A Study of MK-7145 Compared to Placebo and Hydrochlorothiazide for Lowering Blood Pressure in Male Participants With Hypertension (MK-7145-009)

A Phase Ib, Randomized, Double-Blind, 4-Treatment, 2-Period Incomplete Block Study to Evaluate the Multiple Dose Effects of MK-7145 and Hydrochlorothiazide Compared to Placebo on Blood Pressure in Male Patients With Hypertension

This study is being done to evaluate the antihypertensive efficacy and tolerability of MK-7145 in participants with mild-to-moderate hypertension.

The primary hypotheses for the study were as follows:

1. Multiple dose administration of 6-mg MK-7145 results in a reduction in systolic blood pressure (SBP) in male participants with mild to moderate hypertension that is superior to placebo, as measured by time weighted average change from baseline over 24 hours postdose (TWA0-24hrs) on dosing Day 28
2. Multiple dose administration of 6-mg MK-7145 results in a reduction in SBP in male participants with mild to moderate hypertension that is similar to hydrochlorothiazide (HCTZ), as measured by TWA0-24hrs on dosing Day 28
3. The effect of MK-7145 and HCTZ on natriuresis (UNaV) as well as SBP and diastolic blood pressure (DBP), both as measured by TWA0-24hrs, will be estimated
4. Multiple dose administration of MK-7145 for 4 weeks will be generally safe and well-tolerated.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Hydrochlorothiazide (HCTZ); Drug: MK-7145; Drug: Placebo to HCTZ; Drug: Placebo to MK-7145

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion criteria:

• Diagnosis of essential hypertension
• Body mass index (BMI) ≤35 kg/m^2
• Participant in general good health
• No history of clinically significant arrhythmias or clinically significant abnormality on electrocardiogram (ECG)
• No history of clinically significant cardiac disease
• Treatment-naïve or taking up to 2 antihypertensive therapeutic agents
• Non-smoker and/or has not used nicotine or nicotine-containing products for at least 6 months

Exclusion criteria:

• Participant has low plasma potassium
• History of stroke, chronic seizures, or major neurological disorder
• History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases
• History of osteoporosis
• Active or history of nephrocalcinosis, nephrolithiasis or hypercalciuria
• Orthostatic change in vital sign measurements while going from a semi-recumbent to standing position accompanied by symptoms
• Functional disability that can interfere with rising from a semi-recumbent position to the standing position
• History of malignant neoplastic disease. Exceptions: (1) adequately treated non-melanomatous skin carcinoma; (2) other malignancies which have been successfully treated >10 years prior to the prestudy (screening) visit, (3) unlikely to sustain a recurrence
• Participant is unable to refrain from the use of prescription and non-prescription drugs such as high-dose aspirin (≥325 mg/day), strong/moderate Cytochrome P450 3A4 (CYP3A4) inhibitors (such as ritonavir, indinavir, nelfinavir, erythromycin, telithromycin, clarithromycin, chloramphenicol, fluconazole, ketoconazole, itraconazole, nefazodone, aprepitant, verapamil, or diltiazem) as well as strong/moderate CYP3A4 inducers (such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, rifampicin, modafinil, St Johns Wort, cyproterone, or progestin) beginning approximately 2 weeks (or 5 half-lives), prior to administration of the initial dose of study drug until the post study visit
• Current use of non-steroidal anti-inflammatory drugs (NSAIDs) other than low dose aspirin, aluminum- or magnesium-containing antacids, sucralfate, metal cations such as iron, multivitamins containing iron or zinc that cannot be discontinued at least 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug until the post study visit
• Consumption of excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day
• Participant consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day
• Major surgery, donation or lost 1 unit of blood (approximately 500 mL), or participation in another investigational study within 4 weeks prior to the prestudy (screening)
• History of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
• Regular use of any illicit drugs or history of drug abuse within approximately 6 months
• Dehydration or volume-depletion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: MK-7145 6 mg (Treatment A); MK-7145 3 mg (three x 1-mg MK-7145 capsules administered orally) and placebo to HCTZ (two 12.5-mg capsules) then three x 1-mg MK-7145 capsules 4 hours later, daily for 4 weeks.	Drug: MK-7145; Drug: Placebo to HCTZ
EXPERIMENTAL: MK-7145 3 mg (Treatment B); MK-7145 3 mg (one 2mg MK-7145 and one MK-7145 placebo capsule) then one 1-mg MK-7145 capsule and two MK-7145 placebo capsules 4 hours later and placebo to HCTZ (2 capsules once daily) daily for 4 weeks.	Drug: MK-7145; Drug: Placebo to HCTZ; Drug: Placebo to MK-7145
ACTIVE_COMPARATOR: Hydrochlorothiazide 25 mg (Treatment C); HCTZ 25 mg (two 12.5-mg capsules) and placebo to MK-7145 (one 3-mg capsule) then placebo for MK-7145 (one 3-mg capsule) 4 hours later daily for 4 weeks.	Drug: Hydrochlorothiazide (HCTZ); Drug: Placebo to MK-7145
PLACEBO_COMPARATOR: Placebo (Treatment D); Placebo to MK-7145 (2 x 3-mg capsules) and placebo to HCTZ 25 mg (2 capsules) then placebo to MK-7145 (2 x 3-mg capsules) 4 hours later daily for 4 weeks	Drug: Placebo to HCTZ; Drug: Placebo to MK-7145

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP)	Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average systolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded.	Baseline and Day 28
Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP)	Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average diastolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded.	Baseline and Day 28
Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1	Urine sodium (Na) levels were measured over 24-hours on Day -1 (baseline) and on Day 1. The total amount of Na excreted in the urine for Day-1 (baseline) and Day1 were calculated and the difference between the 2 values was recorded.	Baseline (Day-1) and Day 1
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE during the study was summarized by study drug taken at the time of the AE.	Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period)
Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE)	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. The percentage of participants who had the administration of the study drug discontinued during the study was summarized by study drug taken at the time of the AE. Participants may or may not have completed the study.	up to 4 weeks of each treatment period
Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE)	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE that was reported as at least possibly-related to the study was summarized by study drug taken at the time of the AE.	Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28	Urine potassium (K+) levels were measured over 24-hours on Day -1 and on Day 28. The total amount of K+ excreted in the urine for Day-1 (baseline) and Day 28 were calculated and the difference between the 2 values was recorded.	Baseline (Day -1) and Day 28

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 15, 2011
• Primary Completion (ACTUAL): December 19, 2011
• Study Completion (ACTUAL): January 26, 2012

Study Registration Dates

• First Submitted: June 8, 2011
• First Submitted That Met QC Criteria: June 8, 2011
• First Posted (ESTIMATE): June 10, 2011

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

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; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium Chloride Symporter Inhibitors; Hydrochlorothiazide
• Other Study ID Numbers: 7145-009

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf