A Multiple Dose Study of MK-3614 (MK-3614-002)

An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study intervention, 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 study intervention, was also an adverse event. The number of participants who experienced an AE was reported.

An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study intervention, 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 study intervention, was also an adverse event. The number of participants who discontinued study treatment due to an AE was reported.

Blood samples were collected at pre-specified timepoints on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the AUC 0-12hrs of MK-3614 in Panel A participants per protocol. AUC 0-12hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 12 hours postdose.

Blood samples were collected at pre-specified timepoints to determine the AUC 0-12hrs on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) to determine the AUC 0-12hrs of MK-3614 in Panel D participants per protocol. AUC 0-12hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 12 hours postdose.

Blood samples were collected at pre-specified timepoints to determine the AUC 0-inf of MK-3614 in Panel D participants who received single daily dosing on Day 1. AUC 0-inf was defined as the area under the concentration-time curve of MK-3614 from time zero to infinity. Geometric mean and 95%CI were not reported because the single day dosing of MK-3614 was only administered on Day 1 for Panel D participants. Instead, AUC 0-24 hours was reported for Panel D participants on Day 1 which is included in the 'other pre-specified outcomes'.

Blood samples were collected at pre-specified timepoints to determine the AUC 0-24hrs on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the AUC 0-24hrs of MK-3614 in Panel B & C participants per protocol. AUC0-24hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 24 hours postdose.

Blood samples were collected predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing (Day 10) for the determination of Cmax in Panel A participants. Cmax was defined as the maximum concentration of MK-3614 reached over 12 hours.

Blood samples were collected at predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) for the determination of Cmax in Panel D participants. Cmax was defined as the maximum concentration of MK-3614 reached over 12 hours after administration of multiple doses of MK-3614.

Blood samples were collected at predose and up to 24 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) for the determination of Cmax in Panel B & C participants. Cmax was defined as the maximum concentration of MK-3614 reached over 24 hours.

Blood samples were collected at predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the Tmax in Panel A participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 12 hours.

Blood samples were collected at predose and up to 12 hours on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) to determine the Tmax in Panel D participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 12 hours among participants in Panel D.

Blood samples were collected at predose and up to 24 hours on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the Tmax in Panel B & C participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 24 hours.

Blood samples were collected at pre-specified time points on Day 10 to determine t½ in Panels A, B, & C participants who received multiple doses of MK-3614. Apparent t½ was defined as the time required to eliminate half the amount of MK-3614 from plasma concentration.

Blood samples were collected at pre-specified time points on Day 13 to determine t½ in Panel D participants who received multiple doses of MK-3614. Apparent t½ was defined as the time required to eliminate half the amount of MK-3614 from plasma concentration.

Aortic AIx is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. Aortic AIx was measured at pre-specified timepoints by aplanation tonometry of radial artery. Linear model containing panel as a fixed effect was used to report the change from baseline in aortic Aix at 24 hours postdose. The 90% confidence intervals (CIs) for the true mean difference (MK-3614-placebo) in change from baseline were obtained using the mean square error from the linear model. Placebo data was pooled across all panels for the analysis. A decrease in the point estimate of ≥ 5 percentage points was considered clinically meaningful.

HR was measured with a validated automatic device. TWA 0-12hrs equals all HR values over 12-hr observation period multiplied by length of time participant spent at each HR value by that HR value; added products together,& divided by observation period duration. Linear mixed effects model with panel, day, panel by day interaction as fixed effects & participant-within-panel as random effect was used to generate TWA 0-12hrs on 1st day of single dosing (Panel D: Day 1) or 1st day of multiple dosing of MK-3614/placebo (Panels A,B,C: Day 1; Panel D: Day 4) and last day of multiple dosing of MK-3614/placebo (Panels A,B,C: Day 10; Panel D: Day 13) & 90% CIs for true TWA using appropriate components of variance. Pooled placebo data at Day 1 indicates first day of single dosing (Panel D: Day 1) & first day of multiple dosing of placebo (Panels A,B,C: Day 1; Panel D: Day 4) & at Day 10 indicates last day of multiple dosing of placebo from all panels (Panels A,B,C: Day 10; Panel D: Day 13).

Peripheral SBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral SBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on first day of multiple dosing (Panels A, B, C: Day 1; Panel D: Day 4) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Peripheral SBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral SBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Peripheral SBP was measured by the SphygmoCor® device. TWA 0-24hrs was obtained as follows: For all peripheral SBP values obtained over the 24-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 24 hour postdose on last day of multiple dosing (Panels A, B & C - Day 10; Panel D - Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Peripheral DBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral DBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on first day of multiple dosing (Panels A, B, C: Day 1; Panel D: Day 4) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Peripheral DBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral DBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Peripheral DBP was measured by the SphygmoCor® device. TWA 0-24hrs was obtained as follows: For all peripheral DBP values obtained over the 24-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo.

Blood was drawn at baseline (0 hours) and 5 hours postdose on last day (Panels B, C: Day 10; Panel D: Day 13 per protocol) to assess bleeding time using a Newborn Surgicutt device. Linear model containing panel as a fixed effect was used to generate fold change from baseline and associated 90% CIs. Placebo data was pooled across panels B, C and D for the analysis.

Whole Blood was drawn at predose (baseline) and at 4, 24 hours postdose on last day of multiple dosing of MK-3614 (Panels A, B & C: Day 10; Panel D: Day 13) to measure cGMP concentration levels. Linear mixed effects model containing panel, time, and panel by time interaction as fixed effects and participant within panel as a random effect was used to generate geometric mean and associated 90% CIs. Placebo data was pooled across all panels for the analysis.

Blood samples were collected at pre-specified timepoints to determine the AUC 0-24hrs of MK-3614 in Panel D participants who received single daily dosing on Day 1. AUC 0-24hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 24 hours. AUC 0-24hrs was reported instead of AUC 0-inf since Panel D participants received single daily dosing only on Day 1.