Hepatitis C Virus Infection
Conditions
Keywords
Hepatitis C Virus (HCV), Ledipasvir/Sofosbuvir, Ribavirin
Brief summary
The primary objective of this study is to evaluate the efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination (FDC) for 12 weeks with or without ribavirin (RBV) in participants without cirrhosis, and LDV/SOF FDC for 12 weeks with RBV or LDV/SOF FDC for 24 weeks without RBV in participants with cirrhosis.
Interventions
DRUGLDV/SOF
90/400 mg FDC tablet administered orally once daily
DRUGRBV
Tablets administered orally in a divided daily dose according to 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
Key Inclusion Criteria: * HCV RNA \> 15 IU/mL at screening * HCV genotype 1 or 4 * Chronic HCV infection (≥ 6 months) * Prior virologic failure after treatment with SOF in combination with simeprevir (SMV) ± RBV or with RBV ± pegylated interferon (PEG) * Cirrhotic and non-cirrhotic as determined by standard methods * Male and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception Key
Exclusion criteria
* Prior exposure to approved or experimental non-structural protein (NS5A) inhibitors * Prior exposure to nucleos(t)ide polymerase inhibitors, other than SOF * Pregnant or nursing female or male with pregnant female partner * Coinfection with HIV or hepatitis B virus * Current or prior history of clinical hepatic decompensation * 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 individual's treatment, assessment or compliance with the protocol Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation 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 Discontinued From Study Treatment for an Adverse Event | Up to 24 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | 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 Viral Breakthrough | Up to 24 weeks | Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while receiving treatment. |
| Percentage of Participants With Viral Relapse | Up to Posttreatment Week 24 | Viral relapse was defined as confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \<LLOQ at last on-treatment visit. |
| Number of Participants With Emerging Resistance | Up to Posttreatment Week 24 | The full-length NS3, NS5A, and NS5B coding regions were deep sequenced at pretreatment (baseline) for all participants included in the Full Analysis Set, and at posttreatment for all participants who relapsed. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States (including a site in Puerto Rico), and Canada. The first participant was screened on 11 November 2015. The last study visit occurred on 29 May 2017.
Pre-assignment details
120 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis LDV/SOF (90/400 mg) fixed-dose combination (FDC) tablet orally once daily for 12 weeks in participants without cirrhosis | 16 |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis LDV/SOF (90/400 mg) FDC tablet orally once daily + RBV tablets (1000 or 1200 mg daily based on weight) for 12 weeks in participants without cirrhosis | 17 |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis LDV/SOF FDC (90 mg/400 mg) tablet orally once daily + RBV (1000 or 1200 mg/day divided twice daily) for 12 weeks in participants with compensated cirrhosis | 25 |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis LDV/SOF (90/400 mg) FDC tablet orally once daily for 24 weeks in participants with compensated cirrhosis | 24 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 3 | 0 | 5 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Overall Study | Randomized but Not Treated | 1 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | LDV/SOF + RBV 12 Weeks, Without Cirrhosis | LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | LDV/SOF 12 Weeks, Without Cirrhosis | LDV/SOF 24 Weeks, With Compensated Cirrhosis | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 5.5 | 58 years STANDARD_DEVIATION 7.8 | 58 years STANDARD_DEVIATION 5.7 | 60 years STANDARD_DEVIATION 4.5 | 59 years STANDARD_DEVIATION 6.1 |
| HCV RNA | 6.4 log10 IU/mL STANDARD_DEVIATION 0.48 | 6.1 log10 IU/mL STANDARD_DEVIATION 0.59 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.45 | 6.0 log10 IU/mL STANDARD_DEVIATION 0.89 | 6.2 log10 IU/mL STANDARD_DEVIATION 0.67 |
| HCV RNA Category < 800,000 IU/mL | 4 Participants | 7 Participants | 1 Participants | 8 Participants | 20 Participants |
| HCV RNA Category ≥ 800,000 IU/mL | 13 Participants | 18 Participants | 15 Participants | 16 Participants | 62 Participants |
| IL28b Status CC | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants |
| IL28b Status CT | 11 Participants | 16 Participants | 12 Participants | 17 Participants | 56 Participants |
| IL28b Status TT | 4 Participants | 9 Participants | 3 Participants | 6 Participants | 22 Participants |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 6 Participants | 6 Participants | 3 Participants | 20 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 4 Participants | 2 Participants | 7 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 14 Participants | 21 Participants | 14 Participants | 17 Participants | 66 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 18 Participants | 10 Participants | 19 Participants | 58 Participants |
| Region of Enrollment Canada | 2 participants | 2 participants | 1 participants | 7 participants | 12 participants |
| Region of Enrollment Puerto Rico | 1 participants | 0 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 14 participants | 23 participants | 14 participants | 16 participants | 67 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 6 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Male | 13 Participants | 19 Participants | 10 Participants | 19 Participants | 61 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 | 0 / 16 | 0 / 17 | 0 / 25 | 0 / 24 |
| other Total, other adverse events | 11 / 16 | 14 / 17 | 19 / 25 | 15 / 24 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 | 0 / 25 | 1 / 24 |
Outcome results
Primary
Percentage of Participants Who Discontinued From Study Treatment for an Adverse Event
Time frame: Up to 24 weeks
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants Who Discontinued From Study Treatment for an Adverse Event | 0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants Who Discontinued From Study Treatment for an Adverse Event | 0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants Who Discontinued From Study Treatment for an Adverse Event | 0 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants Who Discontinued From Study Treatment for an Adverse Event | 0 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation 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 by Actual Treatment: participants were grouped according to their cirrhotic status and the treatment/duration they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation of Therapy (SVR12) | 81.3 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation of Therapy (SVR12) | 100.0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation of Therapy (SVR12) | 80.0 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants With Sustained Virologic Response 12 Weeks After Cessation of Therapy (SVR12) | 91.7 percentage of participants |
p-value: 0.06595% CI: [-40.7, 3.2]Cochran-Mantel-Haenszel
p-value: 0.2595% CI: [-32.1, 8.8]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Emerging Resistance
The full-length NS3, NS5A, and NS5B coding regions were deep sequenced at pretreatment (baseline) for all participants included in the Full Analysis Set, and at posttreatment for all participants who relapsed.
Time frame: Up to Posttreatment Week 24
Population: Full Analysis Set by Actual Treatment who have pre-existing NS5B, NS5A, and NS3/4A resistance-associated variants (RAVs) at baseline and who experienced virologic failure were analyzed. There were no participants with pre-existing RAVs who experienced virologic failure in the LDV/SOF+RBV 12 weeks, without cirrhosis group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Number of Participants With Emerging Resistance | 3 Participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Number of Participants With Emerging Resistance | 5 Participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Number of Participants With Emerging Resistance | 2 Participants |
Secondary
Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment
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 by Actual Treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR4 | 93.8 percentage of participants |
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR24 | 81.3 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR24 | 100.0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR4 | 100.0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR4 | 88.0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR24 | 80.0 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR4 | 95.8 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants With HCV RNA < the Lower Limit of Quantitation (LLOQ) at 4 and 24 Weeks Posttreatment | SVR24 | 91.7 percentage of participants |
Secondary
Percentage of Participants With Viral Breakthrough
Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while receiving treatment.
Time frame: Up to 24 weeks
Population: Full Analysis Set by Actual Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants With Viral Breakthrough | 0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants With Viral Breakthrough | 0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants With Viral Breakthrough | 0 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants With Viral Breakthrough | 0 percentage of participants |
Secondary
Percentage of Participants With Viral Relapse
Viral relapse was defined as 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 by Actual Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks, Without Cirrhosis | Percentage of Participants With Viral Relapse | 18.8 percentage of participants |
| LDV/SOF + RBV 12 Weeks, Without Cirrhosis | Percentage of Participants With Viral Relapse | 0 percentage of participants |
| LDV/SOF + RBV 12 Weeks, With Compensated Cirrhosis | Percentage of Participants With Viral Relapse | 20.0 percentage of participants |
| LDV/SOF 24 Weeks, With Compensated Cirrhosis | Percentage of Participants With Viral Relapse | 8.3 percentage of participants |