Hepatitis C
Conditions
Brief summary
This multiple dose study will assess the safety, tolerability, pharmacokinetics and pharmacodynamics of grazoprevir (MK-5172) in Genotype (GT) 1 and GT3 Hepatitis C virus (HCV)- infected participants. The primary hypothesis is that administration of grazoprevir for 7 days is sufficiently safe and well tolerated in HCV-infected males.
Interventions
DRUGGrazoprevir
10, 30, 50, 100, 200, 400, 600 or 800 mg Grazoprevir tablets, orally, once a day for 7 days
DRUGPlacebo
Placebo tablet, orally, once a day for 7 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Baseline health is stable. * Has a clinical diagnosis of chronic HCV infection.
Exclusion criteria
* Has a history of stroke or chronic seizures. * Has a history of cancer. * Has a history of human immunodeficiency virus (HIV) infection. * Has had major surgery, donated blood or participated in another investigational study within the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical and Laboratory Adverse Events (AEs) | All AEs: 15 Days after last dose; Serious AEs (SAEs) up to 2 months after last dose (Up to 67 days) | An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | Day 7 at the following time points: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose | Blood samples were collected on Day 7 at pre-dose up to 24 hours post-dose in order to determine the AUC 0-24hrs of Grazoprevir. It is hypothesized that the Geometric Mean of Day 7 Grazoprevir AUC0-24hr. exceeds 3.2 uM.hr. |
| 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | Day 7 at 24 hours post-dose | Blood samples were collected on Day 7 at 24 hours post-dose in order to determine the C24hr of Grazoprevir. It is hypothesized that the Geometric Mean of Day 7 Grazoprevir C24hr exceeds 28 nM. |
| Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | Baseline and up to approximately 2 months | Blood samples were collected at baseline and at intervals up to 2 months post-dose in order to determine the maximum log10 reduction from baseline in plasma HCV RNA, expressed in international units (IU)/mL. |
| Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | Baseline and up to approximately 2 months | Blood samples were collected at baseline and at intervals up to 2 months post-dose in order to determine the maximum log10 reduction from baseline in plasma HCV RNA. |
Participant flow
Recruitment details
One of the originally planned treatment groups (50 mg Grazoprevir - GT3) was not conducted because other results indicated that further evaluation of 50 mg Grazoprevir in GT3 participants was not necessary. It is therefore not included in the Participant Flow.
Participants by arm
| Arm | Count |
|---|---|
| 400 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 400 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 600 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 600 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 800 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 800 mg Grazoprevir orally, once daily for 7 consecutive days | 15 |
| 400 mg Grazoprevir - GT3 GT3 HCV-infected Participants: 400 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 600 mg Grazoprevir - GT3 GT3 HCV-infected Participants: 600 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 800 mg Grazoprevir - GT3 GT3 HCV-infected Participants: 800 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 200 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 200 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 100 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 100 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 50 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 50 mg Grazoprevir orally, once daily for 7 consecutive days | 6 |
| 200 mg Grazoprevir - GT3 GT3 HCV-infected Participants: 200 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 100 mg Grazoprevir - GT3 GT3 HCV-infected Participants: 100 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 30 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 30 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| 10 mg Grazoprevir - GT1 GT1 HCV-infected Participants: 10 mg Grazoprevir orally, once daily for 7 consecutive days | 5 |
| Placebo for Grazoprevir - GT1 and GT3 GT1 and GT3 HCV-infected Participants: Placebo for Grazoprevir orally, once daily for 7 consecutive days | 15 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 400 mg Grazoprevir - GT1 | 600 mg Grazoprevir - GT1 | 800 mg Grazoprevir - GT1 | 400 mg Grazoprevir - GT3 | 600 mg Grazoprevir - GT3 | 800 mg Grazoprevir - GT3 | 200 mg Grazoprevir - GT1 | 100 mg Grazoprevir - GT1 | 50 mg Grazoprevir - GT1 | 200 mg Grazoprevir - GT3 | 100 mg Grazoprevir - GT3 | 30 mg Grazoprevir - GT1 | 10 mg Grazoprevir - GT1 | Placebo for Grazoprevir - GT1 and GT3 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 42.4 Years STANDARD_DEVIATION 12.8 | 47.2 Years STANDARD_DEVIATION 12.2 | 46.7 Years STANDARD_DEVIATION 9.7 | 42.8 Years STANDARD_DEVIATION 14.4 | 38.0 Years STANDARD_DEVIATION 13.1 | 46.2 Years STANDARD_DEVIATION 10.8 | 51.0 Years STANDARD_DEVIATION 16.2 | 48.4 Years STANDARD_DEVIATION 5.9 | 36.8 Years STANDARD_DEVIATION 6 | 40.0 Years STANDARD_DEVIATION 10.2 | 31.4 Years STANDARD_DEVIATION 6.3 | 55.8 Years STANDARD_DEVIATION 5.4 | 48.4 Years STANDARD_DEVIATION 13.1 | 45.6 Years STANDARD_DEVIATION 11.5 | 44.7 Years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 15 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 6 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 15 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 10 | 3 / 10 | 13 / 20 | 4 / 10 | 1 / 10 | 0 / 6 | 3 / 5 | 4 / 5 | 2 / 15 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 20 | 0 / 10 | 0 / 10 | 0 / 6 | 0 / 5 | 0 / 5 | 0 / 15 |
Outcome results
Primary
Number of Participants With Clinical and Laboratory Adverse Events (AEs)
An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.
Time frame: All AEs: 15 Days after last dose; Serious AEs (SAEs) up to 2 months after last dose (Up to 67 days)
Population: All participants who received at least one dose of the investigational drug according to the treatment(s) they actually received. Participants with either GT1 or GT3 who received the same treatment were combined for the summary into a single GT1 and GT3 arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 400 mg Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 6 Participants |
| 600 mg Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 3 Participants |
| 800 mg Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 13 Participants |
| 200 mg Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 4 Participants |
| 100 mg Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 1 Participants |
| 50 mg Grazoprevir - GT1 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 0 Participants |
| 30 mg Grazoprevir - GT1 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 3 Participants |
| 10 mg Grazoprevir - GT1 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 4 Participants |
| Placebo for Grazoprevir - GT1 and GT3 | Number of Participants With Clinical and Laboratory Adverse Events (AEs) | 2 Participants |
Secondary
24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7
Blood samples were collected on Day 7 at 24 hours post-dose in order to determine the C24hr of Grazoprevir. It is hypothesized that the Geometric Mean of Day 7 Grazoprevir C24hr exceeds 28 nM.
Time frame: Day 7 at 24 hours post-dose
Population: Participants who complied with the protocol sufficiently to ensure that these data will exhibit the effects of treatment, according to the underlying scientific model. GT1 or GT3 participants who received the same treatment were combined into a single arm. Participants with placebo were not analyzed as they did not receive grazoprevir.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 400 mg Grazoprevir - GT1 and GT3 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 70.2 nM |
| 600 mg Grazoprevir - GT1 and GT3 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 93.2 nM |
| 800 mg Grazoprevir - GT1 and GT3 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 174 nM |
| 200 mg Grazoprevir - GT1 and GT3 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 22.2 nM |
| 100 mg Grazoprevir - GT1 and GT3 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 20.1 nM |
| 50 mg Grazoprevir - GT1 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 12.7 nM |
| 30 mg Grazoprevir - GT1 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 7.20 nM |
| 10 mg Grazoprevir - GT1 | 24 Hour Plasma Concentration (C[24hr]) of Grazoprevir on Day 7 | 2.41 nM |
Secondary
Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7
Blood samples were collected on Day 7 at pre-dose up to 24 hours post-dose in order to determine the AUC 0-24hrs of Grazoprevir. It is hypothesized that the Geometric Mean of Day 7 Grazoprevir AUC0-24hr. exceeds 3.2 uM.hr.
Time frame: Day 7 at the following time points: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose
Population: Participants who complied with the protocol sufficiently to ensure that these data will exhibit the effects of treatment, according to the underlying scientific model. GT1 or GT3 participants who received the same treatment were combined into a single arm. Participants with placebo were not analyzed as they did not receive grazoprevir.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 400 mg Grazoprevir - GT1 and GT3 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 18.2 uM.hr |
| 600 mg Grazoprevir - GT1 and GT3 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 41.9 uM.hr |
| 800 mg Grazoprevir - GT1 and GT3 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 72.5 uM.hr |
| 200 mg Grazoprevir - GT1 and GT3 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 3.21 uM.hr |
| 100 mg Grazoprevir - GT1 and GT3 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 1.16 uM.hr |
| 50 mg Grazoprevir - GT1 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 0.419 uM.hr |
| 30 mg Grazoprevir - GT1 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 0.260 uM.hr |
| 10 mg Grazoprevir - GT1 | Area Under the Curve for 0 to 24 Hours Post-dose (AUC[0-24hr]) of Grazoprevir on Day 7 | 0.0628 uM.hr |
Secondary
Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo
Blood samples were collected at baseline and at intervals up to 2 months post-dose in order to determine the maximum log10 reduction from baseline in plasma HCV RNA, expressed in international units (IU)/mL.
Time frame: Baseline and up to approximately 2 months
Population: Participants who complied with the protocol sufficiently to ensure that these data will exhibit the effects of treatment, according to the underlying scientific model. One GT1 participant treated with 50 mg grazoprevir, who discontinued, and all GT3 participants treated with grazoprevir were excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 400 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.14 log10 IU/mL |
| 600 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.32 log10 IU/mL |
| 800 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.72 log10 IU/mL |
| 200 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.53 log10 IU/mL |
| 100 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 4.74 log10 IU/mL |
| 50 mg Grazoprevir - GT1 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.26 log10 IU/mL |
| 30 mg Grazoprevir - GT1 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.06 log10 IU/mL |
| 10 mg Grazoprevir - GT1 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 3.84 log10 IU/mL |
| Placebo for Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT1 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 0.39 log10 IU/mL |
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.3, 5.44]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [2.89, 4.03]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.11, 5.25]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [3.78, 4.92]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.58, 5.72]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.19, 5.33]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.36, 5.5]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT1 viral load by at least 3 log1090% CI: [4.93, 5.74]
Secondary
Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo
Blood samples were collected at baseline and at intervals up to 2 months post-dose in order to determine the maximum log10 reduction from baseline in plasma HCV RNA.
Time frame: Baseline and up to approximately 2 months
Population: Participants who complied with the protocol sufficiently to ensure that these data will exhibit the effects of treatment, according to the underlying scientific model. One GT3 participant treated with 800 mg grazoprevir, who discontinued, and all GT1 participants were excluded from analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 400 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 4.23 log10 IU/mL |
| 600 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 5.36 log10 IU/mL |
| 800 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 4.60 log10 IU/mL |
| 200 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 3.32 log10 IU/mL |
| 100 mg Grazoprevir - GT1 and GT3 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 2.64 log10 IU/mL |
| 50 mg Grazoprevir - GT1 | Maximum log10 HCV RNA Reduction From Baseline Following Administration of Grazoprevir in Participants With GT3 HCV or Pooled GT1 and GT3 HCV Participants Treated With Placebo | 0.39 log10 IU/mL |
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT3 viral load by at least 2 log1090% CI: [1.7, 2.81]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT3 viral load by at least 2 log1090% CI: [2.38, 3.49]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT3 viral load by at least 2 log1090% CI: [3.29, 4.4]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT3 viral load by at least 2 log1090% CI: [4.42, 5.53]
Comparison: It is hypothesized that one or more doses of Grazoprevir will reduce GT3 viral load by at least 2 log1090% CI: [3.6, 4.81]