Trial Outcomes & Findings for An Open-Label Study Investigating MK-8931 in Participants With Mild and Moderate Hepatic Insufficiency (MK-8931-016) (NCT NCT02910739)

Results Overview

Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-∞, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) extrapolated to infinity after a single oral dose of MK-8931 40 mg. Individual AUC0-∞ values were natural log (ln) transformed and evaluated with an analysis of covariance (ANCOVA) model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-∞ in each arm.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

16 participants

Primary outcome timeframe

Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Results posted on

2018-10-01

Participant Flow

Per protocol, this study was divided into Part I and an optional Part II, with Part II initiating only after interim analysis (IA) of Part I. Following Part I IA, the pharmacokinetic (PK) criterion necessary to initiate enrollment for Part II was not met. As a result, the study was completed normally without enrollment into the optional Part II.

Participant milestones

Participant milestones
Measure	Part I: MK-8931 40 mg in Moderate HI Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate Hepatic Insufficiency (HI) in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Overall Study STARTED	8	8
Overall Study COMPLETED	7	8
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Part I: MK-8931 40 mg in Moderate HI Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate Hepatic Insufficiency (HI) in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)	Part II: MK-8931 40 mg in Mild HI Participants Single oral dose of MK-8931 (40 mg tablet) in participants with mild HI in fasted state (Part II)	Part II: MK-8931 40 mg in Healthy Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part II)
Overall Study Adverse Event	1	0	0	0

Baseline Characteristics

An Open-Label Study Investigating MK-8931 in Participants With Mild and Moderate Hepatic Insufficiency (MK-8931-016)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)	Total n=16 Participants Total of all reporting groups
Age, Continuous	61.0 years STANDARD_DEVIATION 6.1 • n=93 Participants	61.4 years STANDARD_DEVIATION 4.8 • n=4 Participants	61.2 years STANDARD_DEVIATION 5.3 • n=27 Participants
Sex: Female, Male Female	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Sex: Female, Male Male	7 Participants n=93 Participants	7 Participants n=4 Participants	14 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) White	7 Participants n=93 Participants	7 Participants n=4 Participants	14 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Body Mass Index (BMI)	29.688 kg/m^2 n=93 Participants	30.313 kg/m^2 n=4 Participants	30.000 kg/m^2 n=27 Participants

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-∞. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.

Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-∞, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) extrapolated to infinity after a single oral dose of MK-8931 40 mg. Individual AUC0-∞ values were natural log (ln) transformed and evaluated with an analysis of covariance (ANCOVA) model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-∞ in each arm.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=7 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to Infinity (AUC0-∞)	3.48 micromolar(µM)*hour(hr) Interval 2.85 to 4.25	3.34 micromolar(µM)*hour(hr) Interval 2.77 to 4.03

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Cmax.

Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Cmax, defined as the maximum plasma concentration of MK-8931 observed following oral dosing. Individual Cmax values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for Cmax in each arm.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Maximum Observed Plasma Concentration of MK-8931 (Cmax)	154 nanomolar (nM) Interval 116.0 to 206.0	144 nanomolar (nM) Interval 108.0 to 192.0

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-last. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.

Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-last, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) to the time of the last sample with quantifiable MK-8931 (above the lower limit of quantification; LLOQ) after a single oral dose of MK-8931 40 mg. Individual AUC0-last values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-last in each arm.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=7 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to the Time of the Last Quantifiable (Above LLOQ) Sample (AUC0-last)	3.35 µM*hr Interval 2.72 to 4.11	3.22 µM*hr Interval 2.66 to 3.91

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of AUC0-24hr.

Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine AUC0-24hr, defined as the area under the MK-8931 concentration versus time curve from 0 (predose) until 24 hours after single oral dosing of MK-8931 40 mg. Individual AUC0-24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for AUC0-24hr in each arm.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Area Under the Concentration Versus Time Curve of MK-8931 From 0 to 24 Hours (AUC0-24hr)	1.90 µM*hr Interval 1.56 to 2.32	1.88 µM*hr Interval 1.54 to 2.3

PRIMARY outcome

Timeframe: 24 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of C24hr.

Blood samples were collected 24 hours following oral dosing of MK-8931 and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified to determine C24hr, defined as the plasma concentration of MK-8931 at 24 hours after single oral dosing of MK-8931 40 mg. Individual C24hr values were ln-transformed and evaluated with an ANCOVA model containing a categorical factor for participant group (Moderate HI, Healthy Matched Control) and continuous covariates for age and BMI. This ANCOVA model was used to compute a geometric least-squares mean and 95% confidence interval for C24hr in each arm.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Plasma Concentration of MK-8931 at 24 Hours (C24hr)	51.1 nM Interval 43.6 to 59.8	47.1 nM Interval 40.2 to 55.2

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of CL/F. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.

Geometric mean apparent clearance of MK-8931 after extravascular administration (CL/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine CL/F, defined as the rate of MK-8931 elimination normalized to the bioavailability of MK-8931 in the plasma following oral MK-8931 administration.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=7 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Apparent Clearance of MK-8931 After Extravascular Administration (CL/F)	28.4 Liters/hr Geometric Coefficient of Variation 26.3	29.0 Liters/hr Geometric Coefficient of Variation 22.7

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Tmax.

Median time to maximum observed MK-8931 plasma drug concentration (Tmax) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Tmax, defined as the amount of time required following MK-8931 administration for the plasma concentration of MK-8931 to reach maximum observed concentration.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Time to Maximum Observed MK-8931 Plasma Drug Concentration (Tmax)	1.00 hr Interval 0.5 to 4.0	2.00 hr Interval 0.5 to 4.0

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of t1/2. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.

Geometric mean apparent terminal half-life (t1/2) of MK-8931 was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine t1/2, defined as the time required for the plasma MK-8931 concentration to decrease to 50% of maximum.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=7 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Apparent Terminal Half-Life of MK-8931 (t1/2)	23.0 hr Geometric Coefficient of Variation 15.7	24.7 hr Geometric Coefficient of Variation 9.3

PRIMARY outcome

Timeframe: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after MK-8931 40 mg dose

Population: All participants who received the single dose of MK-8931 40 mg, complied with trial protocol, and had blood samples available for the evaluation of Vz/F. One participant with moderate HI discontinued study prior to collection of samples at 72, 96, and 120 hours post-dose and was excluded from analysis.

Geometric mean apparent volume of distribution of MK-8931 during the terminal phase after extravascular administration (Vz/F) was assessed. Blood samples were collected at each pre-specified time point and plasma was isolated for analysis. Plasma MK-8931 concentration was then quantified at each time point to determine Vz/F, defined as the total amount of MK-8931 administered normalized to the bioavailability of MK-8931 in the plasma during the terminal phase following oral MK-8931 administration.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=7 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Apparent Volume of Distribution of MK-8931 During the Terminal Phase After Extravascular Administration (Vz/F)	940 Liters Geometric Coefficient of Variation 27.3	1030 Liters Geometric Coefficient of Variation 26.1

SECONDARY outcome

Timeframe: Up to 14 days following MK-8931 40 mg administration.

Population: All participants as treated, consisting of all participants receiving the single dose of MK-8931 40 mg.

The number of participants experiencing an adverse event (AE) was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Number of Participants Experiencing an Adverse Event	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 14 days following MK-8931 40 mg administration.

Population: All participants as treated, consisting of all participants receiving the single dose of MK-8931 40 mg.

The number of participants discontinuing study due to an AE was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

Outcome measures

Outcome measures
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 Participants Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Number of Participants Discontinuing Study Due to an Adverse Event	1 Participants	0 Participants

Adverse Events

Part I: MK-8931 40 mg in Moderate HI Participants

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Part I: MK-8931 40 mg in Healthy Participants

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Part I: MK-8931 40 mg in Moderate HI Participants n=8 participants at risk Single oral dose of MK-8931 (40 mg tablet) in participants with moderate HI in fasted state (Part I)	Part I: MK-8931 40 mg in Healthy Participants n=8 participants at risk Single oral dose of MK-8931 (40 mg tablet) in healthy matched participants in fasted state (Part I)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	12.5% 1/8 • Number of events 1 • Up to 14 days following MK-8931 40 mg administration.	0.00% 0/8 • Up to 14 days following MK-8931 40 mg administration.

Other adverse events

Adverse event data not reported

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
Publication restrictions are in place

Restriction type: OTHER