Ledipasvir/Sofosbuvir Fixed-Dose Combination Plus Ribavirin in Participants With Chronic HCV With Advanced Liver Disease or Post-Liver Transplant
- Registration Number
- NCT02010255
- Lead Sponsor
- Gilead Sciences
- Brief Summary
This study will evaluate ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) plus ribavirin (RBV) in participants with advanced liver disease or posttransplant and chronic genotype 1 or 4 hepatitis C virus (HCV) infection.
* Cohort A: decompensated cirrhosis (advanced liver disease), no prior liver transplant;
* Cohort B: post-liver transplant, with or without cirrhosis;
* Group assignment within cohorts is based on severity of liver impairment at screening (Child-Pugh-Turcotte (CPT) score for participants with cirrhosis; fibrosis; or presence of disease for fibrosing cholestatic hepatitis (FCH) groups)
* Randomization is 1:1 within groups to 12 or 24 weeks of LDV/SOF+RBV treatment.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 334
- Able to provide written informed consent
- Chronic genotype 1 and/or 4 HCV infection
- Normal ECG
- Negative serum pregnancy test for female subjects
- Male subjects and female subjects of childbearing potential must agree to use contraception
- Able to comply with the dosing instructions for study drug and able to complete the study schedule of assessments, including all required post treatment visits
- Serious or active medical or psychiatric illness
- HIV or hepatitis B viral (HBV) infection
- Stomach disorder that could interfere with the absorption of the study drug
- Treated with an anti-HCV medication in the last 30 days
- Any prior exposure to an HCV nonstructural protein (NS)5a-specific inhibitor
- Use of human granulocyte-macrophage colony-stimulating factor (GM-CSF), epoetin alfa or other therapeutic hematopoietic agents within 2 weeks of screening
- History of clinically significant medical condition associated with other chronic liver disease
- Active spontaneous bacterial peritonitis at screening
- Females who are breastfeeding
- Infection requiring systemic antibiotics
- Participated in a clinical study with an investigational drug or biologic within the last 30 days
- Active or history (last 6 months) of drug or alcohol abuse
- History of organ transplant other than liver, kidney, or corneal.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort A, Group 1 (12 wk): CPT Class B (7-9) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class B (CPT score 7-9) Cohort A, Group 1 (12 wk): CPT Class B (7-9) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class B (CPT score 7-9) Cohort A, Group 1 (24 wk): CPT Class B (7-9) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class B (CPT score 7-9) Cohort A, Group 1 (24 wk): CPT Class B (7-9) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class B (CPT score 7-9) Cohort A, Group 2 (12 wk): CPT Class C (10-12) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class C (CPT score 10-12) Cohort A, Group 2 (12 wk): CPT Class C (10-12) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class C (CPT score 10-12) Cohort A, Group 2 (24 wk): CPT Class C (10-12) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class C (CPT score 10-12) Cohort A, Group 2 (24 wk): CPT Class C (10-12) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class C (CPT score 10-12) Cohort B, Group 3 (12 wk): F0-F3 Fibrosis LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with Fibrosis Stage F0-F3 Cohort B, Group 3 (12 wk): F0-F3 Fibrosis RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with Fibrosis Stage F0-F3 Cohort B, Group 3 (24 wk): F0-F3 Fibrosis LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with Fibrosis Stage F0-F3 Cohort B, Group 3 (24 wk): F0-F3 Fibrosis RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with Fibrosis Stage F0-F3 Cohort B, Group 4 (12 wk): CPT Class A (5-6) LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with CPT Class A (CPT score 5-6) Cohort B, Group 4 (12 wk): CPT Class A (5-6) RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with CPT Class A (CPT score 5-6) Cohort B, Group 4 (24 wk): CPT Class A (5-6) LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with CPT Class A (CPT score 5-6) Cohort B, Group 4 (24 wk): CPT Class A (5-6) RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with CPT Class A (CPT score 5-6) Cohort B, Group 5 (12 wk): CPT Class B (7-9) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class B (CPT score 7-9) Cohort B, Group 5 (12 wk): CPT Class B (7-9) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class B (CPT score 7-9) Cohort B, Group 5 (24 wk): CPT Class B (7-9) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class B (CPT score 7-9) Cohort B, Group 5 (24 wk): CPT Class B (7-9) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class B (CPT score 7-9) Cohort B, Group 6 (12 wk): CPT Class C (10-12) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class C (CPT score 10-12) Cohort B, Group 6 (12 wk): CPT Class C (10-12) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 12 weeks in participants with CPT Class C (CPT score 10-12) Cohort B, Group 6 (24 wk): CPT Class C (10-12) LDV/SOF LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class C (CPT score 10-12) Cohort B, Group 6 (24 wk): CPT Class C (10-12) RBV LDV/SOF (90/400 mg) plus RBV (starting at 600 mg, then adjusted ± based on tolerability \[weight-based maximum: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg\]) for 24 weeks in participants with CPT Class C (CPT score 10-12) Cohort B, Group 7 (12 wk): FCH LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with FCH Cohort B, Group 7 (24 wk): FCH LDV/SOF LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with FCH Cohort B, Group 7 (12 wk): FCH RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 12 weeks in participants with FCH Cohort B, Group 7 (24 wk): FCH RBV LDV/SOF (90/400 mg) plus RBV (weight-based: \< 75 kg = 1000 mg, ≥ 75 kg = 1200 mg) for 24 weeks in participants with FCH
- Primary Outcome Measures
Name Time Method Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) Posttreatment Week 12 SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment.
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event Up to 24 weeks
- Secondary Outcome Measures
Name Time Method HCV RNA Levels and Change From Baseline at Week 4 Baseline; Week 4 Percentage of Participants With HCV RNA < LLOQ at Week 6 Week 6 Percentage of Participants With Virologic Failure Up to Posttreatment Week 24 Virologic failure was defined as:
* On-treatment virologic failure:
* Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ on 2 consecutive measurements while on treatment), or
* Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment)
* Virologic relapse:
* Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit.Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 Posttreatment Week 12 pTVR was defined as HCV RNA \< LLOQ at Week 12 after transplant.
Percentage of Participants With SVR 4 Weeks After Discontinuation of Therapy (SVR4) Posttreatment Week 4 SVR4 was defined as HCV RNA \< LLOQ at 4 weeks after stopping study treatment.
Percentage of Participants With SVR 8 Weeks After Discontinuation of Therapy (SVR8) Posttreatment Week 8 SVR8 was defined as HCV RNA \< LLOQ at 8 weeks after stopping study treatment.
Percentage of Participants With HCV RNA < LLOQ at Week 1 Week 1 Percentage of Participants With HCV RNA < LLOQ at Week 12 Week 12 Percentage of Participants With SVR 2 Weeks After Discontinuation of Therapy (SVR2) Posttreatment Week 2 SVR2 was defined as HCV RNA \< LLOQ at 2 weeks after stopping study treatment.
Percentage of Participants With SVR 24 Weeks After Discontinuation of Therapy (SVR24) Posttreatment Week 24 SVR24 was defined as HCV RNA \< LLOQ at 24 weeks after stopping study treatment.
Percentage of Participants With HCV RNA < LLOQ at Week 2 Week 2 Percentage of Participants With HCV RNA < LLOQ at Week 4 Week 4 Percentage of Participants With HCV RNA < LLOQ at Week 8 Week 8 Percentage of Participants With HCV RNA < LLOQ at Week 16 Week 16 Percentage of Participants With HCV RNA < LLOQ at Week 20 Week 20 Percentage of Participants With HCV RNA < LLOQ at Week 24 Week 24 HCV RNA Levels and Change From Baseline at Week 8 Baseline; Week 8 Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in CPT Score Baseline to Posttreatment Week 4 CPT scores grade the severity of cirrhosis and are used to determine the need for liver transplantation. Scores can range from 5 to 15 (maximum score for entry into the study was 12); higher scores/increased scores indicate greater severity of disease. Groups are arranged by cohort, then by duration of treatment, then by CPT class at baseline.
HCV RNA Levels and Change From Baseline at Week 1 Baseline; Week 1 HCV RNA Levels and Change From Baseline at Week 2 Baseline; Week 2 HCV RNA Levels and Change From Baseline at Week 6 Baseline; Week 6 HCV RNA Levels and Change From Baseline at Week 12 Baseline; Week 12 Percentage of Participants With a Decrease, No Change, or Increase Between Baseline and Posttreatment Week 4 in MELD Score Baseline to Posttreatment Week 4 Model for End-Stage Liver Disease (MELD) scores are used to assess prognosis and suitability for liver transplantation. Scores can range from 6 to 40; higher scores/increased scores indicate greater severity of disease.
Trial Locations
- Locations (34)
Hospital Mondor \\ Service d'Hépatologie et de Gastroentérologie,
🇫🇷Créteil, France
Medizinische Universitat Wien
🇦🇹Wien, Austria
Universitätsklinikum RWTH Aachen
🇩🇪Aachen, Germany
Division of Gastroenterology, University of Alberta, Edmonton
🇨🇦Edmonton, Alberta, Canada
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
IRCCS Cà Grande Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
McGill University Health Centre \\ Royal Victoria Hospital
🇨🇦Montreal, Quebec, Canada
UCL St-Luc Brussels
🇧🇪Brussels, Belgium
Hospital General Universitari Vall d' Hebron
🇪🇸Barcelona, Spain
Hopital Paul Brousse
🇫🇷Villejuif Cedex, France
Hospital Beaujon
🇫🇷Clichy Cedex, France
Austin Repatriation Hospital (Melbourne) // Victorian Transplant Centre
🇦🇺Heidelberg, Victoria, Australia
Hopital St. Luc
🇨🇦Montreal, Quebec, Canada
Medizinische Universitaet Innsbruck
🇦🇹Innsbruck, Austria
Hopital Saint-Eloi
🇫🇷Montpellier, France
Medical School of Hannover
🇩🇪Hannover, Germany
Erasmus MC in Rotterdam
🇳🇱Rotterdam, Netherlands
Royal Infirmary of Edinburgh \\ Scottish Liver Transplant Unit-Edinburgh
🇬🇧Edinburgh, United Kingdom
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
University Hospitals Birmingham NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Royal Prince Alfred Hospital, University of Sydney
🇦🇺Camperdown, New South Wales, Australia
University Health Network // Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Universitätsklinikum Essen - klinikum für Gastroenterolgie und Hepatologie
🇩🇪Essen, Germany
Azienda Ospedaliera San Giovanni, Battista di Torino \\ Professor of Gastroenterology-San Giovanni Battista Hospital-University of Torino
🇮🇹Torino, Italy
University Hospital Johann Wolfgang Goethe University, Department of Internal Medicine I
🇩🇪Frankfurt, Germany
Auckland City Hospital
🇳🇿Auckland, New Zealand
Hospital Universitario y Politecnico La Fe de Valencia
🇪🇸Valencia, Spain
University of Berne
🇨🇭Bern, Switzerland
Puerta de Hierro, Madrid
🇪🇸Madrid, Spain
Kings College Hospital, Institute of Liver Studies
🇬🇧London, United Kingdom
University Hospital Zurich
🇨🇭Zurich, Switzerland
Hospital Clinic i Provincial
🇪🇸Barcelona, Spain
University of British Columbia and Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre-University Hospital
🇨🇦London, Ontario, Canada