Safety, Pharmacokinetics and Pharmacodynamics of Elbasvir (MK-8742) in Hepatitis C Infected Males (MK-8742-002)

Study Overview
=================
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).

Official Title
-----------------
A Multiple Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of MK-8742 in Hepatitis C Infected Males

Conditions
-----------------
Hepatitis, Viral, Human

Intervention / Treatment
-----------------
* Drug: Elbasvir
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GT1 HCV 10-mg Elbasvir (Panel A)<br>Participants with GT1 HCV receive 10 -mg elbasvir or matching placebo for 5 consecutive days during Part I of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GTI HCV 50-g Elbasvir (Panel B)<br>Participants with GT1 HCV receive 50-mg elbasvir or matching placebo for 5 consecutive days during Part I of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT1 HCV 5-mg Elbavir (Panel C)<br>Participants with GT1 HCV receive 5-mg elbasvir or matching placebo for 5 consecutive days during Part I of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT1 HCV 200-mg Elbasvir (Panel D)<br>Participants with GT1 HCV receive 200-mg elbasvir or matching placebo for 5 consecutive days during Part I of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT3 HCV 10-mg Elbasvir (Panel E)<br>Participants with GT3 HCV receive 10-mg elbasvir or matching placebo for 5 consecutive days during Part II of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT3 HCV 50-mg Elbasvir (Panel F)<br>Participants with GT3 HCV receive 50-mg elbasvir or matching placebo for 5 consecutive days during Part II of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT3 HCV 100-mg Elbasvir (Panel G)<br>Participants with GT3 HCV receive 100-mg elbasvir or matching placebo for 5 consecutive days during Part II of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT3 HCV 200-mg Elbasvir (Panel H)<br>Participants with GT3 HCV receive 200-mg elbasvir or matching placebo for 5 consecutive days during Part II of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT1a HCV 10-mg Elbasvir (Panel I)<br>Participants with GT1a only HCV receive 10-mg elbasvir or matching placebo for 5 consecutive days during Part III of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|
| Experimental: GT1a HCV 50-mg Elbasvir (Panel J)<br>Participants with GT1a only HCV receive 50-mg elbasvir or matching placebo for 5 consecutive days during Part III of the study. | Drug: Elbasvir<br>* Elbasvir was administered orally by tablet(s)<br>Drug: Placebo<br>* Dose-matched placebo tablets were administered orally.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | 
| 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 | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | 
| 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. | Baseline (Predose on Day 1) and 24-hour post-dose on Day 5 | 
| 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. | Up to 5 days | 
| 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. | Up to 5 days | 
| 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. | Up to 5 days | 
| 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. | Up to 5 days | 
| 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. | Up to 5 days |