participants With SVR 8 Weeks After Discontinuation of Therapy (SVR8) | SVR8 was defined as HCV RNA < LLOQ at 8 weeks after stopping study treatment. | Posttreatment Week 8 | 
| Percentage of Participants With SVR 24 Weeks After Discontinuation of Therapy (SVR24) | SVR24 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment. | Posttreatment Week 24 | 
| Percentage of Participants With Virologic Failure | Virologic failure was defined as: On-treatment virologic failure: Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ on 2 consecutive measurements while on treatment), or Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment) Virologic relapse: Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit. | Up to Posttreatment Week 24 | 
| Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 | pTVR was defined as HCV RNA < LLOQ at Week 12 after transplant. | Posttreatment Week 12 | 
| 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 6 |  | Week 6 | 
| 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 16 |  | Week 16 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 20 |  | Week 20 | 
| Percentage of Participants With HCV RNA < LLOQ at Week 24 |  | Week 24 | 
| HCV RNA Levels and Change From Baseline at Week 1 |  | Baseline; Week 1 | 
| HCV RNA Levels and Change From Baseline at Week 2 |  | Baseline; Week 2 | 
| HCV RNA Levels and Change From Baseline at Week 4 |  | Baseline; Week 4 | 
| HCV RNA Levels and Change From Baseline at Week 6 |  | Baseline; Week 6 | 
| HCV RNA Levels and Change From Baseline at Week 8 |  | Baseline; Week 8 | 
| HCV RNA Levels and Change From Baseline at Week 12 |  | Baseline; Week 12 | 
| Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in MELD Score | Model for End-Stage Liver Disease (MELD) scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40; higher scores/increased scores indicate greater severity of disease. | Baseline to Posttreatment Week 4 | 
| Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in CPT Score | CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15 (maximum score for entry into the study was 12); higher scores/increased scores indicate greater severity of disease. Groups are arranged by cohort, then by duration of treatment, then by CPT class at baseline. | Baseline to Posttreatment Week 4 |