HCV, Hepatitis C
Conditions
Keywords
HCV, Previously treated
Brief summary
The study will enroll well-compensated cirrhotic as well as non-cirrhotic subjects treatment experienced with an NS5a Inhibitor + sofosbuvir and will include patients who did not complete the prescribed duration due to adverse event or any reason other than for non/poor compliance. Subjects will be randomized to 12 or 16 weeks of treatment.
Detailed description
The primary purpose of this study is to compare the efficacy and safety of glecaprevir and pibrentasvir (G/P) for 12 weeks to G/P for 16 weeks in non-cirrhotic NS5A (non-structural protein 5a)-inhibitor plus sofosbuvir ± RBV (Ribavirin) treatment-experienced adults with HCV genotype 1 (GT1) infection, and to compare the efficacy and safety of G/P with RBV for 12 weeks to G/P without RBV for 16 weeks in NS5A-inhibitor plus sofosbuvir (SOF) ± RBV treatment-experienced adults with compensated cirrhosis and GT1 infection.
Interventions
DRUGGlecaprevir/Pibrentasvir (G/P) 300mg/120mg
daily
DRUGRibavirin 200Mg Tablet
Weight-based 1000-1200 mg
Sponsors
University of North Carolina, Chapel Hill
AbbVie
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Main Study Up to 225 subjects will be enrolled into 4 study arms A, B, C and D with Glecaprevir/Pibrentasvir (G/P) with or without Ribavirin (RBV). About 75-90 non-cirrhotic subjects will be randomized in a 2:1 ratio to Arms A and B, and about 110-135 compensated cirrhotic subjects will be randomized in a 1:1 ratio to Arms C and D. Non-cirrhotic subjects will be randomized 2:1 to: 1. Arm A: G/P 300 mg/120 mg Once a day for 12 weeks 2. Arm B: G/P 300 mg/120mg Once a day for 16 weeks Subjects with compensated cirrhosis will be randomized 1:1 to: 3. Arm C: G/P 300 mg/120 mg QD + weight-based RBV (Ribavirin) Twice a day (1000 mg or 1200 mg total daily dose) for 12 weeks 4. Arm D: G/P 300 mg/120 mg QD for 16 weeks Retreatment sub-study Up to 11 subjects who still have hepatitis C virus after being treated in the Main study will have the option to enter the Retreatment sub-study and receive G/P plus Sofosbuvir and with or without RBV.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female at least 18 years of age at time of screening. 2. A history of previous treatment with an NS5A-inhibitor plus sofosbuvir therapy ± RBV for chronic HCV genotype 1 infection. 3. Treatment must have been completed at least 1 month prior to Screening Visit. 4. Screening laboratory result indicating chronic HCV GT1 infection. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements and must voluntarily sign and date an informed consent.
Exclusion criteria
1. History of severe, life-threatening or other significant sensitivity to any drug. 2. Female who is pregnant, planning to become pregnant during the study or breastfeeding; or male whose partner is pregnant or planning to become pregnant during the study. 3. Recent (within 6 months prior to study drug administration) history of drug or alcohol abuse that could preclude adherence to the protocol in the opinion of the investigator. 4. Positive test result at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody (HIV Ab) in patient without known history of HIV infection. 5. HCV genotype performed during screening indicating co-infection with more than one HCV genotype. 6. History or presence of liver decompensation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants | Up to 28 weeks | Number of non-cirrhotic treatment-experienced HCV genotype 1 with a NS5Ai inhibitor + SOF +/-RBV participants with undetectable HCV RNA (HCV RNA \<Lower Limit of Quantification -LLOQ) 12 weeks after completing G/P 300 mg/100 mg daily for 12 weeks (Arm A) vs. 16 weeks of G/P 300 mg/100 mg daily (Arm B) |
| Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks | Up to 28 weeks | Number of cirrhotic participants who are treatment experienced with a NS5A inhibitor + SOF +/RBV with undetectable HCV RNA 12 weeks after completing G/P plus RBV for 12 wks vs. G/P for 16 Wks |
| Tolerability of G/P +/-RBV | Up to 16 weeks | Number of subjects who discontinued G/P due to adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in % of Relapse Between Cirrhotic Arms C & D | Up to 28 weeks | Difference in the percentage of compensated cirrhotic subjects with post-treatment relapse (defined as confirmed HCV RNA\>=Lower limit of quantification (LLOQ) between end of treatment and 12 weeks after last dose of study drug among subjects who completed treatment as planned with HCV RNA\<LLOQ at end of treatment) after receiving 12 weeks G/P +/-Ribavirin (RBV) (Arm C) versus 16 weeks G/P (Arm D) |
| Difference in On-Treatment Virologic Failure Between Arms A & B (Non-cirrhotic Subjects) | Up to 28 weeks | Difference in % of subjects with on-treatment virologic failure further defined as either 1)Breakthrough a)Confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< Lower Limit of Quantification (LLOQ) at some point during the Treatment Period or confirmed increase from nadir in HCV RNA (two consecutive measurements \> 1 log10 IU/mL above nadir) at any time point during the Treatment Period, or b) a single value indicating viral breakthrough (≥ 100 IU/mL or \> 1 log10 above nadir), followed by patient status of 'Lost to Follow-up', the latter not requiring confirmation by a proximate measurement) or 2) End of Treatment Failure defined as HCV RNA ≥ LLOQ at end of treatment and following at least 6 weeks of treatment. |
| Difference in SVR12 Rates for 12-wk vs 16 wk | 28 weeks | Difference in proportions of SVR 12 rates will be determined for 12-week vs. 16-week treatment durations using contrasts within a logistic regression model with cirrhosis status and HCV genotype (1b vs non-1b) as factors |
| Difference in Relapse Between Arms A & B in Non-cirrhotic Subjects | Up to 28 weeks | Difference in Post-treatment relapse (defined as confirmed HCV RNA\>= Lower limit of quantification (LLOQ) between end of treatment and 12 weeks after the last dose of study drug among subjects who completed treatment as planned with HCV RNA \< LLOQ at end of treatment, excluding subjects with subjects with reinfection) |
| Difference in On-Treatment Virologic Failure Between Arms C and D in Cirrhotic Subjects | Up to 28 weeks | Difference in percentage of cirrhotic subjects experiencing on-treatment virologic failure (confirmed increase of \> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< 15 IU/mL during treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks of treatment) after 12 weeks of G/P with or without RBV for 12 weeks versus 16 weeks of G/P |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks Non-cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg (3 Glecaprevir/Pibrentasvir (G/P) 100mg/40mg Tablets once-daily by mouth) for 12 weeks.
Glecaprevir/Pibrentasvir (G/P) 300mg/120mg: daily | 78 |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks Non-cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once-daily by mouth for 16 weeks (G/P 300 mg/120 mg QD for 16 Wks)
Glecaprevir/Pibrentasvir (G/P) 300mg/120mg: daily | 49 |
| Arm C: G/P 300 mg/120 mg QD + RBV 12 Wks Cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once daily plus Ribavirin 200Mg Tablet (2-3 tablets) twice a day for 12 weeks (G/P 300 mg/120 mg QD + RBV 12 Wks)
Glecaprevir/Pibrentasvir (G/P) 300mg/120mg: daily
Ribavirin 200Mg Tablet: Weight-based 1000-1200 mg | 21 |
| Arm D: G/P 300 mg/120 mg QD for 16 Wks Cirrhotic subjects will take Glecaprevir/Pibrentasvir (G/P) 300mg/120mg once daily for 16 weeks (G/P 300 mg/120mg QD for 16 Wks)
Glecaprevir/Pibrentasvir (G/P) 300mg/120mg: daily | 29 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A: G/P 300 mg/120 mg QD for 12 Wks | Arm B: G/P 300 mg/120 mg QD for 16 Wks | Arm C: G/P 300 mg/120 mg QD + RBV 12 Wks | Arm D: G/P 300 mg/120 mg QD for 16 Wks | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 25 Participants | 18 Participants | 5 Participants | 13 Participants | 61 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 31 Participants | 16 Participants | 16 Participants | 116 Participants |
| Age, Continuous | 60.99 years | 61.37 years | 59.10 years | 62.59 years | 61.3 years |
| Albumin | 4.10 g/dL | 4.10 g/dL | 4.10 g/dL | 3.90 g/dL | 4.10 g/dL |
| ALT | 41 u/L | 38 u/L | 59 u/L | 70 u/L | 45 u/L |
| APRI | .46 Index | .45 Index | 1.23 Index | 1.47 Index | .57 Index |
| Estimated GFR | 88.36 ml/min/1.73M2 | 86.08 ml/min/1.73M2 | 94.99 ml/min/1.73M2 | 96.61 ml/min/1.73M2 | 90.41 ml/min/1.73M2 |
| HCV Genotype, non-1b | 60 Participants | 39 Participants | 17 Participants | 26 Participants | 142 Participants |
| HCV RNA | 6.4 LOG10 IU/mL | 6.4 LOG10 IU/mL | 6.3 LOG10 IU/mL | 6.4 LOG10 IU/mL | 6.4 LOG10 IU/mL |
| HIV | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 9 Participants |
| PLATELET | 204.50 10E3 cells/uL | 193 10E3 cells/uL | 125 10E3 cells/uL | 134 10E3 cells/uL | 178 10E3 cells/uL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 32 Participants | 25 Participants | 8 Participants | 12 Participants | 77 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 44 Participants | 23 Participants | 12 Participants | 17 Participants | 96 Participants |
| Region of Enrollment United States | 78 participants | 49 participants | 21 participants | 29 participants | 180 participants |
| Sex: Female, Male Female | 14 Participants | 9 Participants | 5 Participants | 6 Participants | 34 Participants |
| Sex: Female, Male Male | 64 Participants | 40 Participants | 16 Participants | 23 Participants | 143 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 | 1 / 78 | 0 / 49 | 0 / 21 | 0 / 29 |
| other Total, other adverse events | 50 / 78 | 32 / 49 | 17 / 21 | 17 / 29 |
| serious Total, serious adverse events | 4 / 78 | 2 / 49 | 1 / 21 | 0 / 29 |
Outcome results
Primary
Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks
Number of cirrhotic participants who are treatment experienced with a NS5A inhibitor + SOF +/RBV with undetectable HCV RNA 12 weeks after completing G/P plus RBV for 12 wks vs. G/P for 16 Wks
Time frame: Up to 28 weeks
Population: Cirrhotic subjects achieving Virologic Response at Post-Treatment Week 12
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks | Virologic Response | 18 Participants |
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks | Virologic Failure | 3 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks | Virologic Response | 28 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Comparison of Cirrhotic Participants Achieving SVR 12 After G/P Plus RBV for 12 Wks vs. G/P for 16 Wks | Virologic Failure | 1 Participants |
Primary
SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants
Number of non-cirrhotic treatment-experienced HCV genotype 1 with a NS5Ai inhibitor + SOF +/-RBV participants with undetectable HCV RNA (HCV RNA \<Lower Limit of Quantification -LLOQ) 12 weeks after completing G/P 300 mg/100 mg daily for 12 weeks (Arm A) vs. 16 weeks of G/P 300 mg/100 mg daily (Arm B)
Time frame: Up to 28 weeks
Population: These analyses were completed on Modified ITT -Genotype Population defined as all treated subjects representing their actual study regimen and who received at least one dose of study drug.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants | Virologic Response | 70 Participants |
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants | Virologic Failure | 8 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants | Virologic Response | 46 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | SVR After G/P 12 Wks (Arm A) vs. G/P Given for 16 Weeks (Arm B) to Non-cirrhotic Treatment-experienced GT1 HCV Participants | Virologic Failure | 3 Participants |
Primary
Tolerability of G/P +/-RBV
Number of subjects who discontinued G/P due to adverse events
Time frame: Up to 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Tolerability of G/P +/-RBV | 0 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Tolerability of G/P +/-RBV | 0 Participants |
| Arm C: G/P 300 mg/120 mg QD + RBV 12 Wks | Tolerability of G/P +/-RBV | 0 Participants |
| Arm D: G/P 300 mg/120 mg QD for 16 Wks | Tolerability of G/P +/-RBV | 0 Participants |
Secondary
Difference in % of Relapse Between Cirrhotic Arms C & D
Difference in the percentage of compensated cirrhotic subjects with post-treatment relapse (defined as confirmed HCV RNA\>=Lower limit of quantification (LLOQ) between end of treatment and 12 weeks after last dose of study drug among subjects who completed treatment as planned with HCV RNA\<LLOQ at end of treatment) after receiving 12 weeks G/P +/-Ribavirin (RBV) (Arm C) versus 16 weeks G/P (Arm D)
Time frame: Up to 28 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Difference in % of Relapse Between Cirrhotic Arms C & D | 1 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Difference in % of Relapse Between Cirrhotic Arms C & D | 1 Participants |
Comparison: Excludes re-infection and death95% CI: [-13.85, 10.22]
Secondary
Difference in On-Treatment Virologic Failure Between Arms A & B (Non-cirrhotic Subjects)
Difference in % of subjects with on-treatment virologic failure further defined as either 1)Breakthrough a)Confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< Lower Limit of Quantification (LLOQ) at some point during the Treatment Period or confirmed increase from nadir in HCV RNA (two consecutive measurements \> 1 log10 IU/mL above nadir) at any time point during the Treatment Period, or b) a single value indicating viral breakthrough (≥ 100 IU/mL or \> 1 log10 above nadir), followed by patient status of 'Lost to Follow-up', the latter not requiring confirmation by a proximate measurement) or 2) End of Treatment Failure defined as HCV RNA ≥ LLOQ at end of treatment and following at least 6 weeks of treatment.
Time frame: Up to 28 weeks
Population: Analysis was performed the study population as treated further defined as mITT-all subjects representing their actual study regimen and who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Difference in On-Treatment Virologic Failure Between Arms A & B (Non-cirrhotic Subjects) | 1 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Difference in On-Treatment Virologic Failure Between Arms A & B (Non-cirrhotic Subjects) | 1 Participants |
Comparison: The difference in the percentage of subjects with on-treatment virologic failure (Defined as increase of \>1 log10 IU/mL above nadir during treatment, or HCV RNA \>= 15 IU/mL at end of treatment with at least 6 weeks of treatment between Arms A and B are summarized with two-sided 95% Wilson score intervals.95% CI: [-9.48, 5.12]
Secondary
Difference in On-Treatment Virologic Failure Between Arms C and D in Cirrhotic Subjects
Difference in percentage of cirrhotic subjects experiencing on-treatment virologic failure (confirmed increase of \> 1 log10 IU/mL above nadir during treatment, confirmed HCV RNA ≥ 100 IU/mL after HCV RNA \< 15 IU/mL during treatment, or HCV RNA ≥ LLOQ at the end of treatment with at least 6 weeks of treatment) after 12 weeks of G/P with or without RBV for 12 weeks versus 16 weeks of G/P
Time frame: Up to 28 weeks
Population: Analysis was performed the study population as treated further defined as mITT-all subjects representing their actual study regimen and who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Difference in On-Treatment Virologic Failure Between Arms C and D in Cirrhotic Subjects | 2 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Difference in On-Treatment Virologic Failure Between Arms C and D in Cirrhotic Subjects | 0 Participants |
95% CI: [-3.03, 22.08]
Secondary
Difference in Relapse Between Arms A & B in Non-cirrhotic Subjects
Difference in Post-treatment relapse (defined as confirmed HCV RNA\>= Lower limit of quantification (LLOQ) between end of treatment and 12 weeks after the last dose of study drug among subjects who completed treatment as planned with HCV RNA \< LLOQ at end of treatment, excluding subjects with subjects with reinfection)
Time frame: Up to 28 weeks
Population: Analysis performed on any subject with study drug duration of 77 days or greater for Arm A or 105 days or greater for Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Difference in Relapse Between Arms A & B in Non-cirrhotic Subjects | 5 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Difference in Relapse Between Arms A & B in Non-cirrhotic Subjects | 2 Participants |
95% CI: [-10.49, 5.49]
Secondary
Difference in SVR12 Rates for 12-wk vs 16 wk
Difference in proportions of SVR 12 rates will be determined for 12-week vs. 16-week treatment durations using contrasts within a logistic regression model with cirrhosis status and HCV genotype (1b vs non-1b) as factors
Time frame: 28 weeks
Population: Modified Intent to Treat Population (mITT) analysis (All subjects enroll in Main study receiving at least one dose of study drug and according to the treatment arm in which they were actually treated)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: G/P 300 mg/120 mg QD for 12 Wks | Difference in SVR12 Rates for 12-wk vs 16 wk | 70 Participants |
| Arm B: G/P 300 mg/120 mg QD for 16 Wks | Difference in SVR12 Rates for 12-wk vs 16 wk | 46 Participants |
| Arm C: G/P 300 mg/120 mg QD + RBV 12 Wks | Difference in SVR12 Rates for 12-wk vs 16 wk | 18 Participants |
| Arm D: G/P 300 mg/120 mg QD for 16 Wks | Difference in SVR12 Rates for 12-wk vs 16 wk | 28 Participants |
p-value: 0.16195% CI: [-1.947, 0.323]Chi-squared
p-value: 0.8995% CI: [-1.239, 1.076]Chi-squared
Comparison: Comparison of 12 weeks vs 16 weeks in Genotype 1b vs non-1bp-value: 0.26595% CI: [-0.74, 2.694]Chi-squared