Sofosbuvir Plus Ribavirin, or Ledipasvir/Sofosbuvir in Adults With HCV Infection and Renal Insufficiency

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the safety and efficacy of sofosbuvir (SOF) plus ribavirin (RBV) for 24 weeks and ledipasvir/sofosbuvir (LDV/SOF) for 12 weeks, and to evaluate the steady state pharmacokinetics (PK) of SOF and its metabolites and LDV in participants with genotype (GT) 1, 3, or 4 hepatitis C virus (HCV) infection who have chronic renal insufficiency (impaired kidney function).

Official Title
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A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination (FDC) Tablet for 12 Weeks in Genotype 1 or 4 HCV Infected Subjects With Renal Insufficiency

Conditions
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HCV Infection

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


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Cohorts 1 and 2: chronic genotype 1 or 3 HCV infection Cohort 3: chronic genotype 1 or 4 HCV infection HCV RNA ≥ 10^4 IU/mL at screening Screening labs within defined thresholds Cirrhosis determination at screening Key Exclusion Criteria: Females who are pregnant or nursing or males who have a pregnant partner Prior null response to pegylated interferon (Peg-IFN)+RBV therapy (Cohorts 1 and 2) or for individuals with cirrhosis, prior treatment failure with IFN-based therapy not resulting from treatment intolerance (Cohort 3) Current of prior history of hepatic decompensation Infection with hepatitis B virus (HBV) or HIV History of clinically significant illness (including psychiatric or cardiac) or any other medical disorder that may interfere with individual's treatment and/or adherence to the protocol Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOF 200 mg + RBV 200 mg (Cohort 1)<br>Participants with genotype 1 or 3 HCV infection will receive SOF 200 mg (2 × 100 mg tablets) plus RBV once daily for 24 weeks. | Drug: SOF<br>* Tablet(s) administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 200 mg tablet administered orally once daily<br>|
| Experimental: SOF 400 mg + RBV 200 mg (Cohort 2)<br>Participants with genotype 1 or 3 HCV infection will receive SOF 400 mg (4 × 100 mg tablets or 1 × 400 mg tablet) plus RBV once daily for 24 weeks. | Drug: SOF<br>* Tablet(s) administered orally once daily<br>* Other names: GS-7977;Drug: RBV<br>* 200 mg tablet administered orally once daily<br>|
| Experimental: LDV/SOF (Cohort 3)<br>Participants with genotype 1 or 4 HCV infection will receive LDV/SOF once daily for 12 weeks. | Drug: LDV/SOF<br>* 90/400 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: Harvoni®;|

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 Experiencing Treatment-Emergent Adverse Events |  | Up to 24 weeks plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increased by at least 1 toxicity grade from baseline at any time postbaseline up to the date of last dose of study drug plus 30 days. | Up to 24 weeks plus 30 days | 
| Percentage of Participants Experiencing Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities |  | Up to 24 weeks plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events Associated With Vital Sign Abnormalities |  | Up to 24 weeks plus 30 days | 
| Pharmacokinetic (PK) Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | Cmax is defined as the maximum concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | Cmax is defined as the maximum concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | Cmax is defined as the maximum concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With SVR at 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 at 24 Weeks After Discontinuation of Therapy (SVR24) | SVR4 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment. | Posttreatment Week 24 | 
| Percentage of Participants With Overall Virologic Failure | Virologic failure was 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. | Up to Posttreatment Week 24 | 
| PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | Clast is defined as the last observable concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | Clast is defined as the last observable concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | Clast is defined as the last observable concentration of drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | Tmax is defined as the time (observed time point) of Cmax. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | Tmax is defined as the time (observed time point) of Cmax. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | Tmax is defined as the time (observed time point) of Cmax. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | Tlast is defined as the time (observed time point) of Clast. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | Tlast is defined as the time (observed time point) of Clast. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | Tlast is defined as the time (observed time point) of Clast. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 | 
| PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 | 
| PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12 | 
| PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 |