Sofosbuvir and Ribavirin in Patients With Chronic HCV With Cirrhosis and Portal Hypertension With or Without Liver Decompensation

A Phase 2, Multicenter, Open-Label, Randomized Study to Investigate the Safety and Efficacy of GS-7977 and Ribavirin Administered for 48 Weeks in Patients Infected With Chronic HCV With Cirrhosis and Portal Hypertension With or Without Liver Decompensation

This study will evaluate the antiviral efficacy of combination therapy with sofosbuvir (SOF) plus ribavirin (RBV) for 48 weeks in adults with compensated and decompensated chronic hepatitis C virus (HCV) infection. Approximately 50 adults will be randomized (1:1) to receive study drug for 48 weeks or take part in an untreated observational arm for the first 24 weeks followed by study drug for another 48 weeks.

Study Overview

• Status: Completed
• Conditions: Hepatitis C; Cirrhosis; Portal Hypertension; With or Without Liver Decompensation
• Intervention / Treatment: Drug: RBV; Drug: SOF

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Newtown, New South Wales, Australia
• France
  • Clichy
    • Leclerc, Clichy, France
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand
• Spain
  • Barcelona, Spain
  • Madrid
    • Majadahonda, Madrid, Spain
• United States
  • Colorado
    • Aurora, Colorado, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Minnesota
    • Rochester, Minnesota, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chronic infection with Hepatitis C with HCV RNA > 1000 IU/mL
• Individuals with cirrhosis with Child-Pugh score < 10
• Esophageal or gastric varices on endoscopy within 6 months prior to or at screening
• Hepatic Venous Pressure Gradient (HVPG) > 6 mmHg
• Body mass index (BMI) ≥ 18 kg/m^2
• Naïve to all nucleotides/nucleoside treatments for chronic HCV infection

Exclusion Criteria:

• Have any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance
• HIV or chronic hepatitis B virus (HBV) infection (HBsAg positive)
• Alpha-fetoprotein (AFP) > 50 unless negative imaging for hepatic masses within the last 6 months or during screening
• Refractory ascites as defined by requiring paracentesis > twice within 1 month prior to screening
• Active variceal bleeding within 6 months of screening
• Expected survival of < 1 year
• History of hepatorenal, or hepatopulmonary syndrome.
• Evidence of renal impairment (CrCl < 50 mL/min)
• History of major organ transplantation, including liver transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SOF+RBV; Participants will receive SOF+RBV for 48 weeks.	Drug: RBV; 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); Drug: SOF; SOF 400 mg tablet administered orally once daily; Other Names: Sovaldi®; GS-7977
Experimental: Observation, then SOF+RBV; Participants will undergo 24 weeks of observation and then receive SOF+RBV for 48 additional weeks.	Drug: RBV; 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); Drug: SOF; SOF 400 mg tablet administered orally once daily; Other Names: Sovaldi®; GS-7977

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, 25 IU/mL) at 12 weeks after stopping study treatment. For the Observation/SOF+RBV group, SVR12 during the observational period was defined as HCV RNA < LLOQ for 12 consecutive weeks, any time during the observational period.	Posttreatment Week 12 (SOF+RBV) and up to 24 weeks (Observation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48)	SVR4, SVR24, and SVR48 were defined as HCV RNA < LLOQ at 4, 24, and 48 weeks after stopping study treatment, respectively.	Posttreatment Weeks 4, 24, and 48
Percentage of Participants Experiencing On-Treatment Virologic Failure	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)	Up to 48 weeks
Percentage of Participants Experiencing Viral Relapse	Viral relapse was defined as HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last available post-treatment measurement.	Up to Posttreatment Week 24
Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment	HVPG closely reflects the degree of portal hypertension in patients with cirrhosis. The end of treatment for the Observation group was defined as the end of the observation period. The treatment period for Group 2 was defined as the end of the observation period to the end of the treatment. Baseline values were the last available values on or prior to first dose date of any study drug.	Baseline; Week 24 (Observation) and Week 48 (SOF+RBV)
Change From Baseline in Child-Pugh-Turcotte (CPT) Score	CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease. Data are presented as improvement, no change, or worsening in CPT scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in CPT score was defined as having a decrease in CPT score from baseline, no change in CPT score was defined as having no change in CPT score from baseline, and worsening in CPT score was defined as having an increase in CPT score from baseline. Baseline values were the last available values on or prior to first dose date of any study drug.	Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)
Change From Baseline in Model for End Stage Liver Disease (MELD) Scores	MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity. Data are presented as improvement, no change, or worsening in MELD scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in MELD score was defined as having a baseline MELD score of 11-15 or 16-20 that changed to 0-10, or a baseline MELD score of 16-20 that changed to 11-15; no change in MELD score was defined as having no change in score group (0-10, 11-15, or 16-20) from baseline; and worsening in MELD score was defined as having a baseline MELD score of 0-10 that changed to 11-15 or 16-20, or a baseline MELD score of 11-15 that changed to 16-20. Baseline values were the last available values on or prior to first dose date of any study drug.	Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: September 12, 2012
• First Submitted That Met QC Criteria: September 13, 2012
• First Posted (Estimate): September 18, 2012

Study Record Updates

• Last Update Posted (Estimate): September 16, 2016
• Last Update Submitted That Met QC Criteria: August 5, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Fibrosis; Hypertension; Liver Failure; Hepatitis C; Liver Cirrhosis; Hypertension, Portal; Anti-Infective Agents; Antiviral Agents; Sofosbuvir
• Other Study ID Numbers: GS-US-334-0125; 2012-002457-29 (EudraCT Number)