Safety, Tolerability, and Pharmacokinetics of MK-8266 in Elderly Participants With High Blood Pressure (MK-8266-003)

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study. The hypothesis for this study is that single oral doses of MK-8266 selected for this study are sufficiently safe and well tolerated by elderly male and elderly female participants with hypertension to permit continued clinical investigation.

Detailed Description
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Two panels, each consisting of eight participants (8 elderly males with mild to moderate hypertension in Panel A and 8 elderly females with mild to moderate hypertension in Panel B) will be randomized to receive either MK-8266 or matching placebo in a 3:1 ratio. Participants will receive single doses of MK-8266 or matching placebo in three treatment periods (Periods 1 through 3). In both Panel A and Panel B, doses will escalate in a rising, fixed sequence. In Period 1 (0.3 mg), Period 2 (0.6 mg), and Period 3 (0.7 mg and then 0.3 mg 10 hours later) once daily doses of MK-8266 or matching placebo will be administered. All participants will receive at least 2 doses of MK-8266. Participants completing placebo treatment in Period 1 will flow to the MK-8266 arm in the next period, with 2 participants from the MK-8266 arm receiving placebo in the next period. Blood samples will be obtained pre-dose and at selected time points up to 48 hours post-dose for determination of MK-8266 plasma concentrations.

Official Title
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A Single Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-8266 in Elderly Subjects With Hypertension

Conditions
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Hypertension

Intervention / Treatment
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* Drug: MK-8266
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants are male or non-childbearing female. Participant with essential hypertension (HTN), Grade 1 or 2 (as per European Society of Hypertension [ESH]) or isolated mild to moderate systolic HTN. High normal systolic BP ≥130 mmHg will be also allowed. Blood pressures to be confirmed on at least three occasions pre-study. The possibility of secondary causes of HTN should be assessed. Participants who are being treated for HTN with drugs (including beta blocking medications) may be able to participate if the drug doses can be reduced or discontinued, at the discretion of the investigator. Participants with a Body Mass Index (BMI) ≤35 kg/m^2 at the screening visit. Participants judged to be generally in good health based on medical history, physical examination, vital sign measurements (with the exception of HTN), and laboratory safety tests performed at the screening visit. Participant has no clinically significant abnormality (confirmed by the investigator in consultation with the Merck Clinical Monitor) on electrocardiogram (ECG) or Holter Monitor Evaluation performed at the screening visit and/or prior to administration of the initial dose of study drug. Participants must have a platelet count ≥150,000 cu/mL at the screening and pre-study visit. Participants, at screening, will have a positive Augmentation Index. Participant has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least 6 months; participants who have discontinued smoking or the use of nicotine/nicotine containing products for at least 3 months may be enrolled at the discretion of the investigator. Participant is willing to comply with the study restrictions. Participant has a negative test for hidden blood in the stool at screening. Exclusion criteria: Participants who have had situational depression may be enrolled in the study at the discretion of the investigator. Participant has an estimated creatinine clearance of ≤60 mL/min based on the Cockcroft-Gault equation. Participant has a history of stroke, chronic seizures, or major neurological disorder. Participant has a history of clinically significant endocrine, gastrointestinal, cardiovascular (with the exception of HTN), hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases. Participants with a history of uncomplicated kidney stones or childhood asthma may be enrolled in the study at the discretion of the investigator. Patient demonstrates low blood pressure at screening and Pre-dose Day 1 while going from a semi-recumbent to standing position. Participant has a functional disability that can interfere with rising from a semi-recumbent position to the standing position. Participant has any personal or family history of a bleeding or a clotting disorder. Participant has a history of frequent nosebleeds. Participant has a history of cancer with the exceptions of: adequately treated non-melanoma skin carcinoma or carcinoma in situ of the cervix; other malignancies which have been successfully treated >10 years prior to the screening visit, for which in the judgment of both the investigator and treating physician, appropriate follow-up has revealed no evidence of recurrence from the time of treatment through the time of the screening visit; or, participants, who, in the opinion of the study investigator, are highly unlikely to sustain a recurrence for the duration of the study. Participant has a history of clinically significant cardiac disease including, but not limited to hemodynamically relevant heart valve disease (if there would be any uncertainty about the diagnosis, confirmation with an echocardiography within 3 months of screening is required), or evidence of secondary cardiac damage. Participant is categorized as a class II or greater functional classification for heart failure according to the New York Heart Association (NYHA). Participant is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies (such as St. John's Wort [Hypericum perforatum]) beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study until the post-study visit. Certain medication use may be permitted after consultation with the Merck clinical monitor. Participant currently and regularly uses aspirin (including low dose) and cannot be discontinued from it from 2 weeks prior to study start or has used aspirin within 2 weeks prior to study start (and anticipates using it during the course of the study); this applies also to any pain relievers and cold or sinus remedies that have aspirin in them, and the use of anti-platelet drugs, such as clopidogrel or dipyridamole. Chronic use of certain non-steroidal anti-inflammatory drugs (NSAIDs) such as ≥500 mg of naproxen twice a day must be also avoided beginning at least 2 weeks prior the study and until the post-study visit. Participant anticipates using sildenafil (Viagra®), tadalafil (Cialis®), or Vardenafil (Levitra®). Participant uses or anticipates using organic nitrate preparations (for example, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate or pentaerythritol) during the course of the study. Participant consumes 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. Participants that consume 4 glasses of alcoholic beverages per day may be enrolled at the discretion of the investigator. 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. Participant has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks prior to the screening visit. The 4-week window will be derived from the date of the last study procedure (i.e., post-study, AE follow-up, etc.) in the previous study to the screening visit of the current study. Participant has a 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. Participant is currently a regular user of illicit drugs or has a history of drug/alcohol abuse within approximately 1 year of the screening visit.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A MK-8266 0.3 mg (Elderly Males with Mild/Mod. HTN)<br>MK-8266 single dose 0.3 mg | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Experimental: Panel A MK-8266 0.6 mg (Elderly Males with Mild/Mod. HTN)<br>MK-8266 single dose 0.6 mg | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Experimental: Panel A MK-8266 0.7/0.3 mg (Elderly Males with Mild/Mod. HTN)<br>MK-8266 single dose 0.7 mg and then 0.3 mg after 10 hours | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Placebo Comparator: Panel A Placebo to MK-8266 (Elderly Males with Mild/Mod. HTN)<br>Placebo to MK-8266 single dose | Drug: Placebo<br>* Oral placebo capsules to match MK-8266 capsules<br>|
| Experimental: Panel B MK-8266 0.3 mg (Elderly Females with Mild/Mod. HTN)<br>MK-8266 single dose 0.3 mg | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Experimental: Panel B MK-8266 0.6 mg (Elderly Females with Mild/Mod. HTN)<br>MK-8266 single dose 0.6 mg | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Experimental: Panel B MK-8266 0.7/0.3 mg (Elderly Fem. with Mild/Mod. HTN)<br>MK-8266 single dose 0.7 mg and then 0.3 mg after 10 hours | Drug: MK-8266<br>* Oral capsules, 0.1 mg potency<br>|
| Placebo Comparator: Panel B Placebo to MK-8266 (Elderly Fem. with Mild/Mod. HTN)<br>Placebo to MK-8266 single dose | Drug: Placebo<br>* Oral placebo capsules to match MK-8266 capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to 48 days | 
| Number of Participants With Abnormal Laboratory Hematology Values Reported as an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Abnormal laboratory hematology value was any AE reported under the System Organ Class of Investigations that was related to an abnormal laboratory hematology value. | Up to 48 days | 
| Number of Participants With Abnormal Laboratory Chemistry Values Reported as an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Abnormal laboratory chemistry value was any AE reported under the System Organ Class of Investigations that was related to an abnormal laboratory chemistry value. | Up to 48 days | 
| Number of Participants With Abnormal Laboratory Urinalysis Values Reported as an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Abnormal laboratory urinalysis value was any AE reported under the System Organ Class of Investigations that was related to an abnormal laboratory urinalysis value. | Up to 37 days | 
| Change From Baseline in Systolic Blood Pressure (SBP) | Participants rested for at least 10 minutes prior to having vital sign measurements obtained. | Baseline and 0 to 8 hours postdose | 
| Change From Baseline in Heart Rate | Participants rested for at least 10 minutes prior to having vital sign measurements obtained. Heart rate measurements were obtained in the semirecumbent position and 3 sets of measurements were obtained approximately 1 minute apart. | Baseline and 0 to 8 hours postdose | 
| Number of Participants With Abnormal Electrocardiograms (ECG) Reported as an AE | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. An abnormal ECG value was any AE reported under the System Organ Classes of Investigations or Cardiac that was related to an abnormal ECG value. | Up to 48 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MK-8266 Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. (AUC[0-inf]) is a measure of the mean concentration levels of drug in the plasma after the dose. | Period 1, 2 and 3: Predose, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours postdose. | 
| MK-8266 PK Parameter Observed Maximum (Peak) Plasma Concentration (Cmax) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. | Period 1, 2 and 3: Predose, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours postdose. | 
| MK-8266 PK Parameter Observed Time to Reach Cmax (Tmax) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Nominal instead of actual times are presented. | Period 1, 2 and 3: Predose, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours postdose. | 
| MK-8266 PK Parameter Apparent Half-Life (t1/2) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. t1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. Results are presented for the Harmonic Mean ± Pseudo standard deviation. | Period 1, 2 and 3: Predose, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours postdose. | 
| The Time Weighted Average Systolic Blood Pressure (SBP) Evaluated Over 8 Hours Post Dose (TWA[0-8hrs]) Following a Single Oral Dose of MK-8266. | Participants rested for at least 10 minutes prior to having vital sign measurements obtained. Single dose effects on central SBP were estimated as a time-weighted average over the 8-hour post single dose observation period. | Up to 8 hours post dose in each dosing period (Up to 8 hours) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension