Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination and Sofosbuvir + Ribavirin for Subjects With Chronic Hepatitis C Virus (HCV) and Inherited Bleeding Disorders

Study Overview
=================
Brief Summary
-----------------
The primary objectives of this study are to evaluate the antiviral efficacy, safety, and tolerability of treatment with ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) in participants with genotypes 1 and 4 hepatitis C virus (HCV) infection and sofosbuvir (SOF) plus ribavirin (RBV) in participants with genotypes 2 and 3 HCV infection. Participants with an inherited bleeding disorder and chronic HCV infection (either monoinfected or HIV-1/HCV coinfected) will be enrolled.

Official Title
-----------------
A Phase 2b, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination and Sofosbuvir + Ribavirin for Subjects With Chronic Hepatitis C Virus (HCV) and Inherited Bleeding Disorders

Conditions
-----------------
Chronic HCV Infection

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Hemophilia A, B or C, or Von Willebrand's disease Chronic genotype 1, 2, 3 or 4 HCV infection HCV RNA ≥ 1000 IU/mL at screening Use of protocol specified method(s) of contraception if female of childbearing potential or sexually active male Screening laboratory values within defined thresholds For HIV-1/HCV co-infected individuals: Suppressed HIV-1 RNA on an antiretroviral (ARV) regimen for at least 6 months prior to screening Stable protocol-approved ARV regimen for > 8 weeks prior to screening CD4 T-cell count > 200 cells/mm^3 at screening Exclusion Criteria: Clinically-significant illness (other than HCV, inherited bleeding disorder or HIV-1) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol Current or prior history of any of the following: Hepatic decompensation Chronic liver disease of a non-HCV etiology Hepatocellular carcinoma (HCC) Infection with hepatitis B virus (HBV) Pregnant or nursing female Prior treatment with inhibitors of nonstructural protein 5A (NS5A) or the NS5B polymerase Chronic use of systemically administered immunosuppressive agents For HIV-1/HCV co-infected individuals: Opportunistic infection within 6 months prior to screening Active, serious infection (other than HIV-1 or HCV) requiring parental antibiotics, antivirals or antifungals within 30 days prior to baseline

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDV/SOF GT 1 or 4<br>Participants with chronic genotypes (GT) 1 or 4 HCV infection will receive LDV/SOF for 12 or 24 weeks. Treatment-experienced cirrhotic participants with genotype 1 HCV infection will receive LDV/SOF for 24 weeks. | Drug: LDV/SOF<br>* 90/400 mg FDC tablet administered orally<br>* Other names: GS-5885/GS-7977;|
| Experimental: SOF+RBV 12 wks GT 2<br>Participants with chronic genotype 2 HCV infection will receive SOF+RBV for 12 weeks. | Drug: SOF<br>* 400 mg tablet administered orally once daily<br>* Other names: PSI-7977;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: SOF+RBV 24 wks GT 3<br>Participants with chronic genotype 3 HCV infection will receive SOF+RBV for 24 weeks. | Drug: SOF<br>* 400 mg tablet administered orally once daily<br>* Other names: PSI-7977;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?
-----------------
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 Permanently Discontinued Any 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 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 HCV RNA < LLOQ at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 |  | Weeks 1, 2, 4, 8, 12, 16, 20, and 24 | 
| Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 |  | Baseline; Weeks 1, 2, 4, 8, 12, 16, 20, and 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 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 | 
| Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL at Weeks 4, 8, 12, 16, 20, and 24 (HIV-1/HCV Co-infected Participants Only) |  | Weeks 4, 8, 12, 16, 20, and 24 | 
| Change From Baseline in Serum Creatinine at the End of Treatment and at Posttreatment Week 12 (HIV-1/HCV Co-infected Participants Only) |  | Baseline; Weeks 12, 24, and Posttreatment Week 12 |