Clinical trial NCT01188772: Sofosbuvir in Combination With Pegylated Interferon and Ribavirin and in Treatment-Naive Hepatitis C-infected Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C Virus
Keywords: Hepatitis C Virus
HCV
hepatitis
Genotype 1
Genotype 2
Genotype 3
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2010-08-25
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period
timeFrame: Baseline to Week 12 plus 30 days
Secondary outcomes:
measure: Change in HCV RNA From Baseline to Week 12
timeFrame: Baseline to Week 12
measure: Percentage of Participants With Rapid Virologic Response at Week 4
timeFrame: Week 4
measure: Percentage of Participants With Complete Early Virologic Response at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Extended Rapid Virologic Response
timeFrame: Week 4 to Week 12
measure: Percentage of Participants With Virologic Response at the End of Treatment
timeFrame: Week 48 (genotype 1) or Week 12 (genotype 2/3)
measure: Percentage of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12) and 24 (SVR24)
timeFrame: Post-treatment Weeks 12 and 24
measure: Plasma Pharmacokinetics of GS-331007 (Cmax at Day 8)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Plasma Pharmacokinetics of GS-331007 (Cmax at Day 15)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Plasma Pharmacokinetics of GS-331007 (Cmax at Day 29)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 8)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 15)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 29)
timeFrame: 1, 2, 4, 8, and 12 hours postdose
measure: Percentage of Participants Who Developed Resistance to Sofosbuvir
timeFrame: Baseline to Week 12
Other outcomes:
Locations:
city: Montgomery
country: United States
facility: Alabama Liver and Digestive Specialists
state: Alabama
city: Anaheim
country: United States
facility: Advanced Clinical Research Institute
state: California
city: Coronado
country: United States
facility: SCTI Research Foundation
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: Dr. Jay Lalezari
state: California
city: San Francisco
country: United States
facility: Dr. Natalie Bzowej
state: California
city: Gainesville
country: United States
facility: Dr. David Nelson
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Lutherville
country: United States
facility: Dr. Mark Sulkowski
state: Maryland
city: Boston
country: United States
facility: Liver Research Center Beth Israel Deaconess Medical Center
state: Massachusetts
city: Kansas City
country: United States
facility: Kansas City Gastroenterology and Hepatology
state: Missouri
city: St. Louis
country: United States
facility: Dr. Bruce Bacon
state: Missouri
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Dr. Ira Jacobson
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Chapel Hill
country: United States
facility: Dr. Jama Darling
state: North Carolina
city: Philadelphia
country: United States
facility: Dr. Raj Reddy
state: Pennsylvania
city: Columbia
country: United States
facility: Columbia Gastroenterology and Liver Associates
state: South Carolina
city: San Antonio
country: United States
facility: Dr. Eric Lawitz
state: Texas
city: Seattle
country: United States
facility: Digestive Disease Institute Virginia Mason Medical Center
state: Washington
city: Santurce
country: Puerto Rico
facility: Fundacion de Investigacion de Diego
Study officials:
affiliation: Gilead Sciences
name: Robert H. Hyland, DPhil
role: STUDY_DIRECTOR
References:
citation: 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.