Hepatitis C
Conditions
Brief summary
This is a study comparing grazoprevir (MK-5172) plus elbasvir (MK-8742) treatment with sofosbuvir (SOF) plus Pegylated Interferon plus Ribavirin (RBV) \[PR\] treatment in treatment-naïve and prior PR treatment failure participants with chronic Hepatitis C Virus (HCV) genotype (GT)1, GT4, or GT6 infection. The primary objectives are to compare efficacy (assessed by the percentage of participants achieving sustained virologic response 12 weeks after ending study treatment \[SVR12\]) and safety between the grazoprevir plus elbasvir treatment arm and the SOF plus PR treatment arm. The primary hypothesis is that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir treatment arm is non-inferior to that in the SOF plus PR treatment arm.
Interventions
DRUGGrazoprevir/Elbasvir (100 mg/50 mg) FDC
Grazoprevir/Elbasvir (100 mg/50 mg) FDC, taken PO QD for 12 weeks.
DRUGSofosbuvir
400 mg tablets, taken orally (PO) every day (QD) for 12 weeks.
BIOLOGICALPegIntron
PegIntron administered subcutaneously every week (QW) at 1.5 mcg/kg for 12 weeks.
DRUGRibavirin
Capsule and/or tablet administered PO twice daily (BID) based on weight (1000 - 1200 mg) for 12 weeks.
Sponsors
Merck Sharp & Dohme LLC
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
* Weigh ≥40 kg and ≤125 kg * documented chronic HCV GT1, GT4, or GT6 infection * cirrhosis/absence of cirrhosis defined by liver biopsy, Fibroscan, or FibroSure® * either treatment naïve or PR Null Responder, PR Partial Responder, or PR Prior Relapser * participant and partner both agree to use at least use at least 2 effective methods of contraception from at least 2 weeks prior to Day 1 and continue until up to 6 months after last dose of study drug, or longer if dictated by local regulations
Exclusion criteria
* has evidence of decompensated liver disease * is coinfected with hepatitis B virus (e.g. hepatitis B surface antigen positive) or human immunodeficiency virus * history of malignancy ≤5 years prior to signing informed consent, or is under evaluation for other active or suspected malignancy * has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC * has any of the following conditions: immunologically-mediated disease, organ transplants other than cornea and hair, poor venous access that precludes routine peripheral blood sampling, history of gastric surgery or malabsorption disorders, or any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial, history of chronic hepatitis not caused by HCV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12) | 12 weeks after end of all therapy (Study Week 24) | Hepatitis C Virus ribonucleic acid (HCV-RNA) levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR12 was defined as HCV RNA below the lower limit of quantification (\<LLOQ) at 12 weeks after the end of all study therapy. The primary efficacy hypothesis for this study was that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was non-inferior to the percentage in the SOF plus PR arm. A secondary statistical analysis was performed to determine whether the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was superior to the percentage in the SOF plus PR arm. |
| Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days | Treatment + First 14 days of follow-up (Up to Week 14) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who experienced at least one AE was reported for each treatment arm. |
| Percentage of Participants Discontinuing Study Treatment Due to an AE | Up to Week 12 | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who discontinued study treatment due to an AE was reported for each treatment arm. Participants that discontinued study drug treatment due to an AE may have still continued on trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Treatment + First 14 days of follow-up (Up to Week 14) | Tier 1 safety events were pre-specified by the protocol to evaluate safety and test the safety superiority hypothesis. Tier 1 safety events were chosen to assess broad tolerability, hematological side effects and liver-related laboratory abnormalities. For this study, Tier 1 safety events included: any serious drug-related AE, any drug-related AE leading to permanent discontinuation (DC) of all study drugs, neutrophil count \<0.75 x 10\^9/L, hemoglobin \<10 g/dL, severe depression, hepatic events of clinical interest (defined by abnormal increases in alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or alkaline phosphatase \[ALP\]), or events meeting stopping rule criteria for DC from trial (due to abnormal increases of ALT, AST, or ALP with/without pre-specified related AEs). The percentage of participants who experienced each individual event that was defined as a Tier 1 safety event during the study treatment period was reported for each treatment arm. |
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24) | 24 weeks after end of all therapy (Study Week 36) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy. |
| Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4) | 4 weeks after end of all therapy (Study Week 16) | HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR4 was defined as HCV RNA \<LLOQ at 4 weeks after the end of all study therapy. |
Participant flow
Pre-assignment details
A total of 257 participants were randomized to treatment: 129 to Grazoprevir + Elbasvir arm and 128 to Sofosbuvir plus Pegylated Interferon/Ribavirin (SOF + PR) arm. Two participants in the SOF + PR arm withdrew from study prior to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Grazoprevir + Elbasvir Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up. | 129 |
| SOF + PR Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up. | 126 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Grazoprevir + Elbasvir | SOF + PR | Total |
|---|---|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 12.4 | 48.2 years STANDARD_DEVIATION 12.4 | 47.9 years STANDARD_DEVIATION 12.4 |
| Sex: Female, Male Female | 74 Participants | 64 Participants | 138 Participants |
| Sex: Female, Male Male | 55 Participants | 62 Participants | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 129 | 114 / 126 |
| serious Total, serious adverse events | 1 / 129 | 6 / 126 |
Outcome results
Primary
Percentage of Participants Discontinuing Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who discontinued study treatment due to an AE was reported for each treatment arm. Participants that discontinued study drug treatment due to an AE may have still continued on trial.
Time frame: Up to Week 12
Population: ASaT population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.8 percentage of participants |
| SOF + PR | Percentage of Participants Discontinuing Study Treatment Due to an AE | 0.8 percentage of participants |
Primary
Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor's product, was also an AE. The percentage of participants who experienced at least one AE was reported for each treatment arm.
Time frame: Treatment + First 14 days of follow-up (Up to Week 14)
Population: All Subjects as Treated (ASaT) population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days | 51.9 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period Plus First 14 Follow-up Days | 93.7 percentage of participants |
Comparison: The percentage of participants with an event were assessed via point estimates with 95% CIs provided for between-group comparisons.95% CI: [-51.1, -31.9]
Primary
Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12)
Hepatitis C Virus ribonucleic acid (HCV-RNA) levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR12 was defined as HCV RNA below the lower limit of quantification (\<LLOQ) at 12 weeks after the end of all study therapy. The primary efficacy hypothesis for this study was that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was non-inferior to the percentage in the SOF plus PR arm. A secondary statistical analysis was performed to determine whether the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was superior to the percentage in the SOF plus PR arm.
Time frame: 12 weeks after end of all therapy (Study Week 24)
Population: FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir | Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12) | 99.2 percentage of participants |
| SOF + PR | Primary: Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of All Treatment (SVR12) | 90.5 percentage of participants |
Comparison: Primary Analysis Approach: Non-Inferiority~Analyses of the percentage of participants achieving SVR12 was conducted using the Miettinen \& Nurminen (M\&N) method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir+elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% confidence intervals (CIs) and p-values were provided.p-value: <0.00195% CI: [3.6, 15.3]Miettinen & Nurminen Method
Comparison: Secondary Analysis Approach: Superiority~Analyses of the percentage of participants achieving SVR12 was conducted using the M\&N method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir +elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% CIs and p-values were provided.p-value: 0.00195% CI: [3.6, 15.3]Miettinen & Nurminen Method
Secondary
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24)
HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy.
Time frame: 24 weeks after end of all therapy (Study Week 36)
Population: FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24) | 98.4 percentage of participants |
| SOF + PR | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Ending Study Treatment (SVR24) | 89.7 percentage of participants |
Comparison: Analyses of the percentage of participants achieving SVR24 was conducted using the Miettinen \& Nurminen (M\&N) method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir+elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% confidence intervals (CIs) and p-values were provided.95% CI: [3.3, 15.7]
Secondary
Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4)
HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR4 was defined as HCV RNA \<LLOQ at 4 weeks after the end of all study therapy.
Time frame: 4 weeks after end of all therapy (Study Week 16)
Population: FAS; all randomized participants who receive at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir + Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4) | 99.2 percentage of participants |
| SOF + PR | Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After Ending Study Treatment (SVR4) | 92.1 percentage of participants |
Secondary
Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days
Tier 1 safety events were pre-specified by the protocol to evaluate safety and test the safety superiority hypothesis. Tier 1 safety events were chosen to assess broad tolerability, hematological side effects and liver-related laboratory abnormalities. For this study, Tier 1 safety events included: any serious drug-related AE, any drug-related AE leading to permanent discontinuation (DC) of all study drugs, neutrophil count \<0.75 x 10\^9/L, hemoglobin \<10 g/dL, severe depression, hepatic events of clinical interest (defined by abnormal increases in alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or alkaline phosphatase \[ALP\]), or events meeting stopping rule criteria for DC from trial (due to abnormal increases of ALT, AST, or ALP with/without pre-specified related AEs). The percentage of participants who experienced each individual event that was defined as a Tier 1 safety event during the study treatment period was reported for each treatment arm.
Time frame: Treatment + First 14 days of follow-up (Up to Week 14)
Population: ASaT population; all randomized participants who received at least one dose of study treatment. Two participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Total Tier 1 AEs | 0.8 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Serious drug-related AE | 0.0 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: DC due to drug-related AE | 0.0 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Neutrophil count <0.75 x 10^9/L | 0.0 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Hemoglobin <10 g/dL | 0.8 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Severe depression | 0.0 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Hepatic event of clinical interest | 0.0 percentage of participants |
| Grazoprevir + Elbasvir | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Trial DC due to stopping rule | 0.0 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Trial DC due to stopping rule | 0.0 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Total Tier 1 AEs | 27.8 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Hemoglobin <10 g/dL | 14.3 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Serious drug-related AE | 2.4 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Hepatic event of clinical interest | 0.0 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: DC due to drug-related AE | 0.8 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Severe depression | 0.0 percentage of participants |
| SOF + PR | Percentage of Participants Experiencing at Least One Tier 1 Safety Event (Key Safety Parameter) During the Treatment Period and First 14 Follow-up Days | Tier 1 AE: Neutrophil count <0.75 x 10^9/L | 12.7 percentage of participants |
Comparison: Total Tier 1 AEs:~If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.p-value: <0.00195% CI: [-35.5, -19.6]Miettinen & Nurminen Method
Comparison: Serious drug-related AEs:~If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.p-value: 0.07895% CI: [-6.8, 0.6]Miettinen & Nurminen Method
Comparison: DC due to drug-related AE:~If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.p-value: 0.31295% CI: [-4.4, 2.1]Miettinen & Nurminen Method
Comparison: Neutrophil count \<0.75 x 10\^9/L:~If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.p-value: <0.00195% CI: [-19.7, -8]Miettinen & Nurminen Method
Comparison: Hemoglobin \<10 g/dL:~If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.p-value: <0.00195% CI: [-20.8, -7.9]Miettinen & Nurminen Method