Safety, Pharmacodynamics, and Pharmacokinetics of Different Dosing Regimens of MK-8266 in Participants With Hypertension (MK-8266-008)

Phase 1

Completed

• Conditions: Hypertension
• Interventions: Drug: Treatment D; Drug: Treatment A; Drug: Treatment B; Drug: Treatment E; Drug: Treatment F; Drug: Treatment C

• Registration Number: NCT01244035
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

This was designed as a two part study comprising sequential double-dummy, placebo controlled 3-period randomized crossover studies. The study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of different doses and dose regimens of MK-8266. Only Part I of the study was completed.

Detailed Description

Not available

Study Timeline

• Study Start: 2010-08-19
• Study First Submitted: 2010-11-17
• Study First Submitted QC: 2010-11-18
• Study First Posted: 2010-11-19
• Primary Completion: 2010-12-23
• Study Completion: 2010-12-23
• Results First Submitted: 2018-03-20
• Status Verified: 2018-10
• Results First Submitted QC: 2018-10-24
• Last Update Submitted: 2018-10-24
• Results First Posted: 2019-02-28
• Last Update Posted: 2019-02-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 31

Inclusion Criteria

• Participant has essential hypertension who is in grade 1 or 2 hypertension according to the European Society of Hypertension (ESH) as delineated in the European Society of Cardiology (ESC) 2007 guidelines, i.e. systolic blood pressure values of 140-179 and diastolic blood pressure values of 90-109 on at least 3 occasions prior to the study.
• Otherwise healthy participants with grade 1 or 2 arterial hypertension who are treated with a single antihypertensive drug and meet the above blood pressure criteria may be enrolled at the discretion of the investigator
• Participant is generally in good health with the exception of hypertension
• Participant is a nonsmoker and/or has not used nicotine or nicotine-containing products for 6 months

Exclusion Criteria

• Participant has a history of any illness that might confound the results of the study or pose and additional risk to the participant if they take part in the study
• Participant has a history of stroke, chronic seizures, or major neurological disorder
• Participant has a disability that can interfere with rising from a semi-recumbent position to the standing position
• Participant has a personal or family history of a bleeding or clotting disorder
• Participant has a history of frequent nosebleeds or recurrent or active gingivitis
• Participant has a history of cancer, except 1) certain skin cancers; 2) cancer successfully treated more than 10 years prior to the study that has not recurred; or, 3) participants who are unlikely to have a recurrence during the study
• Participant has a history of cardiac disease including but not limited to heart valve disease or evidence of secondary cardiac damage
• Participant is categorized as class II or greater according to the New York Heart Association (NYHA) functional classification for heart failure
• Participant is unable to refrain from use of prescription or non-prescription drugs or herbal remedies (such as St. John's Wort) during the study
• Participant anticipates using phosphodiesterase (PDE5) inhibitors [sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®)] during the study
• Participant consumes excessive amounts of alcohol (more than 3 drinks per day) or caffeine (more than 6 servings a day)
• Participant has had major surgery, donated or lost 1 unit of blood, or participated in another investigational within 4 weeks prior to the study
• Participant has a history of multiple and/or severe allergies, or has had an anaphylactic reaction or intolerance to any drugs or food

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Part II - Sequence EDF	Treatment D	Treatment E in Period 1, Treatment D in Period 2, and Treatment F in Period 3
Part II -Sequence FED	Treatment D	Treatment F in Period 1, Treatment E in Period 2, and Treatment D in Period 3
Part II - Sequence EDF	Treatment F	Treatment E in Period 1, Treatment D in Period 2, and Treatment F in Period 3
Part II - Sequence FDE	Treatment F	Treatment F in Period 1, Treatment D in Period 2, and Treatment E in Period 3
Part I - Sequence ABC	Treatment A	Treatment A in Period 1, Treatment B in Period 2, and Treatment C in Period 3
Part I - Sequence ABC	Treatment B	Treatment A in Period 1, Treatment B in Period 2, and Treatment C in Period 3
Part I - Sequence CAB	Treatment A	Treatment C in Period 1, Treatment A in Period 2, and Treatment B in Period 3
Part I - Sequence ABC	Treatment C	Treatment A in Period 1, Treatment B in Period 2, and Treatment C in Period 3
Part I - Sequence ACB	Treatment A	Treatment A in Period 1, Treatment C in Period 2, and Treatment B in Period 3
Part I - Sequence ACB	Treatment B	Treatment A in Period 1, Treatment C in Period 2, and Treatment B in Period 3
Part I - Sequence ACB	Treatment C	Treatment A in Period 1, Treatment C in Period 2, and Treatment B in Period 3
Part I - Sequence BCA	Treatment A	Treatment B in Period 1, Treatment C in Period 2, and Treatment A in Period 3
Part I - Sequence BCA	Treatment B	Treatment B in Period 1, Treatment C in Period 2, and Treatment A in Period 3
Part I - Sequence BCA	Treatment C	Treatment B in Period 1, Treatment C in Period 2, and Treatment A in Period 3
Part I - Sequence BAC	Treatment A	Treatment B in Period 1, Treatment A in Period 2, and Treatment C in Period 3
Part I - Sequence BAC	Treatment B	Treatment B in Period 1, Treatment A in Period 2, and Treatment C in Period 3
Part I - Sequence BAC	Treatment C	Treatment B in Period 1, Treatment A in Period 2, and Treatment C in Period 3
Part I - Sequence CAB	Treatment B	Treatment C in Period 1, Treatment A in Period 2, and Treatment B in Period 3
Part I - Sequence CAB	Treatment C	Treatment C in Period 1, Treatment A in Period 2, and Treatment B in Period 3
Part I - Sequence CBA	Treatment A	Treatment C in Period 1, Treatment B in Period 2, and Treatment A in Period 3
Part I - Sequence CBA	Treatment B	Treatment C in Period 1, Treatment B in Period 2, and Treatment A in Period 3
Part I - Sequence CBA	Treatment C	Treatment C in Period 1, Treatment B in Period 2, and Treatment A in Period 3
Part II - Sequence DEF	Treatment D	Treatment D in Period 1, Treatment E in Period 2, and Treatment F in Period 3
Part II - Sequence DEF	Treatment E	Treatment D in Period 1, Treatment E in Period 2, and Treatment F in Period 3
Part II - Sequence DEF	Treatment F	Treatment D in Period 1, Treatment E in Period 2, and Treatment F in Period 3
Part II - Sequence DFE	Treatment D	Treatment D in Period 1, Treatment F in Period 2, and Treatment E in Period 3
Part II - Sequence DFE	Treatment E	Treatment D in Period 1, Treatment F in Period 2, and Treatment E in Period 3
Part II - Sequence DFE	Treatment F	Treatment D in Period 1, Treatment F in Period 2, and Treatment E in Period 3
Part II - Sequence EFD	Treatment D	Treatment E in Period 1, Treatment F in Period 2, and Treatment D in Period 3
Part II - Sequence EFD	Treatment E	Treatment E in Period 1, Treatment F in Period 2, and Treatment D in Period 3
Part II - Sequence EFD	Treatment F	Treatment E in Period 1, Treatment F in Period 2, and Treatment D in Period 3
Part II - Sequence EDF	Treatment E	Treatment E in Period 1, Treatment D in Period 2, and Treatment F in Period 3
Part II - Sequence FDE	Treatment D	Treatment F in Period 1, Treatment D in Period 2, and Treatment E in Period 3
Part II - Sequence FDE	Treatment E	Treatment F in Period 1, Treatment D in Period 2, and Treatment E in Period 3
Part II -Sequence FED	Treatment E	Treatment F in Period 1, Treatment E in Period 2, and Treatment D in Period 3
Part II -Sequence FED	Treatment F	Treatment F in Period 1, Treatment E in Period 2, and Treatment D in Period 3

Primary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3	Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3	The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period	The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3	Pre-dose and 0.5, 1, 2, 4, and 8 hours after dosing on Day 1, and pre-dose and 4 and 8 hours after dosing on Day 3 of each period	The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.
Adverse Events (AEs)	MK-8266 1.3 mg BID and 0.9 mg FDD groups: Up to Day 4 in each period; MK-8266 1 mg QD group: the last AE was reported on day 10 after the last dose; Placebo group: Up to 10-14 days after the last dose of placebo	The number of participants with one or more clinical or laboratory AEs was assessed. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period	The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3	Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3	The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 1 and Day 3.
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4	Predose and 2, 4, and 8 hours after dosing on Day 4 of each period	The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 4.
Change From Baseline in Heart Rate (HR)	Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3	The effect of MK-8266 and placebo on changes in HR were assessed, as measured by time weighted average change from baseline in HR over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for HR are shown in the Baseline Characteristics section.
Change From Baseline in Diastolic Blood Pressure (DBP)	Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3	The effect of MK-8266 and placebo on changes in diastolic blood pressure (DBP) were assessed, as measured by time weighted average change from baseline in DBP over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for DBP are shown in the Baseline Characteristics section.