Co-Administration of MK-4618 With Antihypertensive Agents (MK-4618-010)

• ClinicalTrials.gov Identifier: NCT01337674
• Recruitment Status: Completed
• First Posted: April 19, 2011
• Results First Posted: February 2, 2016
• Last Update Posted: December 24, 2018
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

This study will evaluate the safety and tolerability of MK-4618 when coadministered with antihypertensive agents and will evaluate changes in blood pressure following co-administration of MK-4618 with a beta blocker and a vasodilator. The primary hypothesis of the study is that MK-4618 does not result in a clinically meaningful change in systolic blood pressure relative to placebo when co-administered with a beta-blocker or with amlodipine.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: MK-4618; Drug: Placebo for MK-4618; Drug: Metoprolol; Drug: Amlodipine	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Study to Evaluate the Co-Administration of MK-4618 With Antihypertensive Agents
• Actual Study Start Date: April 1, 2011
• Actual Primary Completion Date: November 1, 2011
• Actual Study Completion Date: November 1, 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Panel A: MK-4618 + Met → PBO + Met; Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1.	Drug: MK-4618; Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Placebo for MK-4618; Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Metoprolol; Previously prescribed daily dose of open-label metoprolol for the duration of the study; Other Name: Toprol-XL
Experimental: Panel A: PBO + Met → MK-4618 + Met; Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1.	Drug: MK-4618; Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Placebo for MK-4618; Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Metoprolol; Previously prescribed daily dose of open-label metoprolol for the duration of the study; Other Name: Toprol-XL
Experimental: Panel B: MK-4618 + Amlo → PBO + Amlo; Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1.	Drug: MK-4618; Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Placebo for MK-4618; Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Amlodipine; Previously prescribed daily dose of open-label amlodipine for the duration of the study; Other Name: Norvasc
Experimental: Panel B: PBO + Amlo → MK-4618 + Amlo; Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1.	Drug: MK-4618; Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Placebo for MK-4618; Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7; Drug: Amlodipine; Previously prescribed daily dose of open-label amlodipine for the duration of the study; Other Name: Norvasc

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With a Clinical or Laboratory Adverse Experience [ Time Frame: Up to 42 days ]
   An adverse experience was 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. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product is also an adverse experience. The percentage of participants with a clinical or laboratory adverse experience was recorded.
2. Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A [ Time Frame: Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 ]
   Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement.
3. Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B [ Time Frame: Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 ]
   Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement.

Secondary Outcome Measures :

1. Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618 [ Time Frame: Predose and up to 24 hours postdose on Day 7 ]
   Blood samples were collected on Day 7 predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose for the determination of plasma MK-4618 concentration. The hypothesis for this outcome is that the steady-state AUC0-24hr for MK-4618 is >=0.47 uM*hr.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male or female not of childbearing potential
• Not a nursing mother
• Must be on stable dose of a beta blocker (Panel A only) or amlodipine (Panel B only) for the treatment of hypertension for at least 6 weeks prior to enrollment. Must take the designated daily dose of metoprolol or amlodipine for the duration of the study
• In good health other than hypertension
• Nonsmoker
• Participant has a resting systolic blood pressure <150 and >95 mmHg and a diastolic blood pressure <95 and >75 mmHg at prestudy clinical evaluation

Exclusion Criteria:

• Any illness that might confound the results of the study or pose a risk by participation
• History of orthostatic hypotension (decrease in blood pressure upon standing accompanied by symptoms of lightheadedness or dizziness)
• History of cancer, excepting certain skin or cervical cancers or cancers that were treated successfully 10 or more years prior to screening
• Condition for which there is a warning, contraindication, or precaution against the use of extended release metoprolol (Panel A) or amlodipine (Panel B)
• Consumes excessive amounts of alcohol or caffeine daily
• Has multiple and/or severe allergies (including latex allergy) or has had an anaphylactic reaction or significant intolerance to drugs or food
• Uses illicit drugs or has a history of drug abuse

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

Study Data/Documents: CSR Synopsis 

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT01337674
• Other Study ID Numbers: 4618-010
• First Posted: April 19, 2011
• Results First Posted: February 2, 2016
• Last Update Posted: December 24, 2018
• Last Verified: December 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Metoprolol; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Anti-Arrhythmia Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents