A Single Dose Study of MK-8266 (MK-8266-001)

Phase 1

Completed

• Conditions: Hypertension
• Interventions: Drug: MK-8266 0.1 mg; Drug: MK-8266 1.0 mg; Drug: Placebo

• Registration Number: NCT01025791
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

A three panel study, to determine if MK-8266 given as a single dose is sufficiently safe and well tolerated. Panel A and B will consist of healthy young males and Panel C will consist of subjects with mild to moderate hypertension. The primary hypotheses for the study are that MK-8266 given as single doses is sufficiently safe and well tolerated to permit continued clinical investigation in healthy young male volunteers and male participants with mild-to-moderate hypertension and that in males with mild to moderate hypertension, at a single oral dose of MK-8266 that is sufficiently safe and well-tolerated, postdose mean time-weighted average across 24 hours of aortic augmentation index (TWA0-12hrs AIx) is reduced compared to placebo. A mean decrease of ≥ 5 percentage points is considered clinically meaningful.

Detailed Description

Three panels, each consisting of either 8 or 9 participants (8 healthy young males in Panel A and Panel B; and 9 participants with mild to moderate hypertension in Panel C) will be randomized to receive either MK-8266 or matching placebo in either a 6:2 ratio (Panel A and Panel B) or 6:3 ratio (Panel C), respectively, in up to 5 treatment (1 to 5) periods in Panel A and up to 4 treatment (1 to 4) periods in Panel B and Panel C. In all panels, doses will be escalated in a rising, fixed sequence. Some participants took study drug after fasting and some with food.

Study Timeline

• Study Start: 2009-11-18
• Study First Submitted: 2009-12-03
• Study First Submitted QC: 2009-12-03
• Study First Posted: 2009-12-04
• Primary Completion: 2010-05-14
• Study Completion: 2010-05-14
• Results First Submitted: 2018-02-05
• Status Verified: 2018-10
• Results First Submitted QC: 2018-10-15
• Last Update Submitted: 2018-10-15
• Results First Posted: 2019-02-20
• Last Update Posted: 2019-02-20

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 25

Inclusion Criteria

• For Panel A and B Participant is a healthy male between 18 to 45 years of age. For Panel C Participant is a male with essential hypertension between 18 to 55 years of age
• A non-smoker

Exclusion Criteria

• Has a history of stroke, chronic seizure or major neurological disorder
• Has a disability that can interfere with rising from a sitting position to the standing position
• Has a personal of family history of bleeding or clotting disorders
• Has a history of cancer
• Is unable to refrain from or anticipates the use of any prescription or nonprescription drug during the study
• Consumes excessive amounts of caffeine or alcohol
• Has had major surgery, donated blood or participated in another investigational study in the past 4 weeks

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Panel A, Healthy Male Participants, Sequence 1	MK-8266 0.1 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: placebo/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 1	MK-8266 1.0 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: placebo/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 1	Placebo	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: placebo/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 2	MK-8266 0.1 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: placebo/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 2	MK-8266 1.0 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: placebo/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 2	Placebo	MK-8266 in Period 1: 0.1 mg/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: placebo/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 3	MK-8266 0.1 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: placebo/ Period 3: 0.5/ Period 4: 1.0 mg/ Period 5: placebo.
Panel A, Healthy Male Participants, Sequence 3	MK-8266 1.0 mg	MK-8266 in Period 1: 0.1 mg/ Period 2: placebo/ Period 3: 0.5/ Period 4: 1.0 mg/ Period 5: placebo.
Panel A, Healthy Male Participants, Sequence 3	Placebo	MK-8266 in Period 1: 0.1 mg/ Period 2: placebo/ Period 3: 0.5/ Period 4: 1.0 mg/ Period 5: placebo.
Panel A, Healthy Male Participants, Sequence 4	MK-8266 0.1 mg	MK-8266 in Period 1: placebo/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 4	MK-8266 1.0 mg	MK-8266 in Period 1: placebo/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel A, Healthy Male Participants, Sequence 4	Placebo	MK-8266 in Period 1: placebo/ Period 2: 0.2 mg/ Period 3: 0.5 mg/ Period 4: 1.0 mg/ Period 5: 1.0 mg dose followed in 6 hours by a 0.8 mg dose.
Panel B, Healthy Male Participants, Sequence 1	MK-8266 0.1 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: 1.2 mg/ Period 3: placebo/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 1	MK-8266 1.0 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: 1.2 mg/ Period 3: placebo/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 1	Placebo	MK-8266 in Period 1: 0.4 mg/ Period 2: 1.2 mg/ Period 3: placebo/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 2	MK-8266 0.1 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: placebo/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 2	MK-8266 1.0 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: placebo/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 2	Placebo	MK-8266 in Period 1: 0.4 mg/ Period 2: placebo/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 3	MK-8266 0.1 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: 1.2 mg/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 3	MK-8266 1.0 mg	MK-8266 in Period 1: 0.4 mg/ Period 2: 1.2 mg/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 0.4 mg fed/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 4	MK-8266 0.1 mg	MK-8266 in Period 1: placebo/ Period 2: 1.2 mg/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 4	MK-8266 1.0 mg	MK-8266 in Period 1: placebo/ Period 2: 1.2 mg/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na.
Panel B, Healthy Male Participants, Sequence 4	Placebo	MK-8266 in Period 1: placebo/ Period 2: 1.2 mg/ Period 3: 1.2 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na.
Panel C, Mild/Moderate Hypertension, Sequence 1	MK-8266 0.1 mg	Period 1: placebo/ Period 2 1.2 mg dose followed in 8 hours by a 1.0 mg dose/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 1	MK-8266 1.0 mg	Period 1: placebo/ Period 2 1.2 mg dose followed in 8 hours by a 1.0 mg dose/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 2	MK-8266 0.1 mg	Period 1: placebo/ Period 2 1.2 mg dose followed in 8 hours by a 1.0 mg dose/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 4	MK-8266 0.1 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 4	MK-8266 1.0 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 2	MK-8266 1.0 mg	Period 1: placebo/ Period 2 1.2 mg dose followed in 8 hours by a 1.0 mg dose/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 2	Placebo	Period 1: placebo/ Period 2 1.2 mg dose followed in 8 hours by a 1.0 mg dose/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 3	MK-8266 0.1 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2 placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 3	MK-8266 1.0 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2 placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 3	Placebo	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2 placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 4	Placebo	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: placebo/ Period 3: 1.0 mg dose followed in 6 hours by a 0.6 mg dose followed in 6 hours by a 0.6 mg dose/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 5	MK-8266 0.1 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: 1.2 mg dose followed in 8 hours by a 1.0 mg dose// Period 3: placebo/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 5	MK-8266 1.0 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: 1.2 mg dose followed in 8 hours by a 1.0 mg dose// Period 3: placebo/ Period 4: 1.0 mg dose followed in 6 hours by a 1.0 mg dose followed in 6 hours by a 0.6 mg dose/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 6	MK-8266 0.1 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: 1.2 mg dose followed in 8 hours by a 1.0 mg dose// Period 3: placebo/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 6	MK-8266 1.0 mg	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: 1.2 mg dose followed in 8 hours by a 1.0 mg dose// Period 3: placebo/ Period 4: placebo/ Period 5: na
Panel C, Mild/Moderate Hypertension, Sequence 6	Placebo	Period 1: 1.0 mg dose followed in 8 hours by a 0.8 mg dose/ Period 2: 1.2 mg dose followed in 8 hours by a 1.0 mg dose// Period 3: placebo/ Period 4: placebo/ Period 5: na

Primary Outcome Measures

Name	Time	Method
MK-8266 PK Parameter Observed Time to Reach Cmax (Tmax)	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Tmax was not collected, analyzed or summarized for participants receiving placebo.
MK-8266 Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC\[0-inf\] is a measure of the mean concentration levels of drug in the plasma after the dose. AUC\[0-inf\] was not collected, analyzed or summarized for participants receiving placebo.
MK-8266 PK Parameter Observed Maximum (Peak) Plasma Concentration (Cmax)	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. For Panel A 1.0/0.8 mg MK-8266, the second dose was not well characterized due to limited sampling. Observed exposure likely underestimates the true exposure. Cmax was not collected, analyzed or summarized for participants receiving placebo.
Number of Participants Who Discontinued Study Drug Due to an AE	Up to 43 days	An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Participants in Arms/Groups in which MK-8266 or placebo was administered in more than one period were counted separately for each period.
Aortic Augmentation Index - Time-Weighted Average 0-24 Hours	Predose, 1.5, 3, 12, and 24 hours postdose	Central ascending aortic blood pressure augmentation index (AIx) is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. AIx can be measured non-invasively by radial tonometry using aplanation tonometry of radial artery with the SphygmoCor Pulse Wave Analysis System Guide (SphygmoCor system). AIx was performed at prestudy to ensure an adequate waveform can be obtained. At each time point, a minimum of 2 AIx were completed in an attempt to obtain 2 acceptable quality assessments. A time weighted average was calculated. AIx was adjusted for heart rate. A decrease in the AIx of ≥5 percentage is considered clinically meaningful. Participants in Arms/Groups in which MK-8266 or placebo was administered in more than one period were counted separately for each period. The 12-hour measurement was not collected (per protocol) in all periods of Panels A and B.
Number of Participants Who Experienced One or More Adverse Events	Up to 14 days after administration of last dose of study drug in each study period (Up to 43 Days)	An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Participants in Arms/Groups in which MK-8266 or placebo was administered in more than one period were counted separately for each period.
MK-8266 PK Parameter Apparent t1/2	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. t1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. Harmonic means +/- Pseudo standard deviations are displayed. t1/2 was not collected, analyzed or summarized for participants receiving placebo.

Secondary Outcome Measures

Name	Time	Method
Effect of Food on MK-8266 PK Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24hr) Following Administration of Single Oral Doses of MK-8266 at 0.4 mg to Healthy Male Participants	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC\[0-24 hours\] is a measure of the mean concentration levels of drug in the plasma after the dose. The Fed Group was administered a high fat meal.
Effect of Food on MK-8266 PK Parameter Cmax Following Administration of Single Oral Doses of MK-8266 at 0.4 mg to Healthy Male Participants	Predose, 0.5, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 hours postdose	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. The Fed Group was administered a high fat meal.
Time-Weighted Average of Heart Rate (0-12 Hours)	Up to 12 hours	HR was measured with a validated automatic measuring device. Time weighted average was obtained as follows: For all HR values obtained over the 12-hour observation period, multiply the length of time that the participant spent at each HR value by that HR value, add these products together, and then divide by duration of the observation period. The length of time spent at an identified HR value was defined as the time elapsed since previous post-dose measurement, or time elapsed since drug administration, if there is no previous post-dose measurement. Participants in Arms/Groups in which MK-8266 or placebo was administered in more than one period were counted separately for each period.