Chronic Hepatitis C
Conditions
Brief summary
This is a 2-part study. The purpose of Part A is to assess the efficacy and safety of grazoprevir (MK-5172) 100 mg in combination with elbasvir (MK-8742) 50 mg for 12 weeks in the treatment of chronic HCV GT1, GT4, or GT6 infection in treatment-naïve participants who are on opiate substitution therapy (OST). The primary hypothesis is that the percentage of participants who receive grazoprevir/elbasvir fixed-dose combination (FDC) in the Immediate Treatment Arm and achieve a Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) will be superior to 67%. In addition, participants who received at least 1 dose of grazoprevir/elbasvir in Part A will be eligible to participate in Part B, which is a 3-year observational follow-up.
Interventions
DRUGGrazoprevir 100 mg/Elbasvir 50 mg FDC tablet (MK-5172A)
Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet, taken once daily by mouth for 12 weeks.
DRUGPlacebo to Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet
Placebo Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet, taken once daily by mouth for 12 weeks.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A * Documented chronic HCV GT1, GT4, or GT6 infection with no evidence of GT2, GT3, GT5 or non-typeable genotypes and HCV ribonucleic acid (RNA) confirmed by screening lab results prior to randomization * On opiate substitution therapy (OST; methadone, levamethadone, buprenorphine, naloxone, naltrexone) for at least 3 months prior to screening * Treatment naïve to all HCV therapies * Human Immunodeficiency Virus (HIV)-infected participants enrolled in this study must meet following criteria: * Documented HIV infection * Naïve to treatment with any antiretroviral therapy (ART) OR on HIV ART for at least 8 weeks prior to study entry using a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone of tenofovir or abacavir and either emtricitabine or lamivudine PLUS raltegravir (or dolutegravir or rilpivirine). Dose modifications or changes in ART during the 4 weeks prior to study entry (Day 1) are not permitted * Cluster of differentiation 4 (CD4+) T-cell count \>200 cells/mm\^3 if on ART or \>500 cell/mm\^3 if ART treatment naïve * Undetectable plasma HIV-1 RNA at least 8 weeks prior to screening if on ART or \<50,000 copies/mL if ART treatment naïve * Participants with HIV-1 infection and on ART must have at least one viable antiretroviral regimen alternative beyond their current regimen in the event of HIV virologic failure or the development of anti-retroviral drug resistance * Females who are of reproductive potential must agree to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have her partner use) acceptable contraception during heterosexual activity Part B * Received at least one dose of grazoprevir in combination with elbasvir in Part A. Receiving OST and keeping \>80% of scheduled appointments while on OST were not required for Part B.
Exclusion criteria
Part A * Evidence of decompensated liver disease * For participants with cirrhosis, participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score \>6 * Is co-infected with hepatitis B virus * Has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC * Currently using or intends to use barbiturates during the treatment period of this study * Is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs from Day 1 or anytime during treatment, and 14 days after the last dose of study medication, or longer if dictated by local regulations * Any medical condition requiring or likely to require chronic systemic administration of corticosteroids, Tumor Necrosis Factor (TNF) antagonists, or other immunosuppressant drugs during the course of the trial * Evidence or history of chronic hepatitis not caused by HCV Part B * Mentally or legally incapacitated, has significant emotional problems at the time of pre-study screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures * Has a medical condition or personal circumstance which, in the opinion of the investigator and/or Sponsor, places the participant at unnecessary risk through continued participation in the trial or does not allow the participant to adhere to the requirements of the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | 12 weeks after end of all therapy (Study Week 24 for Immediate Treatment Arm and Study Week 40 for Deferred Treatment Arm) | Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\<LLOQ) at 12 weeks after the end of all study therapy for baseline infection, or HCV RNA≥ LLOQ demonstrated to be due to reinfection (after clearance of baseline infection). The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR12 rate. The primary efficacy analysis for Part A was the percentage of participants in the immediate treatment arm (ITA) who achieved SVR12. SVR12 was also calculated for the Deferred Treatment Arm. |
| Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and First 14 Follow-up Days | DB Treatment period plus first 14 follow-up days (up to Study Week 14) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants experiencing an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period. |
| Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period | DB Treatment period (up to Study Week 12) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants discontinuing study therapy due to an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | 24 weeks after end of all therapy (Study Week 36 for Immediate Treatment Arm and Study Week 52 for Deferred Treatment Arm) | Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which has an LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy. The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR24 rate. The secondary efficacy analysis for Part A evaluated the percentage of participants in the immediate treatment arm (ITA) who achieved SVR24. SVR24 was also calculated for the Deferred Treatment Arm. |
Participant flow
Pre-assignment details
301 participants were randomized to either the Immediate Treatment Arm or to the Deferred Treatment Arm during Part A. 199 participants who completed Part A were enrolled in Part B; of these, 142 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Immediate Treatment Arm: Grazoprevir/Elbasvir In Part A, participants received grazoprevir 100 mg plus elbasvir 50 mg FDC (MK-5172A) once daily for 12 weeks (blinded) and were followed-up for 24 weeks. In Part B, participants could enroll in a 3-year follow-up period where they were followed every 6 months for 3 years in an observational cohort (no treatment was administered during Part B). | 201 |
| Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir In Part A, participants received placebo to MK-5172A once daily for 12 weeks (blinded), followed by 4 weeks of follow-up. Afterwards, participants received 12 weeks of open-label treatment with the MK-5172A FDC and were followed-up for 24 weeks. In Part B, participants could enroll in a 3-year follow-up period where they were followed every 6 months for 3 years in an observational cohort (no treatment was administered during Part B). | 100 |
| Total | 301 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part A: Double-Blind | Adverse Event | 1 | 0 |
| Part A: Double-Blind | Death | 0 | 1 |
| Part A: Double-Blind | Lost to Follow-up | 15 | 11 |
| Part A: Double-Blind | Physician Decision | 0 | 1 |
| Part A: Double-Blind | Status Unknown | 0 | 2 |
| Part A: Double-Blind | Withdrawal by Subject | 4 | 2 |
| Part B: Observational Follow-up | Death | 2 | 1 |
| Part B: Observational Follow-up | Lost to Follow-up | 23 | 15 |
| Part B: Observational Follow-up | Physician Decision | 3 | 1 |
| Part B: Observational Follow-up | Withdrawal by Subject | 9 | 3 |
Baseline characteristics
| Characteristic | Immediate Treatment Arm: Grazoprevir/Elbasvir | Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir | Total |
|---|---|---|---|
| Age, Continuous | 47.4 years STANDARD_DEVIATION 9.9 | 46.4 years STANDARD_DEVIATION 9.9 | 47.1 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 48 Participants | 23 Participants | 71 Participants |
| Sex: Female, Male Male | 153 Participants | 77 Participants | 230 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 201 | 1 / 100 | 1 / 95 |
| other Total, other adverse events | 108 / 201 | 46 / 100 | 36 / 95 |
| serious Total, serious adverse events | 16 / 201 | 4 / 100 | 7 / 95 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12)
Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (\<LLOQ) at 12 weeks after the end of all study therapy for baseline infection, or HCV RNA≥ LLOQ demonstrated to be due to reinfection (after clearance of baseline infection). The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR12 rate. The primary efficacy analysis for Part A was the percentage of participants in the immediate treatment arm (ITA) who achieved SVR12. SVR12 was also calculated for the Deferred Treatment Arm.
Time frame: 12 weeks after end of all therapy (Study Week 24 for Immediate Treatment Arm and Study Week 40 for Deferred Treatment Arm)
Population: Modified FAS (mFAS): All randomized participants receiving ≥1 dose of active study treatment and excluding participants for study discontinuation for reasons unrelated to treatment regimen, response to HCV treatment, or BL genotype (GT)2, GT3, or GT5. The primary efficacy hypothesis was evaluated within participants of the Immediate Treatment Arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Arm: Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | 95.5 Percentage of Participants |
| Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) | 96.6 Percentage of Participants |
Comparison: A one-sided exact test was used to test the null hypothesis, which was that the SVR12 rate for the ITA was less than 67% (historical reference rate derived from NCT01667731). The p-value was based on a one-sided exact test for a binomial proportion. A one-sided p-value \<0.025 supports a conclusion that the true SVR12 is \>67%.p-value: <0.001One-sided exact test
Primary
Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants discontinuing study therapy due to an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period.
Time frame: DB Treatment period (up to Study Week 12)
Population: All randomized participants who received at least one dose of study treatment during the Part A DB period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Arm: Grazoprevir/Elbasvir | Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period | 0.5 Percentage of Participants |
| Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir | Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period | 1.0 Percentage of Participants |
Comparison: Categorical AE parameters were assessed via point estimates with 95% confidence intervals provided for between-treatment differences in the percentage of participants with events using the Miettinen and Nurminen method, an unconditional, asymptotic method.95% CI: [-5, 1.9]
Primary
Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and 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 to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants experiencing an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period.
Time frame: DB Treatment period plus first 14 follow-up days (up to Study Week 14)
Population: All randomized participants who received at least one dose of study treatment during the Part A DB period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Arm: Grazoprevir/Elbasvir | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and First 14 Follow-up Days | 83.1 Percentage of Participants |
| Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir | Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and First 14 Follow-up Days | 83.0 Percentage of Participants |
Comparison: Categorical AE parameters were assessed via point estimates with 95% confidence intervals provided for between-treatment differences in the percentage of participants with events using the Miettinen and Nurminen method, an unconditional, asymptotic method.95% CI: [-8.3, 10]
Secondary
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24)
Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which has an LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA \<LLOQ at 24 weeks after the end of all study therapy. The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR24 rate. The secondary efficacy analysis for Part A evaluated the percentage of participants in the immediate treatment arm (ITA) who achieved SVR24. SVR24 was also calculated for the Deferred Treatment Arm.
Time frame: 24 weeks after end of all therapy (Study Week 36 for Immediate Treatment Arm and Study Week 52 for Deferred Treatment Arm)
Population: Modified FAS (mFAS): All randomized participants receiving ≥1 dose of active study treatment and excluding participants for study discontinuation for reasons unrelated to treatment regimen, response to HCV treatment, or BL genotype (GT)2, GT3, or GT5. The secondary efficacy analysis was evaluated within participants of the Immediate Treatment Arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Treatment Arm: Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | 94.1 Percentage of Participants |
| Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) | 96.5 Percentage of Participants |