A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-3614
Overview
- Phase
- Phase 1
- Intervention
- MK-3614
- Conditions
- Hypertension
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 30
- Primary Endpoint
- Number of Participants Who Experienced an Adverse Event (AE)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of MK-3614 in male participants with mild to moderate hypertension. The primary hypotheses are: 1) Multiple oral doses of MK-3614 are sufficiently safe and well tolerated to permit continued clinical investigation 2) Aortic Augmentation Index (Aix) is reduced 24 hours post the last dose of MK-3614 administered compared to placebo and 3) Increase in the 12-hour weighted averages (TWA 0-12hours) of the heart rate is within 15 beats per minute (bpm) of baseline on first day of multiple dosing of MK-3614 and within 10 bpm of baseline on last day of multiple dosing of MK-3614.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Has mild to moderate hypertension
- •Has grade 1 or 2 arterial hypertension being treated with a single antihypertensive drug
- •Has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months; or who have discontinued smoking or the use of nicotine/nicotine-containing products for at least approximately 3 months
- •Is in generally good health
Exclusion Criteria
- •Has a history of clinically significant abnormalities or diseases
- •Has a history of stroke, chronic seizures, or major neurological disorder
- •Has a functional disability that can interfere with rising from a sitting position to the standing position
- •Has any personal or family history of a bleeding or a clotting disorder
- •Has a history of frequent nose bleeds or has recurrent or active gingivitis
- •Has a history of cancer
- •Has a history of clinically significant cardiac disease
- •Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies approximately 2 weeks prior to the administration of study drug
- •Consumes excessive amounts of alcohol
- •Consumes excessive amounts of caffeinated beverages per day
Arms & Interventions
MK-3614 0.25 mg (Panel A)
Participants received 0.25 mg of MK-3614 twice daily (BID) every 12 hours orally for 10 days.
Intervention: MK-3614
MK-3614 0.50/0.25 mg (Panel B)
Participants received 0.50 mg of MK-3614 in the morning (AM) and 0.25 mg of MK-3614 in the evening (PM) 12 hours apart orally for 10 days.
Intervention: MK-3614
MK-3614 0.50/0.25 mg (Panel C Repeat)
Participants were to receive 0.75 mg of MK-3614 BID every 12 hours orally for 10 Days. Per protocol amendment, the Panel B dose was repeated, and participants received instead 0.50 mg of MK-3614 in the AM, and 0.25 mg of MK-3614 in the PM, 12 hours apart orally for 10 days.
Intervention: MK-3614
MK-3614 0.50 mg (Panel D)
Participants received 0.50 mg of MK-3614 three times a day (TID) orally every 8 hours on Day 1 followed by a wash out period for Days 2, 3 and 0.50 mg of MK-3614 every 12 hours orally for 10 days (Days 4-13).
Intervention: MK-3614
MK-3614 0.50 mg (Panel E)
Participants were to receive orally 0.50 mg of MK-3614 BID every 12 hours on Day 1 followed by 3 doses (0.50/0.50/0.25 mg) of MK-3614 each 8 hours apart on Day 2; three doses of 0.50 mg of MK-3614 8 hours apart on Days 3,4; and 0.75 mg of MK-3614 BID every 12 hours on Days 5-14. No participants were enrolled in this group.
Intervention: MK-3614
Placebo (All Panels)
Participants received a dose matched placebo orally according to randomization.
Intervention: Placebo for MK-3614
Outcomes
Primary Outcomes
Number of Participants Who Experienced an Adverse Event (AE)
Time Frame: Up to approximately 27 days
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.
Number of Participants Who Discontinued Study Treatment Due to an AE
Time Frame: Up to approximately 13 days
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.
Panel D: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614
Time Frame: Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8 & 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.
Panel A: Maximum Concentration (Cmax) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 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.
Panels A, B & C: Apparent Terminal Half-Life (t1/2) of MK-3614
Time Frame: Day 10: Predose and 1, 2, 4, 6, 8, 12, 16, 24, 36, & 48 hours postdose
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.
Panel D: Area Under the Concentration Time-Curve From 0 to Infinity (AUC 0-inf) of MK-3614
Time Frame: Day 1: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, & 24 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'.
Panels B, C: Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC 0-24hrs) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
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.
Panels B, C: Maximum Concentration (Cmax) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
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.
Panel A: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 hours postdose
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.
Panel D: Maximum Concentration (Cmax) of MK-3614
Time Frame: Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, & 12 hours postdose
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.
Panel D: Apparent Terminal Half-Life (t1/2) of MK-3614
Time Frame: Day 13: Predose and 0.5 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, & 48 hours postdose
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.
Panel A: Time to Maximum Concentration (Tmax) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8, & 12 hours postdose
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.
Panel D: Time to Maximum Concentration (Tmax) of MK-3614
Time Frame: Days 4, 13: Predose and 0.5, 1, 2, 3 ,4, 5, 6, 8 & 12 hours postdose
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.
Panels B, C: Time to Maximum Concentration (Tmax) of MK-3614
Time Frame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
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.
Change From Baseline in Aortic Augmentation Index (AIx) at 24 Hours Postdose After Multiple Doses of MK-3614 or Placebo
Time Frame: Panels A, B & C: Day 10: Baseline & 24 hours postdose; Panel D: Day 13: Baseline & 24 hours postdose; Placebo: Day 10 or Day 13: Baseline & 24 hours postdose
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.
Time-weighted Average Across 12 Hours (TWA 0-12hrs) for Heart Rate (HR) After Administration of MK-3614 or Placebo
Time Frame: Panels A, B, C: Days 1, 10: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose; Panel D: Days 1, 4, 13: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose; Placebo: Days 1 & 10 or 1, 4, 13: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose
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).
Secondary Outcomes
- Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Systolic Blood Pressure (SBP) on First Day of Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 4: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours postdose)
- Change From Baseline in Time-Weighted Average Across 24 Hours (TWA 0-24hrs) of Peripheral Systolic Blood Pressure (SBP) on Last Day of Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 10: Baseline (0 hours) & up to 24 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 24 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 24 hours postdose)
- Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Diastolic Blood Pressure (DBP) on First Day of Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 4: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours postdose)
- Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Systolic Blood Pressure (SBP) on Last Day After Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours; Panel D: Day 4: Baseline (0 hours) & up to 12 hours; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours)
- Change From Baseline in Time-Weighted Average Across 24 Hours (TWA 0-24hrs) of Peripheral Diastolic Blood Pressure (DBP) on Last Day of Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 10: Baseline (0 hours) & up to 24 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 24 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 24 hours postdose)
- Panels B, C, & D: Change From Baseline in Bleeding Time (BT) at 5 Hours Postdose on Last Day After Multiple Doses of MK-3614 or Placebo(Panels B, C: Day 10: Baseline (0 hours) & 5 hours postdose; Panel D: Day 13: Baseline (0 hours) & 5 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & 5 hours postdose)
- Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Diastolic Blood Pressure (DBP) on Last Day of Multiple Dosing of MK-3614 or Placebo(Panels A, B, C: Day 10: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 12 hours postdose)
- Cyclic Guanosine Monophosphate (cGMP) Concentration Levels After Multiple Doses of MK-3614(Panels A, B & C: Day 10: Predose & 4, 24 hours postdose; Panel D: Day 13: Predose & 4, 24 hours postdose; Placebo: Day 10 or Day 13: Predose & 4, 24 hours postdose)