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

Hepatitis C Virus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01188772
• Other study ID #: P7977-0422
• Status: Completed
• Phase: Phase 2
• First received: August 23, 2010
• Last updated: April 2, 2014
• Start date: August 2010
• Est. completion date: May 2012

Study information

• Verified date: April 2014
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 147
• Est. completion date: May 2012
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C Virus

Intervention

Drug:
• Sofosbuvir
Sofosbuvir tablets were administered orally once daily.
• Placebo to match sofosbuvir
Placebo tablets to match sofosbuvir were administered orally once daily.
• PEG
Pegylated interferon alfa-2a (PEG) 180 µg was administered once weekly by subcutaneous injection.
• 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).

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Change in HCV RNA From Baseline to Week 12		Baseline to Week 12	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No