Hepatitis C Virus Infection
Conditions
Keywords
Sofosbuvir, SOF/VEL, Velpatasvir, Hepatitis C, HCV, cirrhosis
Brief summary
The primary objectives of this study are to evaluate the efficacy, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) fixed dose combination (FDC) for 12 weeks in adults with chronic genotype 1, 2, 4, 5, or 6 hepatitis C virus (HCV) infection.
Interventions
DRUGSOF/VEL
400/100 mg FDC tablet administered orally once daily
DRUGPlacebo
Tablet administered orally once daily
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
* Willing and able to provide written informed consent * HCV RNA ≥ 10\^4 IU/mL at screening * HCV genotype 1, 2, 4, 5, 6, or indeterminate assessed at screening by the central laboratory * Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy * Classification as treatment naive or treatment experienced * Males and females of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
Exclusion criteria
* Current or prior history of clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with treatment, assessment, or compliance with the protocol; individuals currently under evaluation for a potentially clinically-significant illness (other than HCV) are also excluded. * Screening ECG with clinically significant abnormalities * Laboratory results outside of acceptable ranges at Screening * Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A inhibitor * Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
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) at 12 weeks after stopping study treatment. |
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | Up to 12 weeks | — |
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 SVR 24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks after stopping study treatment, respectively. |
| Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Weeks 1, 2, 4, 6, 8, 10, and 12 | — |
| Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Baseline; Weeks 1, 2, 4, 6, 8, 10, and 12 | — |
| 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 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
Belgium, Canada, China, France, Germany, Italy, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Canada, Europe, and Asia. The first participant was screened on 18 July 2014. The last study visit occurred on 23 September 2015.
Pre-assignment details
847 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SOF/VEL SOF/VEL (400/100 mg) FDC tablet administered orally once daily for 12 weeks | 624 |
| Placebo SOF/VEL placebo tablet administered orally once daily for 12 weeks | 116 |
| Total | 740 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Investigator's Discretion | 1 | 1 |
| Overall Study | Lack of Efficacy | 2 | 113 |
| Overall Study | Lost to Follow-up | 5 | 0 |
| Overall Study | Randomized/Enrolled but Never Treated | 1 | 0 |
| Overall Study | Withdrew Consent | 2 | 1 |
Baseline characteristics
| Characteristic | SOF/VEL | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 10.9 | 54 years STANDARD_DEVIATION 10.8 | 53 years STANDARD_DEVIATION 10.4 |
| Cirrhosis Status Absent | 501 participants | 596 participants | 95 participants |
| Cirrhosis Status Missing | 2 participants | 2 participants | 0 participants |
| Cirrhosis Status Present | 121 participants | 142 participants | 21 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 31 Participants | 36 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 589 Participants | 700 Participants | 111 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 0 Participants |
| HCV Genotype Genotype 1 | 328 participants | 393 participants | 65 participants |
| HCV Genotype Genotype 2 | 104 participants | 125 participants | 21 participants |
| HCV Genotype Genotype 4 | 116 participants | 138 participants | 22 participants |
| HCV Genotype Genotype 5 | 35 participants | 35 participants | 0 participants |
| HCV Genotype Genotype 6 | 41 participants | 49 participants | 8 participants |
| HCV RNA | 6.3 log10 IU/mL STANDARD_DEVIATION 0.66 | 6.3 log10 IU/mL STANDARD_DEVIATION 0.65 | 6.3 log10 IU/mL STANDARD_DEVIATION 0.58 |
| HCV RNA Category < 800,000 IU/mL | 163 participants | 192 participants | 29 participants |
| HCV RNA Category ≥ 800,000 IU/mL | 461 participants | 548 participants | 87 participants |
| IL28b Status CC | 186 participants | 222 participants | 36 participants |
| IL28b Status CT | 339 participants | 392 participants | 53 participants |
| IL28b Status Missing | 5 participants | 6 participants | 1 participants |
| IL28b Status TT | 94 participants | 120 participants | 26 participants |
| Race/Ethnicity, Customized American Indian/ Alaska Native | 7 participants | 7 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 62 participants | 73 participants | 11 participants |
| Race/Ethnicity, Customized Black or African American | 52 participants | 64 participants | 12 participants |
| Race/Ethnicity, Customized Hawaiian or Pacific Islander | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Not Disclosed | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Other | 6 participants | 9 participants | 3 participants |
| Race/Ethnicity, Customized White | 493 participants | 582 participants | 89 participants |
| Region of Enrollment Belgium | 40 participants | 45 participants | 5 participants |
| Region of Enrollment Canada | 55 participants | 62 participants | 7 participants |
| Region of Enrollment China | 19 participants | 23 participants | 4 participants |
| Region of Enrollment France | 126 participants | 158 participants | 32 participants |
| Region of Enrollment Germany | 44 participants | 52 participants | 8 participants |
| Region of Enrollment Italy | 16 participants | 18 participants | 2 participants |
| Region of Enrollment United Kingdom | 91 participants | 104 participants | 13 participants |
| Region of Enrollment United States | 234 participants | 279 participants | 45 participants |
| Sex: Female, Male Female | 250 Participants | 298 Participants | 48 Participants |
| Sex: Female, Male Male | 374 Participants | 442 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 393 / 624 | 77 / 116 |
| serious Total, serious adverse events | 15 / 624 | 0 / 116 |
Outcome results
Primary
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Time frame: Up to 12 weeks
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF/VEL | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 0.2 percentage of participants |
| Placebo | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 1.7 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) at 12 weeks after stopping study treatment.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants randomized or enrolled into the study and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF/VEL | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 99.0 percentage of participants |
| Placebo | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 0 percentage of participants |
p-value: <0.001Binomial test
Secondary
Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12
Time frame: Baseline; Weeks 1, 2, 4, 6, 8, 10, and 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 1 (SOF/VEL: N= 617; Placebo: N= 114) | -4.29 log10 IU/mL | Standard Deviation 0.647 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 8 (SOF/VEL: N= 622; Placebo: N= 113) | -5.11 log10 IU/mL | Standard Deviation 0.664 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 2 (SOF/VEL: N= 622; Placebo: N= 116) | -4.82 log10 IU/mL | Standard Deviation 0.685 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 10 (SOF/VEL: N= 622; Placebo: N= 112) | -5.12 log10 IU/mL | Standard Deviation 0.662 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 6 (SOF/VEL: N= 623; Placebo: N= 115) | -5.11 log10 IU/mL | Standard Deviation 0.664 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 12 (SOF/VEL: N= 622; Placebo: N= 111) | -5.12 log10 IU/mL | Standard Deviation 0.662 |
| SOF/VEL | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 4 (SOF/VEL: N= 617; Placebo: N= 114) | -5.08 log10 IU/mL | Standard Deviation 0.656 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 12 (SOF/VEL: N= 622; Placebo: N= 111) | -0.06 log10 IU/mL | Standard Deviation 0.58 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 1 (SOF/VEL: N= 617; Placebo: N= 114) | -0.05 log10 IU/mL | Standard Deviation 0.561 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 2 (SOF/VEL: N= 622; Placebo: N= 116) | 0.01 log10 IU/mL | Standard Deviation 0.28 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 4 (SOF/VEL: N= 617; Placebo: N= 114) | -0.01 log10 IU/mL | Standard Deviation 0.297 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 6 (SOF/VEL: N= 623; Placebo: N= 115) | 0.07 log10 IU/mL | Standard Deviation 0.298 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 8 (SOF/VEL: N= 622; Placebo: N= 113) | 0.05 log10 IU/mL | Standard Deviation 0.281 |
| Placebo | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, 8, 10, and 12 | Change at Wk 10 (SOF/VEL: N= 622; Placebo: N= 112) | 0.05 log10 IU/mL | Standard Deviation 0.337 |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12
Time frame: Weeks 1, 2, 4, 6, 8, 10, and 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 4 (SOF/VEL: N = 623; Placebo: N = 116) | 90.5 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 8 (SOF/VEL: N = 622; Placebo: N = 114) | 99.7 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 2 (SOF/VEL: N = 624; Placebo: N = 116) | 56.9 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 10 (SOF/VEL: N = 622; Placebo: N = 114) | 100.0 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 6 (SOF/VEL: N = 623; Placebo: N = 115) | 98.9 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 12 (SOF/VEL: N = 622; Placebo: N = 113) | 100.0 percentage of participants |
| SOF/VEL | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 1 (SOF/VEL: N = 624; Placebo: N = 116) | 18.8 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 12 (SOF/VEL: N = 622; Placebo: N = 113) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 1 (SOF/VEL: N = 624; Placebo: N = 116) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 2 (SOF/VEL: N = 624; Placebo: N = 116) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 4 (SOF/VEL: N = 623; Placebo: N = 116) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 6 (SOF/VEL: N = 623; Placebo: N = 115) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 8 (SOF/VEL: N = 622; Placebo: N = 114) | 0 percentage of participants |
| Placebo | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 10 (SOF/VEL: N = 622; Placebo: N = 114) | 0 percentage of participants |
Secondary
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR 24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks after stopping study treatment, respectively.
Time frame: Posttreatment Weeks 4 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF/VEL | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 99.2 percentage of participants |
| SOF/VEL | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 99.0 percentage of participants |
| Placebo | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 0 percentage of participants |
| Placebo | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 0 percentage of participants |
Secondary
Percentage of Participants With Virologic Failure
Virologic failure was 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: Up to Posttreatment Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF/VEL | Percentage of Participants With Virologic Failure | 0.3 percentage of participants |
| Placebo | Percentage of Participants With Virologic Failure | 100 percentage of participants |