Chronic Hepatitis C Virus
Conditions
Keywords
HCV genotype 1 (GT-1), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, GS-7977, GS-5885, Ribavirin, Open Label, Sofosbuvir, Additional relevant MeSH terms:, Hepatitis, Hepatitis, Chronic, Hepatitis C, Hepatitis C, Chronic, Liver Diseases, Digestive System Diseases, Hepatitis, Viral, Human, Virus Diseases, Enterovirus Infections, Picornaviridae Infections, RNA Virus Infections, Flaviviridae Infections, Antiviral Agents, Anti-Infective Agents, Therapeutic Uses, Pharmacologic Actions, Antimetabolites, Molecular Mechanisms of Pharmacological Action
Brief summary
This study is to evaluate the safety, tolerability, and antiviral efficacy of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) with or without ribavirin (RBV) administered for 8 or 12 weeks in treatment-naive participants with chronic genotype 1 HCV infection.
Interventions
DRUGLDV/SOF
LDV 90 mg/SOF 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)
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 * HCV treatment-naive * HCV RNA \> 10,000 IU/mL at screening * 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 * Presence of cirrhosis * Coinfection 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 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. |
| Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | Up to 12 weeks | The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HCV RNA < LLOQ at Week 4 | Week 4 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 8 | Week 8 | — |
| Change From Baseline in HCV RNA at Week 2 | Baseline; Week 2 | — |
| Percentage of Participants With Sustained Virologic Response 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. |
| Change From Baseline in HCV RNA at Week 8 | Baseline; Week 8 | — |
| Percentage of Participants Experiencing Virologic Failure | Baseline to posttreatment Week 24 | Virologic failure was defined as on-treatment virologic failure or virologic relapse. * 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) Virologic relapse was defined as confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit. |
| Change From Baseline in HCV RNA at Week 4 | Baseline; Week 4 | — |
| Percentage of Participants With HCV RNA < LLOQ at Week 2 | Week 2 | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at a total of 59 study sites in the United States. The first participant was screened on 06 May 2013. The last participant observation occurred on 07 March 2014.
Pre-assignment details
831 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF 8 Week LDV 90 mg/SOF 400 mg FDC tablet once daily for 8 weeks | 215 |
| LDV/SOF+RBV 8 Week LDV 90 mg/SOF 400 mg FDC tablet once daily plus RBV tablets (1000 or 1200 mg daily based on weight) for 8 weeks | 216 |
| LDV/SOF 12 Week LDV 90 mg/SOF 400 mg FDC tablet once daily for 12 weeks | 216 |
| Total | 647 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Investigator's Discretion | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 10 | 9 | 2 |
| Overall Study | Lost to Follow-up | 1 | 6 | 9 |
| Overall Study | Withdrew Consent | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | LDV/SOF+RBV 8 Week | LDV/SOF 12 Week | LDV/SOF 8 Week | Total |
|---|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 11.7 | 53 years STANDARD_DEVIATION 10.6 | 53 years STANDARD_DEVIATION 10.2 | 52 years STANDARD_DEVIATION 10.9 |
| HCV Genotype Genotype 1a | 172 participants | 172 participants | 171 participants | 515 participants |
| HCV Genotype Genotype 1b | 44 participants | 44 participants | 43 participants | 131 participants |
| HCV Genotype Genotype 1 (no confirmed subtype) | 0 participants | 0 participants | 1 participants | 1 participants |
| HCV RNA | 6.4 log10 IU/mL STANDARD_DEVIATION 0.69 | 6.4 log10 IU/mL STANDARD_DEVIATION 0.76 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.76 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.74 |
| HCV RNA Category < 800,000 IU/mL | 45 participants | 44 participants | 34 participants | 123 participants |
| HCV RNA Category ≥ 800,000 IU/mL | 171 participants | 172 participants | 181 participants | 524 participants |
| IL28b Status CC | 60 participants | 56 participants | 56 participants | 172 participants |
| IL28b Status CT | 128 participants | 124 participants | 120 participants | 372 participants |
| IL28b Status TT | 28 participants | 36 participants | 39 participants | 103 participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 3 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized Black or African American | 36 participants | 42 participants | 45 participants | 123 participants |
| Race/Ethnicity, Customized Hawaiian or Pacific Islander | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 12 participants | 14 participants | 13 participants | 39 participants |
| Race/Ethnicity, Customized Not Disclosed | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 204 participants | 202 participants | 200 participants | 606 participants |
| Race/Ethnicity, Customized Other | 0 participants | 3 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized White | 176 participants | 167 participants | 164 participants | 507 participants |
| Sex: Female, Male Female | 99 Participants | 88 Participants | 85 Participants | 272 Participants |
| Sex: Female, Male Male | 117 Participants | 128 Participants | 130 Participants | 375 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 | 146 / 215 | 166 / 216 | 150 / 216 |
| serious Total, serious adverse events | 4 / 215 | 1 / 216 | 5 / 216 |
Outcome results
Primary
Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug
The percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug was summarized.
Time frame: Up to 12 weeks
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 Week | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0 percentage of participants |
| LDV/SOF+RBV 8 Week | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0.9 percentage of participants |
| LDV/SOF 12 Week | Incidence of Adverse Events Leading to Permanent Discontinuation From Any Study Drug | 0.9 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response 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.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants were randomized and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 Week | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 94.0 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 93.1 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 96.3 percentage of participants |
p-value: <0.001Binomial test
p-value: <0.001Binomial test
p-value: <0.001Binomial test
97.5% CI: [-8.3, 1.8]
97.5% CI: [-7.2, 2.5]
95% CI: [-3.9, 5.7]
Secondary
Change From Baseline in HCV RNA at Week 2
Time frame: Baseline; Week 2
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 8 Week | Change From Baseline in HCV RNA at Week 2 | -5.06 log10 IU/mL | Standard Deviation 0.752 |
| LDV/SOF+RBV 8 Week | Change From Baseline in HCV RNA at Week 2 | -5.01 log10 IU/mL | Standard Deviation 0.675 |
| LDV/SOF 12 Week | Change From Baseline in HCV RNA at Week 2 | -4.99 log10 IU/mL | Standard Deviation 0.75 |
Secondary
Change From Baseline in HCV RNA at Week 4
Time frame: Baseline; Week 4
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 8 Week | Change From Baseline in HCV RNA at Week 4 | -5.12 log10 IU/mL | Standard Deviation 0.76 |
| LDV/SOF+RBV 8 Week | Change From Baseline in HCV RNA at Week 4 | -5.05 log10 IU/mL | Standard Deviation 0.682 |
| LDV/SOF 12 Week | Change From Baseline in HCV RNA at Week 4 | -5.05 log10 IU/mL | Standard Deviation 0.758 |
Secondary
Change From Baseline in HCV RNA at Week 8
Time frame: Baseline; Week 8
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LDV/SOF 8 Week | Change From Baseline in HCV RNA at Week 8 | -5.12 log10 IU/mL | Standard Deviation 0.76 |
| LDV/SOF+RBV 8 Week | Change From Baseline in HCV RNA at Week 8 | -5.05 log10 IU/mL | Standard Deviation 0.683 |
| LDV/SOF 12 Week | Change From Baseline in HCV RNA at Week 8 | -5.04 log10 IU/mL | Standard Deviation 0.761 |
Secondary
Percentage of Participants Experiencing Virologic Failure
Virologic failure was defined as on-treatment virologic failure or virologic relapse. * 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) Virologic relapse was defined as 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 8 Week | Percentage of Participants Experiencing Virologic Failure | On-treatment virologic failure | 0 percentage of participants |
| LDV/SOF 8 Week | Percentage of Participants Experiencing Virologic Failure | Virologic relapse | 5.1 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants Experiencing Virologic Failure | On-treatment virologic failure | 0 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants Experiencing Virologic Failure | Virologic relapse | 4.2 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants Experiencing Virologic Failure | On-treatment virologic failure | 0 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants Experiencing Virologic Failure | Virologic relapse | 1.4 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 2
Time frame: Week 2
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 88.4 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 91.1 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With HCV RNA < LLOQ at Week 2 | 91.2 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 4
Time frame: Week 4
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 100.0 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 99.1 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With HCV RNA < LLOQ at Week 4 | 100.0 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Week 8
Time frame: Week 8
Population: Participants in the Full Analysis Set with Available Data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 100.0 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With HCV RNA < LLOQ at Week 8 | 99.5 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 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 8 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 96.3 percentage of participants |
| LDV/SOF 8 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 94.0 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 94.9 percentage of participants |
| LDV/SOF+RBV 8 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 93.1 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 96.3 percentage of participants |
| LDV/SOF 12 Week | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 96.3 percentage of participants |