Ledipasvir/Sofosbuvir Fixed-Dose Combination + Ribavirin in Subjects With Chronic HCV With Advanced Liver Disease or Post-Liver Transplant
- Registration Number
- NCT01938430
- 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
- 339
Inclusion Criteria
- Able to provide written informed consent
- Chronic genotype 1 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
Exclusion Criteria
- 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 or kidney
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 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 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 (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 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 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 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 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 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 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 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 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 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 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 (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 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 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 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 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 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 (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 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 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 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 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 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 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 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
- 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 and Change From Baseline at Week 4 Baseline; Week 4 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 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 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 HCV RNA < LLOQ at Week 2 Week 2 Percentage of Participants With HCV RNA < LLOQ at Week 24 Week 24 Percentage of Participants With HCV RNA < LLOQ at Week 8 Week 8 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 Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 Posttransplant Week 12 pTVR was defined as HCV RNA \< LLOQ at Week 12 after transplant.
Percentage of Participants With HCV RNA < LLOQ at Week 1 Week 1 HCV RNA and Change From Baseline at Week 1 Baseline; Week 1 HCV RNA and Change From Baseline at Week 2 Baseline; Week 2 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 HCV RNA < LLOQ at Week 4 Week 4 Percentage of Participants With HCV RNA < LLOQ at Week 6 Week 6 Percentage of Participants With HCV RNA < LLOQ at Week 16 Week 16 HCV RNA and Change From Baseline at Week 8 Baseline; Week 8 HCV RNA and Change From Baseline at Week 12 Baseline; Week 12 Percentage of Participants With HCV RNA < LLOQ at Week 20 Week 20 Percentage of Participants With HCV RNA < LLOQ at Week 12 Week 12 HCV RNA and Change From Baseline at Week 6 Baseline; Week 6 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.
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.