The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED)

A Double-Blind, Randomized, Placebo-Controlled, 3-Period, Crossover Study to Evaluate the Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Subjects and Patients With Hypertension

This study will test the relationship between CBP (central blood pressure) and PBP (peripheral blood pressure) effects after single and multiple doses of Isosorbide mononitrate extended release (ISMN ER) or Amlodipine besylate in participants with hypertension.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Comparator: Amlodipine; Drug: Comparator: ISMN ER

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant is a male or female between 30 and 65 years of age (inclusive) at the pre-study (screening)
• Female participant of childbearing potential must have a negative pregnancy test
• Participant has a brachial systolic blood pressure >130 mm Hg

and <180 mm Hg

• Participant has a Body Mass Index (BMI) that is >20 kg/m^2 and <35 kg/m^2
• Participant has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months

Exclusion Criteria:

• Female Participant is pregnant or lactating
• Participant anticipates the use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) other than acetaminophen
• Participant is currently a user (including "recreational use") of any illicit drugs, has a history of drug or alcohol abuse within approximately 2 years, or has a positive prestudy urine drug screen
• Participant has a condition for which there is a warning, contraindication, or precaution against the use of ISMN ER including: acute myocardial infarction or congestive heart failure, hypotension, volume depletion, and pregnancy
• Participant has a history of significant drug allergy or any clinically significant adverse experience of a serious nature related to the administration of either a marketed or an investigational drug, including nitrates, nitrites, Amlodipine, and ISMN ER

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo/ISMN ER/Amlodipine (Sequence 1); Participants received a dose-matched Placebo capsule orally for 4 weeks during Period 1, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 2, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 3, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Experimental: ISMN ER/Amlodipine/Placebo (Sequence 2); Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 2, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 3, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Experimental: Amlodipine/Placebo/ISMN ER (Sequence 3); Participants received Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 3, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Experimental: ISMN ER/Placebo/Amlodipine (Sequence 4); Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 3, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Experimental: Placebo/Amlodipine/ISMN ER (Sequence 5); Participants received a dose-matched Placebo capsule orally for 4 weeks during Period 1, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 2, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 3, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Experimental: Amlodipine/ISMN ER/Placebo (Sequence 6); Participants received Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 1, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 2, followed by a dose-matched Placebo capsule for 4 weeks during Period, with a 2-week washout between each period.	Drug: Placebo; Placebo, capsule taken orally once daily during 4 weeks of treatment; Drug: Comparator: Amlodipine; Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks; Drug: Comparator: ISMN ER; ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-weighted Average (TWA) Change From Baseline (0 Hours) to 12 Hours in Heart-Rate-Corrected Augmentation Index (AIx) After A Single Dose of Treatment	The augmentation index (AIx) is a measure of systemic arterial stiffness, and is the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Single dose effects on AIx were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. This value was used for all AIx analyses.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment	The augmentation index (AIx) is a measure of systemic arterial stiffness, and is the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. This value was used for all AIx analyses.	Baseline (0 hrs), 24 hours after the Day 28 dose
TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment	Central SBP was measured by the SphygmoCor® device. Single dose effects on central SBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment	Central SBP was measured by the SphygmoCor® device. Central SBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.	Baseline (0 hrs), 24 hours after the Day 28 dose
TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment	Central DBP was measured by the SphygmoCor® device. Single dose effects on central DBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment	Central DBP was measured by the SphygmoCor® device. Central DBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.	Baseline (0 hrs), 24 hours after the Day 28 dose
TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment	Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Single dose effects on peripheral SBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment	Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Peripheral SBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.	Baseline (0 hrs), 24 hours after the Day 28 dose
TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment	Peripheral DBP was measured by Brachial Sphygmomanometer (standard cuff). Single dose effects on peripheral DBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment	Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Peripheral DBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.	Baseline (0 hrs), 24 hours after the Day 28 dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: May 19, 2010
• First Submitted That Met QC Criteria: May 24, 2010
• First Posted (Estimate): May 25, 2010

Study Record Updates

• Last Update Posted (Estimate): October 9, 2015
• Last Update Submitted That Met QC Criteria: October 8, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Amlodipine
• Other Study ID Numbers: 0000-166; 2010_537