Sofosbuvir in Combination With Pegylated Interferon and Ribavirin and in Treatment-Naive Hepatitis C-infected Patients

A Multi-center, Placebo-Controlled, Dose Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 in Combination With Pegylated Interferon and Ribavirin in Treatment-Naïve Patients With Chronic HCV Infection Genotype 1, and an Open Label Assessment of PSI-7977 in Patients With HCV Genotypes 2 or 3

Genotype 1: Participants with genotype 1 hepatitis C (HCV) infection were randomized to receive sofosbuvir (GS-7977; PSI-7977) 200 mg or 400 mg, or matching placebo, plus pegylated interferon alfa 2a (PEG) and ribavirin (RBV) for 12 weeks, followed by PEG+RBV for an up to an additional 36 weeks. Randomization was stratified by IL28B status (CC, CT, TT) and HCV RNA level (< 800,000 IU/ml or ≥ 800,000 IU/ml) at baseline. Participants were randomized in a 2:2:1 manner; those who achieved an extended rapid virologic response (eRVR) (HCV RNA < lower limit of detection [15 IU/mL] from Weeks 4 through 12) received an additional 12 weeks of PEG+RBV. Subjects not achieving eRVR received an additional 36 weeks of PEG+RBV.

Genotype 2 and 3: Participants with genotype 2 or 3 hepatitis C (HCV) received sofosbuvir 400 mg plus PEG+RBV for 12 weeks.

Study Overview

• Status: Completed
• Conditions: Hepatitis C Virus
• Intervention / Treatment: Drug: Sofosbuvir; Drug: Placebo to match sofosbuvir; Drug: PEG; Drug: RBV

• Study Type: Interventional
• Enrollment (Actual): 147
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • Santurce, Puerto Rico
    • Fundacion de Investigacion de Diego
• United States
  • Alabama
    • Montgomery, Alabama, United States
      • Alabama Liver and Digestive Specialists
  • California
    • Anaheim, California, United States
      • Advanced Clinical Research Institute
    • Coronado, California, United States
      • Scti Research Foundation
    • Los Angeles, California, United States
      • Cedars Sinai Medical Center
    • San Francisco, California, United States
      • Dr. Jay Lalezari
    • San Francisco, California, United States
      • Dr. Natalie Bzowej
  • Florida
    • Gainesville, Florida, United States
      • Dr. David Nelson
    • Orlando, Florida, United States
      • Orlando Immunology Center
  • Georgia
    • Marietta, Georgia, United States
      • Gastrointestinal Specialists of Georgia
  • Illinois
    • Chicago, Illinois, United States
      • University of Chicago
  • Maryland
    • Lutherville, Maryland, United States
      • Dr. Mark Sulkowski
  • Massachusetts
    • Boston, Massachusetts, United States
      • Liver Research Center Beth Israel Deaconess Medical Center
  • Missouri
    • Kansas City, Missouri, United States
      • Kansas City Gastroenterology and Hepatology
    • St. Louis, Missouri, United States
      • Dr. Bruce Bacon
  • New York
    • Manhasset, New York, United States
      • North Shore University Hospital
    • New York, New York, United States
      • Mount Sinai School of Medicine
    • New York, New York, United States
      • Dr. Ira Jacobson
  • North Carolina
    • Chapel Hill, North Carolina, United States
      • Dr. Jama Darling
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Dr. Raj Reddy
  • South Carolina
    • Columbia, South Carolina, United States
      • Columbia Gastroenterology and Liver Associates
  • Texas
    • San Antonio, Texas, United States
      • Dr. Eric Lawitz
  • Washington
    • Seattle, Washington, United States
      • Digestive Disease Institute Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females aged 18 to 70 years, inclusive, at screening
• Documented chronic genotype 1, 2, or 3 HCV infection
• No previous treatment with HCV antiviral mediations
• Body mass index (BMI) of greater than 18 kg/m2, but not exceeding 36 kg/m2.
• Liver biopsy obtained within 3 years prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic as judged by a local pathologist
• Willing to refrain from beginning any new exercise regimens during the first 3 months of the study
• Fasting blood glucose ≤ 300 mg/dl and/or glycosylated hemoglobin (HbA1c) ≤ 8
• History of hypertension only if managed effectively on a stable regimen of two or fewer antihypertensives for at least three (3) months prior to screening

Exclusion Criteria:

• Females who were breastfeeding
• Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study
• Positive test at Screening for HBsAg, anti-HBc IgM Ab, or anti-HIV Ab.
• History of any other clinically significant chronic liver disease
• Treatment with herbal/natural remedies with antiviral activity within 30 days prior to baseline.
• Significant history of immunologically mediated disease, cardiac or pulmonary disease, seizure disorder or anticonvulsant use
• History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease
• Use of medications associated with QT prolongation within 30 days prior to dosing
• Screening electrocardiogram (ECG) QTc value greater than 450 ms and/or clinically significant ECG findings
• Personal or family history of Torsade de pointes.
• Positive results for drugs of abuse test at screening
• Abnormal hematological and biochemical parameters, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 5 times the upper limit of the normal range (ULN)
• History of major organ transplantation with an existing functional graft
• History of uncontrolled thyroid disease or abnormal thyroid-stimulating hormone (TSH) levels at screening
• Clinically significant drug allergy to nucleoside/nucleotide analogs
• History or current evidence of psychiatric illness, immunologic disorder, pulmonary, cardiac disease, seizure disorder, cancer or history of malignancy that in the opinion of the investigator makes the patient unsuitable for the study
• History of systemic antineoplastic or immunomodulatory treatment within 6 months prior to dosing, or the expectation of such treatment during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sofosbuvir 200 mg (Genotype 1); Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 200 mg (2 x 100 mg tablets)+placebo to match sofosbuvir (2 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.	Drug: Sofosbuvir; Sofosbuvir tablets were administered orally once daily.; Other Names: Sovaldi®; GS-7977; PSI-7977; Drug: Placebo to match sofosbuvir; Placebo tablets to match sofosbuvir were administered orally once daily.; Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Names: Pegasys®; Drug: RBV; Ribavirin (RBV) was administered as a tablet orally according to package insert dosing recommendations (Genotype 1: < 75kg = 1000 mg and ≥ 75 kg = 1200 mg; Genotype 2/3: 800 mg).; Other Names: Copegus®
Experimental: Sofosbuvir 400 mg (Genotype 1); Participants with genotype 1 HCV infection were randomized to receive sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.	Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Names: Pegasys®; Drug: RBV; Ribavirin (RBV) was administered as a tablet orally according to package insert dosing recommendations (Genotype 1: < 75kg = 1000 mg and ≥ 75 kg = 1200 mg; Genotype 2/3: 800 mg).; Other Names: Copegus®
Active Comparator: Placebo (Genotype 1); Participants with genotype 1 HCV infection were randomized to receive placebo to match sofosbuvir (4 tablets)+PEG+RBV for 12 weeks followed by PEG+RBV for up to an additional 36 weeks.	Drug: Placebo to match sofosbuvir; Placebo tablets to match sofosbuvir were administered orally once daily.; Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Names: Pegasys®; Drug: RBV; Ribavirin (RBV) was administered as a tablet orally according to package insert dosing recommendations (Genotype 1: < 75kg = 1000 mg and ≥ 75 kg = 1200 mg; Genotype 2/3: 800 mg).; Other Names: Copegus®
Experimental: Sofosbuvir 400 mg (Genotype 2/3); Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.	Drug: Sofosbuvir; Sofosbuvir tablets were administered orally once daily.; Other Names: Sovaldi®; GS-7977; PSI-7977; Drug: PEG; Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.; Other Names: Pegasys®; Drug: RBV; Ribavirin (RBV) was administered as a tablet orally according to package insert dosing recommendations (Genotype 1: < 75kg = 1000 mg and ≥ 75 kg = 1200 mg; Genotype 2/3: 800 mg).; Other Names: Copegus®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period	Adverse events (AEs) occurring during the sofosbuvir treatment period and for 30 days following the last dose of sofosbuvir were summarized across the participant population. A participant was counted once if they had a qualifying event.	Baseline to Week 12 plus 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HCV RNA From Baseline to Week 12		Baseline to Week 12
Percentage of Participants With Rapid Virologic Response at Week 4	Rapid virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at Week 4 (Day 29)	Week 4
Percentage of Participants With Complete Early Virologic Response at Week 12	Complete early virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at Week 12	Week 12
Percentage of Participants With Extended Rapid Virologic Response	Extended rapid virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at Week 4 (Day 29) which was maintained through Week 12.	Week 4 to Week 12
Percentage of Participants With Virologic Response at the End of Treatment	End-of-treatment virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at the last on-treatment visit.	Week 48 (genotype 1) or Week 12 (genotype 2/3)
Percentage of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12) and 24 (SVR24)	SVR12 and SVR24 were defined as HCV RNA below the limit of detection (< 15 IU/mL) at post-treatment Weeks 12 and 24, respectively.	Post-treatment Weeks 12 and 24
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 8)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the maximum observed concentration of drug in plasma (Cmax) at Day 8. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 15)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the Cmax at Day 15. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 29)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the Cmax at Day 29. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 8)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the the area under the plasma concentration versus time curve over the dosing interval (AUCtau) at Day 8. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 15)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the the area under the plasma concentration versus time curve over the dosing interval (AUCtau) at Day 15. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 29)	The pharmacokinetics of sofosbuvir metabolite GS-331007 were analyzed as the the area under the plasma concentration versus time curve over the dosing interval (AUCtau) at Day 29. Blood samples were collected at 1, 2, and 4 hours postdose for all participants, and at 8 and 12 hours postdose for participants enrolled at selected sites.	1, 2, 4, 8, and 12 hours postdose
Percentage of Participants Who Developed Resistance to Sofosbuvir	Resistance monitoring was completed in all subjects who received sofosbuvir and who had non-response, viral rebound, virologic breakthrough, or HCV RNA plateaus between Day 0 and Week 24.	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B, Nelson DR, Dieterich DT, Jacobson IM, Jensen D, Abrams GA, Darling JM, Rodriguez-Torres M, Reddy KR, Sulkowski MS, Bzowej NH, Hyland RH, Mo H, Lin M, Mader M, Hindes R, Albanis E, Symonds WT, Berrey MM, Muir A. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013 May;13(5):401-8. doi: 10.1016/S1473-3099(13)70033-1. Epub 2013 Mar 15.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: August 23, 2010
• First Submitted That Met QC Criteria: August 24, 2010
• First Posted (Estimate): August 25, 2010

Study Record Updates

• Last Update Posted (Estimate): April 21, 2014
• Last Update Submitted That Met QC Criteria: April 2, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: HCV; Hepatitis C Virus; Genotype 1; Genotype 2; Genotype 3; hepatitis
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Sofosbuvir
• Other Study ID Numbers: P7977-0422