Hepatitis C Virus Infection
Conditions
Keywords
HCV genotype 4 (GT-4), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, GS-7977, GS-5885, Ribavirin, Sofosbuvir, ledipasvir, Hepatitis C, Hepatitis C, Chronic, Liver Diseases, Virus Diseases, Antiviral Agents
Brief summary
The primary objective of this study was to evaluate the efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) with or without ribavirin (RBV) in Egyptian adults with chronic genotype 4 hepatitis C virus (HCV) infection.
Interventions
DRUGLDV/SOF
90/400 mg FDC tablet administered orally once daily
DRUGRBV
Tablets administered orally in a divided daily dose based on weight (\< 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
Key Inclusion Criteria: * Willing and able to provide written informed consent * Chronic HCV infection (≥ 6 months) documented by medical history or liver biopsy * HCV genotype 4 at screening * HCV treatment naive or prior participation in this study or study GS-US-334-0138 (Cohorts 1 and 2 only) * Cohort 3 only: HCV treatment-experienced (previously received therapy for HCV infection with an interferon (IFN)-containing regimen, with or without RBV and/or an HCV NS3/NS4A protease inhibitor (PI) * Body mass index (BMI) ≥ 18 kg/m\^2 * Screening laboratory values within defined thresholds * Use of effective protocol-approved contraception methods Key
Exclusion criteria
* History of clinically-significant illness or any other major medical disorder that may interfere with treatment, assessment or compliance with the protocol * Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) * Pregnant or nursing females or male with pregnant female partner * Clinically-relevant drug or alcohol abuse within 12 months of screening Note: Other protocol defined Inclusion/
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) 12 weeks following the last dose of study drug. |
| Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE) | 12 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 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 4 and 24 weeks after the last dose of study drug, respectively. |
| Percentage of Participants With Overall Virologic Failure | Up to Posttreatment Week 24 | Virologic failure was defined as * On-treatment virologic failure * confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ, while on treatment (ie, breakthrough), * confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment (ie, rebound), * HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse) * Relapse * HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement |
Countries
Egypt
Participant flow
Recruitment details
Participants were enrolled in 4 sites in Egypt. The first participant was screened on 07 September 2015 and the last study visit was on 04 February 2017.
Pre-assignment details
289 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF 8 wk TN (Cohort 1, Group 1) LDV/SOF (90/400 mg) FDC tablet administered orally once daily for 8 weeks in TN participants | 43 |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) LDV/SOF (90/400 mg) FDC tablet administered orally once daily + RBV tablets administered orally in a divided daily dose based on weight (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg) for 8 weeks in TN participants | 42 |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) LDV/SOF (90/400 mg) FDC tablet administered orally once daily for 12 weeks in TN participants | 43 |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) LDV/SOF (90/400 mg) FDC tablet administered orally once daily + RBV tablets administered orally in a divided daily dose based on weight (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg) for 12 weeks in TN participants | 42 |
| LDV/SOF 12 wk TE (Cohort 3, Group 1) LDV/SOF (90/400 mg) FDC tablet administered orally once daily in TE participants | 36 |
| LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) LDV/SOF (90/400 mg) FDC tablet administered orally once daily + RBV tablets administered orally in a divided daily dose based on weight (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg) for 12 weeks in TE participants | 38 |
| LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) LDV/SOF (90/400 mg) FDC tablet administered orally once daily + RBV tablets administered orally in a divided daily dose based on weight (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg) for 12 weeks in SOF or LDV/SOF experienced participants. Participants who completed treatment in Study GS-US-334-0138 with SOF+RBV for 12 or 24 weeks or those who participated in Cohort 1 of this study with LDV/SOF ± RBV for 8 weeks and did not achieve SVR12 were enrolled into Cohort 2. | 11 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 4 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | LDV/SOF 8 wk TN (Cohort 1, Group 1) | LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | LDV/SOF 12 wk TN (Cohort 1, Group 3) | LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | LDV/SOF 12 wk TE (Cohort 3, Group 1) | LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) | LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 13.9 | 49 years STANDARD_DEVIATION 12.2 | 49 years STANDARD_DEVIATION 13 | 46 years STANDARD_DEVIATION 12.1 | 49 years STANDARD_DEVIATION 11.8 | 51 years STANDARD_DEVIATION 10.1 | 48 years STANDARD_DEVIATION 16.3 | 50.0 years STANDARD_DEVIATION 12.5 |
| HCV RNA | 6.0 log10 IU/mL) STANDARD_DEVIATION 0.64 | 5.6 log10 IU/mL) STANDARD_DEVIATION 0.63 | 5.7 log10 IU/mL) STANDARD_DEVIATION 0.69 | 5.8 log10 IU/mL) STANDARD_DEVIATION 0.66 | 5.8 log10 IU/mL) STANDARD_DEVIATION 1.1 | 5.8 log10 IU/mL) STANDARD_DEVIATION 1.04 | 6.2 log10 IU/mL) STANDARD_DEVIATION 0.59 | 5.8 log10 IU/mL) STANDARD_DEVIATION 0.79 |
| HCV RNA Category < 800,000 IU/mL | 17 Participants | 26 Participants | 25 Participants | 28 Participants | 16 Participants | 17 Participants | 5 Participants | 134 Participants |
| HCV RNA Category ≥ 800,000 IU/mL | 26 Participants | 16 Participants | 18 Participants | 14 Participants | 20 Participants | 21 Participants | 6 Participants | 121 Participants |
| IL28b Status CC | 12 Participants | 5 Participants | 11 Participants | 9 Participants | 8 Participants | 8 Participants | 0 Participants | 53 Participants |
| IL28b Status CT | 28 Participants | 26 Participants | 26 Participants | 25 Participants | 24 Participants | 21 Participants | 8 Participants | 158 Participants |
| IL28b Status TT | 3 Participants | 11 Participants | 6 Participants | 8 Participants | 7 Participants | 9 Participants | 3 Participants | 47 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 43 Participants | 42 Participants | 43 Participants | 42 Participants | 36 Participants | 38 Participants | 11 Participants | 255 Participants |
| Race/Ethnicity, Customized White | 43 Participants | 42 Participants | 43 Participants | 42 Participants | 36 Participants | 38 Participants | 11 Participants | 255 Participants |
| Sex: Female, Male Female | 18 Participants | 20 Participants | 21 Participants | 20 Participants | 4 Participants | 13 Participants | 3 Participants | 99 Participants |
| Sex: Female, Male Male | 25 Participants | 22 Participants | 22 Participants | 22 Participants | 32 Participants | 25 Participants | 8 Participants | 156 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 43 | 15 / 42 | 23 / 79 | 41 / 91 |
| serious Total, serious adverse events | 0 / 43 | 0 / 42 | 0 / 79 | 3 / 91 |
Outcome results
Primary
Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE)
Time frame: 12 weeks
Population: Safety analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 wk TN (Cohort 1, Group 1) | Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE) | 0 percentage of participants |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE) | 0 percentage of participants |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) | Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE) | 0 percentage of participants |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | Percentage of Participants Who Discontinued LDV/SOF Drug Due to an Adverse Event (AE) | 1.1 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) 12 weeks following the last dose of study drug.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: all randomized or enrolled participants who had genotype 4 HCV infection and who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 wk TN (Cohort 1, Group 1) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 95.3 percentage of participants |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 90.5 percentage of participants |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 97.7 percentage of participants |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 97.6 percentage of participants |
| LDV/SOF 12 wk TE (Cohort 3, Group 1) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 94.4 percentage of participants |
| LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 100.0 percentage of participants |
| LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 100.0 percentage of participants |
Secondary
Percentage of Participants With Overall Virologic Failure
Virologic failure was defined as * On-treatment virologic failure * confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ, while on treatment (ie, breakthrough), * confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment (ie, rebound), * HCV RNA persistently ≥ LLOQ through 8 weeks of treatment (ie, nonresponse) * Relapse * HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement
Time frame: Up to Posttreatment Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 8 wk TN (Cohort 1, Group 1) | Percentage of Participants With Overall Virologic Failure | 4.7 percentage of participants |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | Percentage of Participants With Overall Virologic Failure | 9.5 percentage of participants |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) | Percentage of Participants With Overall Virologic Failure | 2.3 percentage of participants |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | Percentage of Participants With Overall Virologic Failure | 0.0 percentage of participants |
| LDV/SOF 12 wk TE (Cohort 3, Group 1) | Percentage of Participants With Overall Virologic Failure | 2.8 percentage of participants |
| LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) | Percentage of Participants With Overall Virologic Failure | 0.0 percentage of participants |
| LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) | Percentage of Participants With Overall Virologic Failure | 0.0 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR24 were defined as HCV RNA \< LLOQ 4 and 24 weeks after 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 wk TN (Cohort 1, Group 1) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 95.3 percentage of participants |
| LDV/SOF 8 wk TN (Cohort 1, Group 1) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 95.3 percentage of participants |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 95.2 percentage of participants |
| LDV/SOF + RBV 8 wk TN (Cohort 1, Group 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 90.5 percentage of participants |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 97.7 percentage of participants |
| LDV/SOF 12 wk TN (Cohort 1, Group 3) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 97.7 percentage of participants |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 97.6 percentage of participants |
| LDV/SOF + RBV 12 wk TN (Cohort 1, Group 4) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 97.6 percentage of participants |
| LDV/SOF 12 wk TE (Cohort 3, Group 1) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 100.0 percentage of participants |
| LDV/SOF 12 wk TE (Cohort 3, Group 1) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 94.4 percentage of participants |
| LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 100.0 percentage of participants |
| LDV/SOF + RBV 12 wk TE (Cohort 3, Group 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 100.0 percentage of participants |
| LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 100.0 percentage of participants |
| LDV/SOF + RBV 12 wk SOF or LDV/SOF Experienced (Cohort 2) | Percentage of Participants With Sustained Virologic Response 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 100.0 percentage of participants |