Hepatitis, Viral, Human
Conditions
Brief summary
The purpose of this study is to assess the safety, pharmacokinetics (PK) and pharmacodynamics of elbasvir (MK-8742) in Hepatitis C Virus (HCV)-infected participants. There will be 3 parts to this study; Part I will enroll only genotype (GT) 1 HCV-infected participants, Part II will enroll GT3 HCV-infected participants, and Part III will enroll only GT1a HCV-infected participants. All parts may run concurrently, or Parts II and III may be staggered. Hypothesis (Part I): At a once-daily dose that is sufficiently safe and well tolerated in HCV-infected participants, elbasvir administered for 5 consecutive days has superior antiviral activity in GT1 HCV-infected participants compared to placebo, as measured by change from baseline in plasma HCV ribonucleic acid (RNA; log 10 copies/mL) at Day 5, 24-hour postdose timepoint. (a true mean viral RNA reduction of at least 3 log10 is anticipated). Hypothesis (Part II): At a dose that is sufficiently safe in GT3 HCV-infected participants, the mean maximum reduction in HCV viral load is greater following multiple dose oral administration of elbasvir as compared to placebo. Hypothesis (Part III): At a once-daily dose that is sufficiently safe and well tolerated in HCV-infected participants, elbasvir administered for 5 consecutive days has superior antiviral activity in GT1a HCV-infected participants compared to placebo, as measured by change from baseline in plasma HCV RNA (log 10 copies/mL) at Day 5, 24-hour postdose timepoint. (a true mean viral RNA reduction of at least 3 log10 is anticipated).
Interventions
DRUGElbasvir
Elbasvir was administered orally by tablet(s)
DRUGPlacebo
Dose-matched placebo tablets were administered orally.
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 60 Years
Healthy volunteers
No
Inclusion criteria
* Body Mass Index (BMI) of 18 to ≤ 37 kg/m\^2 * Clinical diagnosis of chronic HCV infection defined by positive serology for HCV for at least 6 months and detectable HCV RNA in peripheral blood ≥105 IU/mL at screening * Participant must be infected with HCV GT1a, GT1b, or GT 3
Exclusion criteria
* Co-infection with GT1 and GT3 * Estimated creatinine clearance of ≤70 mL/min based on the Cockcroft-Gault equation * History of stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal (excepting HCV infection), cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases * History of neoplastic disease * Positive Hepatitis B surface antigen at the pre-study (screening) visit * Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks prior to the prestudy (screening) visit. * Previous treatments (s) with nonstructural protein 5A (NS5A) inhibitors * \<4 weeks since administration of any experimental protease inhibitor * Previous exposure to interferon-alpha and/or ribavirin within 3 month prior to the first dose of elbasvir in the study * Clinical or laboratory evidence of advanced or decompensated liver disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1 | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction. |
| Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3 | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction |
| Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT1a | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction. |
| Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1 | Up to 5 days | HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded. |
| Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3 | Up to 5 days | HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded. |
| Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1a | Up to 5 days | HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded. |
| Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | Up to 5 days | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. |
| Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | Up to 5 days | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. Participants who had study drug discontinued due to an AE were recorded. |
Participant flow
Pre-assignment details
2 Panels (Panel D in Part 1 and Panel H in Part 2) were planned but not performed. No participants were enrolled in either of these panels.
Participants by arm
| Arm | Count |
|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) Participants with GT1 Hepatitis who received 10 -mg elbasvir for 5 consecutive days during Part I of the study. | 5 |
| GT1 HCV 50-g Elbasvir (Panel B) Participants with GT1 HCV receive 50-mg elbasvir for 5 consecutive days during Part I of the study. | 5 |
| GT1 HCV 5-mg Elbasvir (Panel C) Participants with GT1 HCV receive 5-mg elbasvir for 5 consecutive days during Part I of the study. | 5 |
| GT3 HCV 10-mg Elbasvir (Panel E) Participants with GT3 HCV receive 10-mg elbasvir for 5 consecutive days during Part II of the study. | 5 |
| GT3 HCV 50-mg Elbasvir (Panel F) Participants with GT3 HCV receive 50-mg elbasvir for 5 consecutive days during Part II of the study. | 5 |
| GT3 HCV 100-mg Elbasvir (Panel G) Participants with GT3 HCV receive 100-mg elbasvir for 5 consecutive days during Part II of the study. | 5 |
| GT1a HCV 10-mg Elbasvir (Panel I) Participants with GT1a only HCV receive 10-mg elbasvir for 5 consecutive days during Part III of the study. | 5 |
| GT1a HCV 50-mg Elbasvir (Panel J) Participants with GT1a only HCV receive 50-mg elbasvir for 5 consecutive days during Part III of the study. | 5 |
| Placebo Participants with GT1, GT3 or GT1a HCV who received placebo in Parts I, II, or II of the study. | 8 |
| Total | 48 |
Baseline characteristics
| Characteristic | GT1 HCV 10-mg Elbasvir (Panel A) | GT1 HCV 50-g Elbasvir (Panel B) | GT1 HCV 5-mg Elbasvir (Panel C) | GT3 HCV 10-mg Elbasvir (Panel E) | GT3 HCV 50-mg Elbasvir (Panel F) | GT3 HCV 100-mg Elbasvir (Panel G) | GT1a HCV 10-mg Elbasvir (Panel I) | GT1a HCV 50-mg Elbasvir (Panel J) | Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 38.8 years STANDARD_DEVIATION 10.8 | 36.8 years STANDARD_DEVIATION 6.9 | 51.6 years STANDARD_DEVIATION 8.8 | 34.8 years STANDARD_DEVIATION 6.4 | 35.8 years STANDARD_DEVIATION 8.9 | 34.6 years STANDARD_DEVIATION 6.8 | 51.0 years STANDARD_DEVIATION 5 | 53.2 years STANDARD_DEVIATION 11.6 | 47.8 years STANDARD_DEVIATION 10.8 | 43.0 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 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 | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 8 Participants | 48 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 5 | 6 / 15 | 7 / 15 | 1 / 5 | 4 / 8 | 0 / 48 |
| serious Total, serious adverse events | 0 / 5 | 0 / 15 | 0 / 15 | 0 / 5 | 0 / 8 | 0 / 48 |
Outcome results
Primary
Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1
HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded.
Time frame: Up to 5 days
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel. Panel D was not conducted.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1 | 4.44 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1 | 5.21 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1 | 4.15 IU/mL |
| Placebo | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1 | 0.54 IU/mL |
90% CI: [3.2, 4.58]
90% CI: [3.98, 5.36]
90% CI: [2.92, 4.3]
Primary
Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1a
HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded.
Time frame: Up to 5 days
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1a | 3.72 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1a | 4.17 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT1a | 0.54 IU/mL |
90% CI: [2.55, 3.8]
90% CI: [3, 4.26]
Primary
Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3
HCV RNA levels were assessed at baseline (predose Day 1) and 24 hours postdose on Days 1-5. using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. The change in log10 LS mean HCV RNA levels was calculated for each timepoint and the maximum change from baseline was recorded.
Time frame: Up to 5 days
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel. Panel H was not conducted.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3 | 1.27 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3 | 3.12 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3 | 3.38 IU/mL |
| Placebo | Mean Maximum Reduction in Log10 HCV Viral Load - HCV GT3 | 0.54 IU/mL |
90% CI: [-0.09, 1.54]
90% CI: [1.75, 3.39]
90% CI: [2.02, 3.66]
Primary
Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT1a
HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction.
Time frame: Baseline (Predose on Day 1) and 24-hour post-dose on Day 5
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT1a | 3.20 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT1a | 3.95 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT1a | 0.00 IU/mL |
90% CI: [2.68, 3.72]
90% CI: [3.44, 4.47]
Primary
Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3
HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction
Time frame: Baseline (Predose on Day 1) and 24-hour post-dose on Day 5
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel. Panel H was not conducted.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3 | 1.01 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3 | 2.06 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3 | 2.72 IU/mL |
| Placebo | Mean Reduction From Baseline in Log10 Plasma HCV RNA at Day 5 - HCV GT3 | 0.00 IU/mL |
90% CI: [0.34, 1.69]
90% CI: [1.39, 2.74]
90% CI: [2.05, 3.39]
Primary
Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1
HCV RNA levels were assessed at baseline (predose on Day 1) and 24 hours postdose on Day 5 using the Roche TaqMan HCV 2.0 assay and transformed to Log10 values. The lower limits of quantification (LLOQ) and detection (LLD) were 25 and 9.3 IU/mL, respectively. Least squares means and confidence intervals obtained from the linear mixed model with log10 HCV RNA reduction as response and a fixed effect for treatment, time and treatment by time interaction.
Time frame: Baseline (Predose on Day 1) and 24-hour post-dose on Day 5
Population: All participants who complied with the protocol sufficiently to ensure that data would likely exhibit the effects of treatment, according to the underlying scientific model and had available data from at least 1 treatment. Data for placebo were grouped together regardless of genotype or randomly assigned panel. Panel D was not conducted.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1 | 4.25 IU/mL |
| GT1 HCV 50-g Elbasvir (Panel B) | Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1 | 4.40 IU/mL |
| GT1 HCV 5-mg Elbasvir (Panel C) | Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1 | 3.56 IU/mL |
| Placebo | Mean Reduction From Baseline in Log10 Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) at Day 5 - HCV GT1 | 0.00 IU/mL |
90% CI: [3.77, 4.74]
90% CI: [3.92, 4.9]
90% CI: [3.08, 4.05]
Primary
Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE.
Time frame: Up to 5 days
Population: All participants who received at least 1 dose of study drug. Events reported by drug taken at time of event and not by panel or genotype
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | 4 Participants |
| GT1 HCV 50-g Elbasvir (Panel B) | Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | 6 Participants |
| GT1 HCV 5-mg Elbasvir (Panel C) | Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | 7 Participants |
| Placebo | Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | 1 Participants |
| Placebo | Number of Participants Experiencing an Adverse Event (AE) - Day 1 to Day 5 | 4 Participants |
Primary
Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. Participants who had study drug discontinued due to an AE were recorded.
Time frame: Up to 5 days
Population: All participants who received at least 1 dose of study drug. Event summarized by drug taken at time of event and not by panel or genotype
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GT1 HCV 10-mg Elbasvir (Panel A) | Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | 0 Participants |
| GT1 HCV 50-g Elbasvir (Panel B) | Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | 0 Participants |
| GT1 HCV 5-mg Elbasvir (Panel C) | Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | 0 Participants |
| Placebo | Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | 0 Participants |
| Placebo | Number of Participants Who Had Study Drug Discontinued Due to an Adverse Event | 0 Participants |