Safety, Pharmacodynamics, and Pharmacokinetics of Different Dosing Regimens of MK-8266 in Participants With Hypertension (MK-8266-008)

Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics Following Different Dosing Regimens of MK-8266 or Placebo in Subjects With Hypertension

This was designed as a two part study comprising sequential double-dummy, placebo controlled 3-period randomized crossover studies. The study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of different doses and dose regimens of MK-8266. Only Part I of the study was completed.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Treatment A; Drug: Treatment B; Drug: Treatment C; Drug: Treatment D; Drug: Treatment E; Drug: Treatment F

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Participant has essential hypertension who is in grade 1 or 2 hypertension according to the European Society of Hypertension (ESH) as delineated in the European Society of Cardiology (ESC) 2007 guidelines, i.e. systolic blood pressure values of 140-179 and diastolic blood pressure values of 90-109 on at least 3 occasions prior to the study.
• Otherwise healthy participants with grade 1 or 2 arterial hypertension who are treated with a single antihypertensive drug and meet the above blood pressure criteria may be enrolled at the discretion of the investigator
• Participant is generally in good health with the exception of hypertension
• Participant is a nonsmoker and/or has not used nicotine or nicotine-containing products for 6 months

Exclusion Criteria:

• Participant has a history of any illness that might confound the results of the study or pose and additional risk to the participant if they take part in the study
• Participant has a history of stroke, chronic seizures, or major neurological disorder
• Participant has a disability that can interfere with rising from a semi-recumbent position to the standing position
• Participant has a personal or family history of a bleeding or clotting disorder
• Participant has a history of frequent nosebleeds or recurrent or active gingivitis
• Participant has a history of cancer, except 1) certain skin cancers; 2) cancer successfully treated more than 10 years prior to the study that has not recurred; or, 3) participants who are unlikely to have a recurrence during the study
• Participant has a history of cardiac disease including but not limited to heart valve disease or evidence of secondary cardiac damage
• Participant is categorized as class II or greater according to the New York Heart Association (NYHA) functional classification for heart failure
• Participant is unable to refrain from use of prescription or non-prescription drugs or herbal remedies (such as St. John's Wort) during the study
• Participant anticipates using phosphodiesterase (PDE5) inhibitors [sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®)] during the study
• Participant consumes excessive amounts of alcohol (more than 3 drinks per day) or caffeine (more than 6 servings a day)
• Participant has had major surgery, donated or lost 1 unit of blood, or participated in another investigational within 4 weeks prior to the study
• Participant has a history of multiple and/or severe allergies, or has had an anaphylactic reaction or intolerance to any drugs or food

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I - Sequence ABC; Treatment A in Period 1, Treatment B in Period 2, and Treatment C in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part I - Sequence ACB; Treatment A in Period 1, Treatment C in Period 2, and Treatment B in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part I - Sequence BCA; Treatment B in Period 1, Treatment C in Period 2, and Treatment A in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part I - Sequence BAC; Treatment B in Period 1, Treatment A in Period 2, and Treatment C in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part I - Sequence CAB; Treatment C in Period 1, Treatment A in Period 2, and Treatment B in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part I - Sequence CBA; Treatment C in Period 1, Treatment B in Period 2, and Treatment A in Period 3	Drug: Treatment A; MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 1.3 mg BID; Drug: Treatment B; MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Other Names: MK-8266 0.9 mg FDD; Drug: Treatment C; Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.; Other Names: Placebo
Experimental: Part II - Sequence DEF; Treatment D in Period 1, Treatment E in Period 2, and Treatment F in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Experimental: Part II - Sequence DFE; Treatment D in Period 1, Treatment F in Period 2, and Treatment E in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Experimental: Part II - Sequence EFD; Treatment E in Period 1, Treatment F in Period 2, and Treatment D in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Experimental: Part II - Sequence EDF; Treatment E in Period 1, Treatment D in Period 2, and Treatment F in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Experimental: Part II - Sequence FDE; Treatment F in Period 1, Treatment D in Period 2, and Treatment E in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Experimental: Part II -Sequence FED; Treatment F in Period 1, Treatment E in Period 2, and Treatment D in Period 3	Drug: Treatment D; MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment E; MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.; Drug: Treatment F; Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs)	The number of participants with one or more clinical or laboratory AEs was assessed. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.	MK-8266 1.3 mg BID and 0.9 mg FDD groups: Up to Day 4 in each period; MK-8266 1 mg QD group: the last AE was reported on day 10 after the last dose; Placebo group: Up to 10-14 days after the last dose of placebo
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3	The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.	Pre-dose and 0.5, 1, 2, 4, and 8 hours after dosing on Day 1, and pre-dose and 4 and 8 hours after dosing on Day 3 of each period
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4	The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3	The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.	Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4	The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3	The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 1 and Day 3.	Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4	The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 4.	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Change From Baseline in Heart Rate (HR)	The effect of MK-8266 and placebo on changes in HR were assessed, as measured by time weighted average change from baseline in HR over 0-24 hours postdose (TWA^0-24 hr) on Day 3. Baseline values for HR are shown in the Baseline Characteristics section.	Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3
Change From Baseline in Diastolic Blood Pressure (DBP)	The effect of MK-8266 and placebo on changes in diastolic blood pressure (DBP) were assessed, as measured by time weighted average change from baseline in DBP over 0-24 hours postdose (TWA^0-24 hr) on Day 3. Baseline values for DBP are shown in the Baseline Characteristics section.	Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2010
• Primary Completion (Actual): December 23, 2010
• Study Completion (Actual): December 23, 2010

Study Registration Dates

• First Submitted: November 17, 2010
• First Submitted That Met QC Criteria: November 18, 2010
• First Posted (Estimate): November 19, 2010

Study Record Updates

• Last Update Posted (Actual): February 28, 2019
• Last Update Submitted That Met QC Criteria: October 24, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: High blood pressure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: 8266-008; 2010-021832-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://www.merck.com/clinicaltrials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf