Chronic HCV Infection
Conditions
Keywords
HCV genotype 1, HCV, Sustained Virologic Response, Direct-Acting Antiviral, Combination Therapy, GS-7977, GS-5885, Ribavirin, Open Label, Sofosbuvir, Treatment-Naive, Protease Inhibitors, PI, Treatment experienced, Cirrhotic
Brief summary
This study will evaluate the antiviral efficacy of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) plus ribavirin (RBV) or LDV/SOF plus GS-9669 in treatment-naive or treatment-experienced participants with chronic genotype 1 hepatitis C virus (HCV) infection. A total of 90 participants are planned to be enrolled in the study for 8 weeks of treatment, approximately 60 having had prior treatment with a regimen containing pegylated interferon (PEG) and RBV for ≥ 12 weeks. Randomization will be stratified by treatment-naive versus treatment-experienced and by HCV genotype (1a versus 1b).
Interventions
DRUGLDV/SOF
Ledipasvir/sofosbuvir (LDV/SOF) 90/400 mg FDC tablet administered orally once daily
DRUGRBV
Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)
DRUGGS-9669
GS-9669 tablet(s) administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18, with chronic genotype 1 HCV infection * Documented HCV treatment-naïve or treatment-experienced subjects who failed previous PEG+RBV regimen * HCV RNA \> 10,000 IU/mL at Screening * Presence of compensated 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 * Co-infection with HIV or hepatitis B virus (HBV) * Current or prior history of clinical hepatic decompensation * 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, 15 IU/mL) 12 weeks following the last dose of study drug. |
| Percentage of Participants Permanently Discontinuing Any Study Drug Due to an Adverse Event | Up to 8 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | Posttreatment Weeks 2, 4, 8, and 24 | SVR2, SVR4, SVR8, and SVR24 was defined as HCV RNA \< LLOQ at 2, 4, 8, and 24 weeks following the last dose of study drug, respectively. |
| Percentage of Participants Experiencing On-treatment Virologic Failure | Up to 8 weeks | On-treatment virologic failure was defined as * 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) |
| Percentage of Participants Experiencing Viral Relapse | Up to Posttreatment Week 24 | Viral relapse was defined as having achieved undetectable HCV RNA levels (HCV RNA \< LLOQ) at end of treatment, but did not achieve an SVR. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at a total of 1 study site in the United States. The first participant was screened on 29 October 2013. The last study visit occurred on 18 July 2014.
Pre-assignment details
117 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF+RBV LDV/SOF 90/400 mg FDC tablet once daily plus RBV tablets (1000 or 1200 mg daily based on weight) in a divided daily dose for 8 weeks | 35 |
| LDV/SOF+GS-9669 250 mg LDV/SOF 90/400 mg FDC tablet plus GS-9669 (1 x 250 mg) tablet once daily for 8 weeks | 32 |
| LDV/SOF+GS-9669 500 mg LDV/SOF 90/400 mg FDC tablet plus GS-9669 (2 x 250 mg) tablets once daily for 8 weeks | 33 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 4 | 2 | 6 |
| Overall Study | Randomized but Never Treated | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | LDV/SOF+RBV | LDV/SOF+GS-9669 250 mg | LDV/SOF+GS-9669 500 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 7.8 | 57 years STANDARD_DEVIATION 7.4 | 57 years STANDARD_DEVIATION 9.3 | 57 years STANDARD_DEVIATION 8.2 |
| HCV Genotype Genotype 1a | 21 participants | 20 participants | 21 participants | 62 participants |
| HCV Genotype Genotype 1b | 14 participants | 12 participants | 12 participants | 38 participants |
| HCV RNA | 6.0 log10 IU/mL STANDARD_DEVIATION 0.5 | 6.1 log10 IU/mL STANDARD_DEVIATION 0.63 | 6.0 log10 IU/mL STANDARD_DEVIATION 0.57 | 6.0 log10 IU/mL STANDARD_DEVIATION 0.56 |
| HCV RNA Category < 800,000 IU/mL | 14 participants | 9 participants | 12 participants | 35 participants |
| HCV RNA Category ≥ 800,000 IU/mL | 21 participants | 23 participants | 21 participants | 65 participants |
| IL28b Status CC | 5 participants | 6 participants | 7 participants | 18 participants |
| IL28b Status CT | 16 participants | 23 participants | 19 participants | 58 participants |
| IL28b Status TT | 14 participants | 3 participants | 7 participants | 24 participants |
| Race/Ethnicity, Customized American Indian/ Alaska Native | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 0 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 14 participants | 13 participants | 12 participants | 39 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 21 participants | 19 participants | 21 participants | 61 participants |
| Race/Ethnicity, Customized White | 32 participants | 32 participants | 28 participants | 92 participants |
| Sex: Female, Male Female | 15 Participants | 8 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Male | 20 Participants | 24 Participants | 21 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 35 | 13 / 32 | 23 / 33 |
| serious Total, serious adverse events | 0 / 35 | 2 / 32 | 0 / 33 |
Outcome results
Primary
Percentage of Participants Permanently Discontinuing Any Study Drug Due to an Adverse Event
Time frame: Up to 8 weeks
Population: Safety Analysis Set: participants were randomized and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF+RBV | Percentage of Participants Permanently Discontinuing Any Study Drug Due to an Adverse Event | 0 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants Permanently Discontinuing Any Study Drug Due to an Adverse Event | 3.1 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants Permanently Discontinuing Any Study Drug Due to an Adverse Event | 0 percentage of participants |
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, 15 IU/mL) 12 weeks following the last dose of study drug.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants were randomized and received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF+RBV | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 88.6 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 90.6 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 81.8 percentage of participants |
Secondary
Percentage of Participants Experiencing On-treatment Virologic Failure
On-treatment virologic failure was defined as * 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)
Time frame: Up to 8 weeks
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF+RBV | Percentage of Participants Experiencing On-treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants Experiencing On-treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants Experiencing On-treatment Virologic Failure | 0 percentage of participants |
Secondary
Percentage of Participants Experiencing Viral Relapse
Viral relapse was defined as having achieved undetectable HCV RNA levels (HCV RNA \< LLOQ) at end of treatment, but did not achieve an SVR.
Time frame: Up to Posttreatment Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF+RBV | Percentage of Participants Experiencing Viral Relapse | 11.4 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants Experiencing Viral Relapse | 9.4 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants Experiencing Viral Relapse | 18.2 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24)
SVR2, SVR4, SVR8, and SVR24 was defined as HCV RNA \< LLOQ at 2, 4, 8, and 24 weeks following the last dose of study drug, respectively.
Time frame: Posttreatment Weeks 2, 4, 8, and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF+RBV | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR2 | 100.0 percentage of participants |
| LDV/SOF+RBV | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR4 | 91.4 percentage of participants |
| LDV/SOF+RBV | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR8 | 88.6 percentage of participants |
| LDV/SOF+RBV | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR24 | 88.6 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR24 | 90.6 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR2 | 100.0 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR8 | 90.6 percentage of participants |
| LDV/SOF+GS-9669 250 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR4 | 90.6 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR24 | 81.8 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR4 | 84.8 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR8 | 81.8 percentage of participants |
| LDV/SOF+GS-9669 500 mg | Percentage of Participants With Sustained Virologic Response at 2, 4, 8, and 24 Weeks After Discontinuation of Therapy (SVR2, SVR4, SVR8, and SVR24) | SVR2 | 97.0 percentage of participants |