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

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Hypertension

Treatments: Drug: Hydrochlorothiazide (HCTZ); Drug: MK-7145; Drug: Placebo to HCTZ; Drug: Placebo to MK-7145

Study type: Interventional

Funder types: Industry

Identifiers

NCT01370655

7145-009

Details and patient eligibility

About

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.

Enrollment: 46 patients

Sex: Male

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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46 participants in 4 patient groups, including a placebo group

MK-7145 6 mg (Treatment A)

Experimental group

Description:

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.

Treatment:

Drug: Placebo to HCTZ

Drug: MK-7145

MK-7145 3 mg (Treatment B)

Experimental group

Description:

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.

Treatment:

Drug: Placebo to MK-7145

Drug: Placebo to HCTZ

Drug: MK-7145

Hydrochlorothiazide 25 mg (Treatment C)

Active Comparator group

Description:

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.

Treatment:

Drug: Placebo to MK-7145

Drug: Hydrochlorothiazide (HCTZ)

Placebo (Treatment D)

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo to MK-7145

Drug: Placebo to HCTZ