Clinical trial NCT01033643: A Multiple Dose Study of MK-3614 (MK-3614-002)
Official title: A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-3614
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hypertension
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2009-12-16
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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
* Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 4 weeks of study
* Has a history of significant multiple and/or severe allergies (including latex) to prescription or non-prescription drugs or food
* Is currently a regular user of any illicit drugs or has a history of drug abuse within approximately 1 year

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 27 days
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 13 days
measure: Panel A: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 hours postdose
measure: Panel D: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614
timeFrame: Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8 & 12 hours postdose
measure: Panel D: Area Under the Concentration Time-Curve From 0 to Infinity (AUC 0-inf) of MK-3614
timeFrame: Day 1: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, & 24 hours postdose
measure: Panels B, C: Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC 0-24hrs) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
measure: Panel A: Maximum Concentration (Cmax) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 hours postdose
measure: Panel D: Maximum Concentration (Cmax) of MK-3614
timeFrame: Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, & 12 hours postdose
measure: Panels B, C: Maximum Concentration (Cmax) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
measure: Panel A: Time to Maximum Concentration (Tmax) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8, & 12 hours postdose
measure: Panel D: Time to Maximum Concentration (Tmax) of MK-3614
timeFrame: Days 4, 13: Predose and 0.5, 1, 2, 3 ,4, 5, 6, 8 & 12 hours postdose
measure: Panels B, C: Time to Maximum Concentration (Tmax) of MK-3614
timeFrame: Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose
measure: Panels A, B & C: Apparent Terminal Half-Life (t1/2) of MK-3614
timeFrame: Day 10: Predose and 1, 2, 4, 6, 8, 12, 16, 24, 36, & 48 hours postdose
measure: Panel D: Apparent Terminal Half-Life (t1/2) of MK-3614
timeFrame: Day 13: Predose and 0.5 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, & 48 hours postdose
measure: Change From Baseline in Aortic Augmentation Index (AIx) at 24 Hours Postdose After Multiple Doses of MK-3614 or Placebo
timeFrame: 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
measure: Time-weighted Average Across 12 Hours (TWA 0-12hrs) for Heart Rate (HR) After Administration of MK-3614 or Placebo
timeFrame: 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
Secondary outcomes:
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Cyclic Guanosine Monophosphate (cGMP) Concentration Levels After Multiple Doses of MK-3614
timeFrame: 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
Other outcomes:
measure: Panel D: Area Under the Concentration Time-Curve From Hour 0 to 24 Hours (AUC 0-24hrs) of MK-3614
timeFrame: Day 1: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, & 24 hours postdose
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Monitor
role: STUDY_DIRECTOR
References: