A Study of Single Dose MK-3614 (MK-3614-001)(COMPLETED)

Phase 1

Completed

• Conditions: Hypertension
• Interventions: Drug: MK-3614

• Registration Number: NCT01104545
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This study will determine if MK-3614, given as single doses, is safe and well tolerated in healthy males and male participants with mild to moderate hypertension.

Detailed Description

Up to three planned panels of either 8 healthy participants (Panels A and B) or 8 participants with mild to moderate hypertension (Panel C) will be enrolled. In Panels A and B, 8 participants will alternately receive single rising doses of MK-3614 or placebo. All doses will be administered in the fasted state, except Panel A, Period 3 in which a standard high-fat breakfast provided approximately 30 minutes prior to dosing. Panel A will begin first. At least 3 days will elapse before participants in the alternate panel (Panel B) will receive the next higher dose. In Panel C, 8 mild to moderate hypertensive male participants will receive single rising doses of MK-8892 or placebo. For all panels, there will be at least 7 days washout between treatment periods for any given participant. Participants may only be enrolled in one panel of the study. All participants in periods of all panels (with exception of 0.25 mg fasted/fed periods) will be randomly assigned to either study drug or placebo, i.e., a participant could be assigned to receive study drug in one period and placebo in another. As per the protocol allocation plan, the same participants will receive 0.25 mg MK-3612 in a fasted and fed state.

Study Timeline

• Study Start: 2008-11-01
• Primary Completion: 2009-05-01
• Study Completion: 2009-05-01
• Study First Submitted: 2010-04-13
• Study First Submitted QC: 2010-04-13
• Study First Posted: 2010-04-15
• Results First Submitted: 2018-09-13
• Status Verified: 2019-06
• Results First Submitted QC: 2019-06-24
• Last Update Submitted: 2019-06-24
• Results First Posted: 2019-08-08
• Last Update Posted: 2019-08-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 24

Inclusion Criteria

• Healthy participants between 18 to 45 years of age; otherwise healthy participants between 18 to 55 years of age newly diagnosed with grade 1 or 2 hypertension
• Participant is in good general health
• Participant is a nonsmoker

Exclusion Criteria

• Participant has a history of stroke, seizure or major neurological disease
• Participant has functional disability that can interfere with rising from a sitting position to a standing position
• Participant has a family history of a bleeding or clotting disorder
• Participant has a history of cancer
• Participant is unable to refrain from or anticipates the use of any prescription or non-prescription medication during the study
• Participant consumes excessive amounts of alcohol or caffeine
• Participant has had major surgery, donated blood or participated in another investigational study in the past 4 weeks.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Panel A - Healthy	MK-3614	Healthy participants receive single oral dose of MK-3614 0.25 mg, 1.25 mg, 0.25 mg w/ food, 0.75 mg or matching placebo. There is at least a 7-day washout between the 4 dosing periods. All doses were administered after an 8-hour fast except for Period 3. Period 3 dose was administered after the ingestion of a high-fat breakfast.
Panel B - Healthy	MK-3614	Healthy participants receive single oral dose of MK-3614 0.5 mg. 0.75 mg, 0.25 mg twice a day (b.i.d.), 0.25 mg three times a day (t.i.d), or matching placebo. There is at least a 7-day washout between the 4 dosing periods. All doses were administered after an 8-hour fast
Panel C - Hypertensive	MK-3614	Hypertensive participants receive single oral dose of MK-3614 0.75 mg. 0.5 mg. 0.75 mg, 0.75 mg or matching placebo. There is at least a 7-day washout between the 4 dosing period. All doses were administered after an 8-hour fast

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Were Discontinued From the Study Due to an AE - Healthy Participants	up to 7 days for each dose level	An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants who were discontinued from the study due to an AE were summarized. AEs are reported by the dose taken at the time of the event.
Maximum Concentration (Cmax) of MK-3614- Hypertensive Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the Cmax of MK-3614 in hypertensive participants
Time to Cmax (Tmax) of MK-3614- Healthy Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the Tmax of MK-3614 in healthy participants.
Apparent Terminal Half-life (t1/2) of MK-3614 of MK-3614- Hypertensive Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the t1/2 of MK-3614 in hypertensive participants
Change From Baseline in Brachial Arterial Systolic Blood Pressure - Healthy Participants	Baseline and 24 hours postdose for each dose level	Brachial arterial systolic blood pressure measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of panel.
Change From Baseline in Brachial Arterial Diastolic Blood Pressure - Healthy Participants	Baseline and 24 hours postdose for each dose level	Brachial arterial diastolic blood pressure measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of panel.
Percentage of Participants Who Report 1 or More Adverse Event (AE) - Hypertensive Participants	up to 7 days for each dose level	An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. The percentage of participants that reported at least 1 AE was summarized. AEs are reported by the dose taken at the time of the event.
Maximum Concentration (Cmax) of MK-3614- Healthy Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the Cmax of MK-3614 in healthy participants.
Apparent Terminal Half-life (t1/2) of MK-3614- Healthy Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the t1/2 of MK-3614 in healthy participants.
Time to Cmax (Tmax) of MK-3614- Hypertensive Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the Tmax of MK-3614 in hypertensive participants
Percentage of Participants Who Reported 1 or More Adverse Event (AE) - Healthy Participants	up to 7 days for each dose level	An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. AEs are reported by the dose taken at the time of the event.
Percentage of Participants Who Were Discontinued From the Study Due to an AE - Hypertensive Participants	up to 7 days for each dose level	An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants who were discontinued from the study due to an AE were summarized. AEs are reported by the dose taken at the time of the event.
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-3614 - Healthy Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the AUC0-inf of MK-3614 in healthy participants.
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-3614 - Hypertensive Participants	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the AUC0-inf of MK-3614 in hypertensive participants
Change From Baseline in Heart Rate - Healthy Participants	Baseline and 24 hours post-dose for each dose level	Heart rate measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of panel.
Change From Baseline in Brachial Arterial Systolic Blood Pressure - Hypertensive Participants	Baseline and 24 hours postdose for each dose level	Brachial arterial systolic blood pressure measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of sequence.
Change From Baseline in Heart Rate - Hypertensive Participants	Baseline and 24 hours postdose for each dose level	HR measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of sequence.
Change From Baseline in Brachial Arterial Diastolic Blood Pressure - Hypertensive Participants	Baseline and 24 hours postdose for each dose level	Brachial arterial diastolic blood pressure measurements were obtained using a validated, semi-automated oscillometric device. The difference between the predose (baseline) measurement and the measurement 24 obtained 24 hours postdose was summarized. Data for each specific dose were combined regardless of sequnce.

Secondary Outcome Measures

Name	Time	Method
Percentage Change From Baseline in Augmentation Index (AIx) at 24 Hours Postdose - Healthy Participants	Baseline and 24 hours postdose for each dose level	Augmentation index was measured at predose (baseline), and 1, 4, 8, 12, and 24 hours postdose by aplanation tonometry of radial artery. The change from baseline at 24 hours postdose was summarized. Data for each specific dose were combined regardless of panel.
Percentage Change in Cyclic Guanosine Monophosphate (GMP) From Baseline at 24 Hours Postdose - Hypertension Participants	Baseline and 24 hours postdose for each dose level	Blood was drawn at predose (baseline) and 1, 4, 8, and 24 hours postdose. The change in cyclic GMP at 24 hours postdose was summarized. Due to change in number of blood draws and total blood volume restrictions, data for GMP were only collected for first 2 periods of each panel. Therefore only limited data were available and summarized.
Percentage Change From Baseline in Platelet Aggregation at 24 Hours Postdose - Healthy Participants	Baseline and 24 hours postdose for each dose level	Platelet aggregation induced by adenosine diphosphate (ADP) was measured at predose (baseline) and 3 and 24 hours postdose. Percent inhibition from baseline at 24 hours postdose was calculated. Due to change in number of blood draws and total blood volume restrictions, data for platelet aggregation were only collected for first 2 periods of each panel. Therefore only limited data were available and summarized. Data for each specific dose were combined regardless of panel.
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of 0.25 mg MK-3614 - Healthy Participants- Fasted Versus Fed	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the AUC0-inf of 0.25 mg MK-3614 in healthy participant when administered after an 8 hour fast and after a high-fat breakfest.
Maximum Concentration (Cmax) of 0.25 mg MK-3614 - Healthy Participants- Fasted Versus Fed	Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose for each dose level	Blood samples taken at Predose, and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose of each dosing period to determine the Cmax of 0.25 mg MK-3614 when administered after an 8 hour fast and after a high-fat breakfest.
Percentage Change From Baseline in Augmentation Index (AIx) at 24 Hours Postdose - Hypertensive Participants	Baseline and 24 hours postdose for each dose level	Augmentation index was measured at predose (baseline), and 1, 4, 8, 12, and 24 hours postdose by aplanation tonometry of radial artery. The change from baseline at 24 hours postdose was summarized.
Percentage Change in Cyclic Guanosine Monophosphate (GMP) From Baseline at 24 Hours Postdose - Healthy Participants	Baseline and 24 hours postdose for each dose level	Blood was drawn at predose (baseline) and 1, 4, 8, and 24 hours postdose. The change in cyclic GMP at 24 hours postdose was summarized. Due to change in number of blood draws and total blood volume restrictions, data for GMP were only collected for first 2 periods of each panel. Therefore only limited data were available and summarized. Data for each specific dose were combined regardless of panel.
Percentage Change From Baseline in Bleeding Time at 24 Hours Postdose - Healthy Participants	Baseline and 24 hours postdose for each dose level	Blood was to be drawn at predose (baseline) and 3 and 24 hours postdose and bleeding time was to be assessed using a Newborn Surgicutt device. Change in bleeding time from baseline at 24 hours postdose were to be summarized. Due to change in number of blood draws and total blood volume restrictions, bleeding time assessment was not performed as planned.
Percentage Change From Baseline in Bleeding Time at 24 Hours Postdose- Hypertension Participants	Baseline and 24 hours postdose for each dose level	Blood was to be drawn at predose (baseline) and 3 and 24 hours postdose and bleeding time was to be assessed using a Newborn Surgicutt device. Change in bleeding time from baseline at 24 hours postdose were to be summarized. Due to change in number of blood draws and total blood volume restrictions, bleeding time assessment was not performed as planned.
Percentage Change From Baseline in Platelet Aggregation at 24 Hours Postdose - Hypertensive Participants	Baseline and 24 hours postdose for each dose level	Platelet aggregation induced by adenosine diphosphate (ADP) was measured at predose (baseline) and 3 and 24 hours postdose. Percent inhibition from baseline at 24 hours postdose was calculated. Due to change in number of blood draws and total blood volume restrictions, data for platelet aggregation were only collected for first 2 periods of each panel. Therefore only limited data were available and summarized.