Back to resultsSofosbuvir in Combination With Pegylated Interferon and Ribavirin and in Treatment-Naive Hepatitis C-infected Patients
Primary Purpose
Hepatitis C Virus
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sofosbuvir
Placebo to match sofosbuvir
PEG
RBV
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis C Virus focused on measuring Hepatitis C Virus, HCV, hepatitis, Genotype 1, Genotype 2, Genotype 3
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
Sites / Locations
- Alabama Liver and Digestive Specialists
- Advanced Clinical Research Institute
- SCTI Research Foundation
- Cedars Sinai Medical Center
- Dr. Jay Lalezari
- Dr. Natalie Bzowej
- Dr. David Nelson
- Orlando Immunology Center
- Gastrointestinal Specialists of Georgia
- University of Chicago
- Dr. Mark Sulkowski
- Liver Research Center Beth Israel Deaconess Medical Center
- Kansas City Gastroenterology and Hepatology
- Dr. Bruce Bacon
- North Shore University Hospital
- Dr. Ira Jacobson
- Mount Sinai School of Medicine
- Dr. Jama Darling
- Dr. Raj Reddy
- Columbia Gastroenterology and Liver Associates
- Dr. Eric Lawitz
- Digestive Disease Institute Virginia Mason Medical Center
- Fundacion de Investigacion de Diego
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Active Comparator
Experimental
Arm Label
Sofosbuvir 200 mg (Genotype 1)
Sofosbuvir 400 mg (Genotype 1)
Placebo (Genotype 1)
Sofosbuvir 400 mg (Genotype 2/3)
Arm Description
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.
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.
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.
Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Change in HCV RNA From 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)
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01188772
Brief Title
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
2. Study Status
Record Verification Date
April 2014
Overall Recruitment Status
Completed
Study Start Date
August 2010 (undefined)
Primary Completion Date
April 2011 (Actual)
Study Completion Date
May 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C Virus
Keywords
Hepatitis C Virus, HCV, hepatitis, Genotype 1, Genotype 2, Genotype 3
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
147 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sofosbuvir 200 mg (Genotype 1)
Arm Type
Experimental
Arm Description
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.
Arm Title
Sofosbuvir 400 mg (Genotype 1)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo (Genotype 1)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Sofosbuvir 400 mg (Genotype 2/3)
Arm Type
Experimental
Arm Description
Participants with genotype 2 or 3 HCV infection received sofosbuvir 400 mg (4 x 100 mg tablets)+PEG+RBV for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Sofosbuvir
Other Intervention Name(s)
Sovaldi®, GS-7977, PSI-7977
Intervention Description
Sofosbuvir tablets were administered orally once daily.
Intervention Type
Drug
Intervention Name(s)
Placebo to match sofosbuvir
Intervention Description
Placebo tablets to match sofosbuvir were administered orally once daily.
Intervention Type
Drug
Intervention Name(s)
PEG
Other Intervention Name(s)
Pegasys®
Intervention Description
Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.
Intervention Type
Drug
Intervention Name(s)
RBV
Other Intervention Name(s)
Copegus®
Intervention Description
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).
Primary Outcome Measure Information:
Title
Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period
Description
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.
Time Frame
Baseline to Week 12 plus 30 days
Secondary Outcome Measure Information:
Title
Change in HCV RNA From Baseline to Week 12
Time Frame
Baseline to Week 12
Title
Percentage of Participants With Rapid Virologic Response at Week 4
Description
Rapid virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at Week 4 (Day 29)
Time Frame
Week 4
Title
Percentage of Participants With Complete Early Virologic Response at Week 12
Description
Complete early virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at Week 12
Time Frame
Week 12
Title
Percentage of Participants With Extended Rapid Virologic Response
Description
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.
Time Frame
Week 4 to Week 12
Title
Percentage of Participants With Virologic Response at the End of Treatment
Description
End-of-treatment virologic response was defined as HCV RNA below the limit of detection (< 15 IU/mL) at the last on-treatment visit.
Time Frame
Week 48 (genotype 1) or Week 12 (genotype 2/3)
Title
Percentage of Participants With Sustained Virologic Response at Post-treatment Week 12 (SVR12) and 24 (SVR24)
Description
SVR12 and SVR24 were defined as HCV RNA below the limit of detection (< 15 IU/mL) at post-treatment Weeks 12 and 24, respectively.
Time Frame
Post-treatment Weeks 12 and 24
Title
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 8)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 15)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Plasma Pharmacokinetics of GS-331007 (Cmax at Day 29)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 8)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 15)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Plasma Pharmacokinetics of GS-331007 (AUCtau at Day 29)
Description
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.
Time Frame
1, 2, 4, 8, and 12 hours postdose
Title
Percentage of Participants Who Developed Resistance to Sofosbuvir
Description
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.
Time Frame
Baseline to Week 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert H. Hyland, DPhil
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
Alabama Liver and Digestive Specialists
City
Montgomery
State/Province
Alabama
Country
United States
Facility Name
Advanced Clinical Research Institute
City
Anaheim
State/Province
California
Country
United States
Facility Name
SCTI Research Foundation
City
Coronado
State/Province
California
Country
United States
Facility Name
Cedars Sinai Medical Center
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Dr. Jay Lalezari
City
San Francisco
State/Province
California
Country
United States
Facility Name
Dr. Natalie Bzowej
City
San Francisco
State/Province
California
Country
United States
Facility Name
Dr. David Nelson
City
Gainesville
State/Province
Florida
Country
United States
Facility Name
Orlando Immunology Center
City
Orlando
State/Province
Florida
Country
United States
Facility Name
Gastrointestinal Specialists of Georgia
City
Marietta
State/Province
Georgia
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
Dr. Mark Sulkowski
City
Lutherville
State/Province
Maryland
Country
United States
Facility Name
Liver Research Center Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Kansas City Gastroenterology and Hepatology
City
Kansas City
State/Province
Missouri
Country
United States
Facility Name
Dr. Bruce Bacon
City
St. Louis
State/Province
Missouri
Country
United States
Facility Name
North Shore University Hospital
City
Manhasset
State/Province
New York
Country
United States
Facility Name
Dr. Ira Jacobson
City
New York
State/Province
New York
Country
United States
Facility Name
Mount Sinai School of Medicine
City
New York
State/Province
New York
Country
United States
Facility Name
Dr. Jama Darling
City
Chapel Hill
State/Province
North Carolina
Country
United States
Facility Name
Dr. Raj Reddy
City
Philadelphia
State/Province
Pennsylvania
Country
United States
Facility Name
Columbia Gastroenterology and Liver Associates
City
Columbia
State/Province
South Carolina
Country
United States
Facility Name
Dr. Eric Lawitz
City
San Antonio
State/Province
Texas
Country
United States
Facility Name
Digestive Disease Institute Virginia Mason Medical Center
City
Seattle
State/Province
Washington
Country
United States
Facility Name
Fundacion de Investigacion de Diego
City
Santurce
Country
Puerto Rico
12. IPD Sharing Statement
Citations:
PubMed Identifier
23499158
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.
Results Reference
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Sofosbuvir in Combination With Pegylated Interferon and Ribavirin and in Treatment-Naive Hepatitis C-infected Patients
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