HCV Infection
Conditions
Keywords
Hepatitis C, HCV, Cirrhosis
Brief summary
This study is to determine the antiviral efficacy of sofosbuvir (SOF)/ledipasvir (LDV) fixed-dose combination (FDC) with and without ribavirin (RBV), and to evaluate the safety and tolerability of each regimen as assessed by review of the accumulated safety data. Approximately 150 participants with genotype 1 HCV infection, who have previously received treatment for HCV, and who have a diagnosis for cirrhosis will be enrolled. Participants will be randomized to 1 of 2 groups. Group 1: SOF/LDV FDC tablet plus placebo to match RBV for 24 weeks Group 2: Delayed treatment group: placebo to match SOF/LDV FDC plus placebo to match RBV for 12 weeks, followed by SOF/LDV FDC once daily plus RBV in a divided daily dose for 12 weeks Randomization will 1:1 to the two groups and will be stratified by HCV genotype (1a, 1b; mixed or other genotype 1 results will be stratified as genotype 1a), and prior HCV therapy treatment response (never achieved HCV RNA \< the lower limit of quantitation (LLOQ), or achieved HCV RNA \< LLOQ).
Interventions
DRUGLDV/SOF
LDV/SOF (90/400 mg) FDC tablet administered orally once daily
DRUGRBV
RBV (200 mg tablets) administered orally in a divided daily dose based on weight (1000 mg per day for participants weighing \< 75 kg; 1200 mg per day for participants weighing ≥ 75 kg)
DRUGPlacebo to match LDV/SOF
Placebo to match LDV/SOF administered orally once daily
Placebo to match RBV administered orally in a divided daily dose
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age equal to or greater than 18 years, with chronic genotype 1 HCV infection * HCV RNA ≥ 10,000 IU/mL at screening * Prior virological failure after treatment with pegylated interferon (PEG-IFN), RBV and a protease inhibitor following documented prior virology failure after treatment with a PEG-IFN + RBV regimen * Evidence of cirrhosis * Screening laboratory values within defined thresholds * Use of two effective contraception methods if female of childbearing potential or sexually active male
Exclusion criteria
* Pregnant or nursing female or male with pregnant female partner * Current or prior history of clinical hepatic decompensation * Prior exposure to approved or experimental HCV specific direct-acting antivirals other than a nonstructural protein (NS)3/4A protease inhibitor * History of solid organ transplantation, including liver transplant * Hepatocellular carcinoma or other malignancy (with exception of certain resolved skin cancers) * Chronic use of systemic immunosuppressive agents * History of clinically significant illness or any other medical disorder that may interfere with subject treatment, assessment or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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, \< 25 IU/mL) 12 weeks following the last dose of study drug. * 1 participant who was randomized to the LDV/SOF + RBV group who received placebo discontinued prior to receiving LDV/SOF + RBV and is excluded from the Full Analysis Set. * 1 participant who was randomized to the LDV/SOF + RBV group received LDV/SOF + placebo, and is counted in the LDV/SOF group for the safety analysis, and in the LDV/SOF+RBV group for the efficacy analysis (ie, in the Full Analysis Set). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | Posttreatment Weeks 4 and 24 | SVR4 and SVR24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively. |
| Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Weeks 1, 2, 4, 8, 12, and 24 | — |
| Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Baseline; Weeks 1, 2, 4, 8, and 12 | — |
| Percentage of Participants With Virologic Failure | Baseline to Posttreatment Week 24 | Virologic failure is defined as * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit. |
Countries
France
Participant flow
Recruitment details
Participants were enrolled study sites in France. The first participant was screened on 26 September 2013. The last study visit occurred on 12 November 2014.
Pre-assignment details
172 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF LDV/SOF (90/400 mg) FDC tablet once daily plus placebo to match RBV in a divided daily dose for 24 weeks | 78 |
| LDV/SOF + RBV Placebo to match LDV/SOF plus placebo to match RBV for 12 weeks, followed by LDV/SOF (90/400 mg) FDC tablet plus RBV (200 mg tablets) administered orally in a divided daily dose based on weight (1000 mg per day for participants weighing \< 75 kg; 1200 mg per day for participants weighing ≥ 75 kg) for 12 weeks | 77 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 2 | 1 |
Baseline characteristics
| Characteristic | LDV/SOF | Total | LDV/SOF + RBV |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 10.7 | 56 years STANDARD_DEVIATION 9.2 | 56 years STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants | 151 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HCV Genotype Genotype 1a | 50 participants | 98 participants | 48 participants |
| HCV Genotype Genotype 1b | 27 participants | 55 participants | 28 participants |
| HCV Genotype Genotype 1 (no confirmed subtype) | 1 participants | 2 participants | 1 participants |
| Hepatitic C Virus (HCV) RNA | 6.5 log10 IU/mL STANDARD_DEVIATION 0.59 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.54 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.47 |
| Race/Ethnicity, Customized Black or African American | 3 participants | 4 participants | 1 participants |
| Race/Ethnicity, Customized White | 75 participants | 151 participants | 76 participants |
| Sex: Female, Male Female | 22 Participants | 41 Participants | 19 Participants |
| Sex: Female, Male Male | 56 Participants | 114 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 78 | 72 / 77 |
| serious Total, serious adverse events | 8 / 78 | 4 / 77 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, \< 25 IU/mL) 12 weeks following the last dose of study drug. * 1 participant who was randomized to the LDV/SOF + RBV group who received placebo discontinued prior to receiving LDV/SOF + RBV and is excluded from the Full Analysis Set. * 1 participant who was randomized to the LDV/SOF + RBV group received LDV/SOF + placebo, and is counted in the LDV/SOF group for the safety analysis, and in the LDV/SOF+RBV group for the efficacy analysis (ie, in the Full Analysis Set).
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participant with genotype 1 HCV infection who were randomized and received at least 1 dose of active study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 97.4 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 96.1 percentage of participants |
Comparison: A sample size of 75 subjects in each treatment group would provide 80% power to detect a difference of 15% in SVR12 rates (80% vs 95%) between the 2 treatment groups.95% CI: [-5.9, 8.6]
Secondary
Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12
Time frame: Baseline; Weeks 1, 2, 4, 8, and 12
Population: Participants in Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDV/SOF | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 8 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.11 log10 IU/mL | Standard Deviation 0.597 |
| LDV/SOF | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 1 (LDV/SOF: n = 75; LDV/SOF + RBV: n = 75) | -4.10 log10 IU/mL | Standard Deviation 0.558 |
| LDV/SOF | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 12 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.11 log10 IU/mL | Standard Deviation 0.595 |
| LDV/SOF | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 2 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -4.74 log10 IU/mL | Standard Deviation 0.926 |
| LDV/SOF | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 4 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.10 log10 IU/mL | Standard Deviation 0.582 |
| LDV/SOF + RBV | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 2 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -4.94 log10 IU/mL | Standard Deviation 0.452 |
| LDV/SOF + RBV | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 4 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.19 log10 IU/mL | Standard Deviation 0.433 |
| LDV/SOF + RBV | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 8 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.20 log10 IU/mL | Standard Deviation 0.448 |
| LDV/SOF + RBV | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 12 (LDV/SOF: n = 77; LDV/SOF + RBV: n = 77) | -5.20 log10 IU/mL | Standard Deviation 0.448 |
| LDV/SOF + RBV | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 8, and 12 | Week 1 (LDV/SOF: n = 75; LDV/SOF + RBV: n = 75) | -4.27 log10 IU/mL | Standard Deviation 0.547 |
Secondary
Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24
Time frame: Weeks 1, 2, 4, 8, 12, and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 4 | 97.4 percentage of participants |
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 8 | 98.7 percentage of participants |
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 12 | 100.0 percentage of participants |
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 1 | 7.8 percentage of participants |
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 24 | 100.0 percentage of participants |
| LDV/SOF | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 2 | 50.6 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 24 | 100.0 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 2 | 59.7 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 4 | 97.4 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 1 | 9.1 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 8 | 100.0 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With HCV RNA < LLOQ (ie, < 25 IU/mL) at Weeks 1, 2, 4, 8, 12, and 24 | Week 12 | 100.0 percentage of participants |
Secondary
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively.
Time frame: Posttreatment Weeks 4 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 97.4 percentage of participants |
| LDV/SOF | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 97.4 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 97.4 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 96.1 percentage of participants |
Secondary
Percentage of Participants With Virologic Failure
Virologic failure is defined as * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit.
Time frame: Baseline to Posttreatment Week 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF | Percentage of Participants With Virologic Failure | Virologic Relapse | 2.6 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF + RBV | Percentage of Participants With Virologic Failure | Virologic Relapse | 3.9 percentage of participants |