A Study of the Effect of MK-8457 on Blood Pressure in Hypertensive Participants (MK-8457-004-AM1)

Study Overview
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Brief Summary
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This study will evaluate the effect of treatment with multiple doses of MK-8457 on systolic blood pressure in participants with mild to moderate hypertension in addition to safety and tolerability. The study hypothesis is that MK-8457 does not increase systolic blood pressure to a clinically significant extent, as measured by 24-hour mean ambulatory systolic blood pressure change from baseline after 10 days of dosing.

Official Title
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A Multiple-Dose Clinical Trial to Study the Effect of MK-8457 on Ambulatory Blood Pressure in Hypertensive Patients

Conditions
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Hypertension

Intervention / Treatment
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* Drug: MK-8457
* Drug: Placebo for MK-8457


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: If female, must be of non-childbearing potential If male with female partner(s) of child-bearing potential must agree to use a medically acceptable method of contraception during the study and for 90 days after the last dose of study drug Body mass index (BMI) ≤35 kg/m^2 Mild-to-moderate hypertension requiring treatment with one or more antihypertensive agents Receiving stable treatment for hypertension for at least 8 weeks prior to the start of dosing and continuing therapy for duration of study No clinically significant arrhythmias or clinically significant abnormality on electrocardiogram Nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months Exclusion Criteria: Any illness that might confound the results of the study or poses an additional risk History of stroke, chronic seizures, or major neurological disorder Clinically significant endocrine, gastrointestinal, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases Clinically significant cardiovascular disease or has active angina History of malignant neoplastic disease Taking 325 mg aspirin daily Taking 3 or more medications for the treatment of hypertension Unable to refrain from or anticipates the use of any non-steroidal anti-inflammatory drugs (NSAIDs) Consumes excessive amounts of alcohol and/or coffee, tea, cola, or other caffeinated beverages Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 4 weeks Significant multiple and/or severe allergies Regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 2 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8457-Placebo Sequence<br>Participants received MK-8457 100 mg twice daily (BID) for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout. | Drug: MK-8457<br>* 10 x 10-mg capsule BID for 10 days<br>Drug: Placebo for MK-8457<br>* 10 x 10-mg capsule BID for 10 days<br>|
| Experimental: Placebo-MK-8457 Sequence<br>Participants received Placebo for 10 days followed by MK-8457 100 mg BID for 10 days. Each treatment was separated by a 10-day washout. | Drug: MK-8457<br>* 10 x 10-mg capsule BID for 10 days<br>Drug: Placebo for MK-8457<br>* 10 x 10-mg capsule BID for 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | SBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour least squares (LS) mean ambulatory SBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour SBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. | Baseline and Day 10 | 
| Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 70 days | 
| Number of Participants Who Discontinued the Study Medication Due to an AE | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 70 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | DBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour LS mean ambulatory DBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour DBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. | Baseline and Day 10 | 
| Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | The effect of drug on resting blood pressure was estimated using maxMAΔ. The maxMAΔ in blood pressure was calculated as the maximum moving average change from baseline to Day 10 of 3 consecutive 15-minute blood pressure measurements across the first 4 hours after the morning (AM) and evening (PM) doses. In this method, the LS means of three consecutive time points over the 4 hour period were determined and the maximum LS mean was used for the endpoint. Blood pressure was determined using continuous monitoring at rest. Increased values represent an increase in hypertensive severity. | Up to 4 hours postdose on Days 1 and 10 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | AUC0-12hr is an estimate of total plasma exposure to study drug over the dosing interval (12hr). Plasma concentrations of MK-8457 were determined on Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group is not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10 | 
| Maximum Concentration (Cmax) of MK-8457 | Maximum plasma concentrations of MK-8521 were determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 | 
| Time to Maximum Concentration (Tmax) of MK-8457 | Tmax was determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 | 
| Trough Plasma Concentration (Ctrough) of MK-8457 | The lowest plasma concentration reached by the drug prior to the next administration was determined for Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group was not included; this endpoint evaluated only the MK-8457 group. | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; pre-AM dose on Day 5 or 6 |