Chronic Hepatitis C (CHC)
Conditions
Brief summary
This is a study designed to compare the safety and efficacy of 3 different doses of grazoprevir (MK-5172) combined with pegylated interferon alfa-2b (PEG-IFN) and ribavirin (RBV) in treatment-naïve participants with genotype 1 (GT1) chronic hepatitis C (CHC). Participants will receive 12 weeks of treatment with grazoprevir combined with Peg-IFN and RBV, and depending on response at Week 4 may go on to receive an additional 12 weeks of treatment with Peg-IFN and RBV.
Interventions
DRUGGrazoprevir
Grazoprevir tablet, orally, once per day at assigned dose
BIOLOGICALpegylated interferon alfa-2b
1.5 mcg/kg/week, administered as a weekly subcutaneous (SC) injection
DRUGRibavirin
Ribavirin capsule, orally, twice daily, at a dose of 800 to 1400 mg based on participant weight
DRUGPlacebo
Placebo to match grazoprevir tablets to maintain dose blinding
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
* Treatment naive * Chronic, compensated HCV GT1 infection * Absence (no medical history or physical findings) of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs or symptoms of advanced liver disease, or cirrhosis * No evidence of cirrhosis or hepatocellular carcinoma by biopsy or noninvasive testing (e.g. FibroScan and/or FibroTest) * Must agree to use two acceptable methods of birth control from at least 2 weeks prior to first dose and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations
Exclusion criteria
* Non-GT1 HCV infection, including a mixed GT infection (with a non-GT1) or a non-typeable genotype. * Documented to be Human Immunodeficiency Virus (HIV) positive or co-infected with hepatitis B virus * Hepatocellular carcinoma (HCC) or under evaluation for HCC * Participating in or has participated in a study with an investigational compound or device within 30 days of signing informed consent * Diabetic and/or hypertensive with clinically significant ocular examination findings * Current or history of central nervous system trauma, seizure disorder, stroke or transient ischemic attack * Chronic pulmonary disease * Current or history of any clinically significant cardiac abnormalities/dysfunction * Active clinical gout within the last year * History of gastric surgery or history of malabsorption disorders * Active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin) * Pregnant, lactating, expecting to conceive or donate eggs, or male participant planning to impregnate or provide sperm donation or with a female partner who is pregnant * Current moderate or severe depression or history of depression associated with hospitalization, electroconvulsive therapy, or severe disruption of daily functions, or suicidal or homicidal ideation and/or attempt, or history of severe psychiatric disorders * Evidence or history of chronic hepatitis not caused by HCV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | 12 weeks after end of treatment (up to 36 weeks total) | Hepatitis C virus ribonucleic acid (HCV RNA) was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR12 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 12 weeks after the end of all study therapy. |
| Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days | 14 days following last dose of study drug (up to 26 weeks) | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
| Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days | Up to 24 weeks | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving SVR24 | 24 weeks after end of treatment (up to 48 weeks total) | HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR24 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 24 weeks after the end of all study therapy. |
| Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | From Treatment Week (TW) 2 through end of treatment (up to 24 weeks) | HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. Undetectable HCV RNA was defined as HCV RNA \< 9.3 IU/mL. |
| Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response | From Day 1 up to Follow-up Week 24 (up to 48 weeks total) | Post-baseline resistance associated variants (RAV) analysis was conducted by comparing the amino acid sequences at virologic failure time points to those at baseline (BL): Day 1, pre-dose. A post-BL variant was defined as an amino acid substitution within HCV NS3/4A that was present after the first dose at virologic failure and follow-up visits but not at BL. Post-BL variant analysis was conducted for participants who did not achieve SVR24 who had sequence data available. |
| Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | From TW 2 through end of treatment (up to 24 weeks) | HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. |
| Percentage of Participants Achieving SVR4 | 4 weeks after end of treatment (up to 28 weeks total) | HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR4 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 4 weeks after the end of all study therapy. |
Participant flow
Pre-assignment details
Of 136 screened participants, 87 were randomized to treatment at 19 sites worldwide.
Participants by arm
| Arm | Count |
|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV After a maximum of a 45 day screening window, randomized participants received 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by RGT. Participants could receive an additional 12 weeks of PEG-IFN plus RBV depending on their HCV RNA level at TW 4. | 29 |
| Grazoprevir 50 mg + PEG-IFN + RBV After a maximum of a 45 day screening window, randomized participants received 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by RGT. Participants could receive an additional 12 weeks of PEG-IFN plus RBV depending on their HCV RNA level at TW 4. | 28 |
| Grazoprevir 100 mg + PEG-IFN + RBV After a maximum of a 45 day screening window, randomized participants received 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by RGT. Participants could receive an additional 12 weeks of PEG-IFN plus RBV depending on their HCV RNA level at TW 4. | 30 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Grazoprevir 25 mg + PEG-IFN + RBV | Grazoprevir 50 mg + PEG-IFN + RBV | Grazoprevir 100 mg + PEG-IFN + RBV |
|---|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 11.6 | 52.0 years STANDARD_DEVIATION 7.9 | 48.5 years STANDARD_DEVIATION 12.5 | 46.4 years STANDARD_DEVIATION 13.3 |
| Sex: Female, Male Female | 41 Participants | 8 Participants | 18 Participants | 15 Participants |
| Sex: Female, Male Male | 46 Participants | 21 Participants | 10 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 29 | 28 / 28 | 27 / 30 |
| serious Total, serious adverse events | 1 / 29 | 2 / 28 | 0 / 30 |
Outcome results
Primary
Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: Up to 24 weeks
Population: APaT Population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days | 1 participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days | 1 participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days | 1 participants |
Primary
Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time frame: 14 days following last dose of study drug (up to 26 weeks)
Population: All Participants as Treated (APaT) Population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days | 28 participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days | 28 participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days | 28 participants |
Primary
Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12)
Hepatitis C virus ribonucleic acid (HCV RNA) was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR12 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 12 weeks after the end of all study therapy.
Time frame: 12 weeks after end of treatment (up to 36 weeks total)
Population: Participants in the Per-Protocol (PP) Population (all randomized participants receiving ≥1 dose of study treatment and no important protocol deviation) with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | 54.2 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | 84.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) | 88.5 percentage of participants |
Secondary
Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response
Post-baseline resistance associated variants (RAV) analysis was conducted by comparing the amino acid sequences at virologic failure time points to those at baseline (BL): Day 1, pre-dose. A post-BL variant was defined as an amino acid substitution within HCV NS3/4A that was present after the first dose at virologic failure and follow-up visits but not at BL. Post-BL variant analysis was conducted for participants who did not achieve SVR24 who had sequence data available.
Time frame: From Day 1 up to Follow-up Week 24 (up to 48 weeks total)
Population: Treated non-SVR24 participants with BL and post-BL samples sequenced for RAVs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response | 9 participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response | 5 participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response | 3 participants |
Secondary
Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point
HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL.
Time frame: From TW 2 through end of treatment (up to 24 weeks)
Population: Participants in the PP Population (all randomized participants receiving ≥1 dose of study treatment and no important protocol deviation) with available data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 2 (n=29, 25, 29) | 86.2 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | End of all Therapy (n=26, 25, 26) | 92.3 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 4 (n=28, 26, 29) | 96.4 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 12 (n=28, 26, 28) | 96.4 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 2 (n=29, 25, 29) | 88.0 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 4 (n=28, 26, 29) | 100.0 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | End of all Therapy (n=26, 25, 26) | 100.0 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 12 (n=28, 26, 28) | 100.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 4 (n=28, 26, 29) | 100.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 2 (n=29, 25, 29) | 96.6 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | End of all Therapy (n=26, 25, 26) | 100.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | Week 12 (n=28, 26, 28) | 100.0 percentage of participants |
Secondary
Percentage of Participants Achieving SVR4
HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR4 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 4 weeks after the end of all study therapy.
Time frame: 4 weeks after end of treatment (up to 28 weeks total)
Population: Participants in the PP Population (all randomized participants receiving ≥1 dose of study treatment and no important protocol deviation) with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving SVR4 | 76.9 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving SVR4 | 88.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving SVR4 | 92.3 percentage of participants |
Secondary
Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point
HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. Undetectable HCV RNA was defined as HCV RNA \< 9.3 IU/mL.
Time frame: From Treatment Week (TW) 2 through end of treatment (up to 24 weeks)
Population: Participants in the PP Population (all randomized participants receiving ≥1 dose of study treatment and no important protocol deviation) with available data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 2 (n=29, 25, 29) | 34.5 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 4 (n=28, 26, 29) | 82.1 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 12 (n=28, 26, 28) | 96.4 percentage of participants |
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | End of All Therapy (n=26, 25, 26) | 92.3 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | End of All Therapy (n=26, 25, 26) | 92.0 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 2 (n=29, 25, 29) | 32.0 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 12 (n=28, 26, 28) | 92.3 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 4 (n=28, 26, 29) | 76.9 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | End of All Therapy (n=26, 25, 26) | 100.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 4 (n=28, 26, 29) | 89.7 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 12 (n=28, 26, 28) | 100.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | Week 2 (n=29, 25, 29) | 55.2 percentage of participants |
Secondary
Percentage of Subjects Achieving SVR24
HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR24 was defined as HCV RNA \<25 IU/mL (either target detected, unquantifiable or target not detected) 24 weeks after the end of all study therapy.
Time frame: 24 weeks after end of treatment (up to 48 weeks total)
Population: Participants in the PP Population (all randomized participants receiving ≥1 dose of study treatment and no important protocol deviation) with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grazoprevir 25 mg + PEG-IFN + RBV | Percentage of Subjects Achieving SVR24 | 54.2 percentage of participants |
| Grazoprevir 50 mg + PEG-IFN + RBV | Percentage of Subjects Achieving SVR24 | 84.0 percentage of participants |
| Grazoprevir 100 mg + PEG-IFN + RBV | Percentage of Subjects Achieving SVR24 | 84.6 percentage of participants |