A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK8266 in Hypertensive Men (MK-8266-002)

A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8266

This study evaluated adverse events (AEs), study discontinuation due to AEs, and pharmacodynamics of MK-8266 in male participants with mild to moderate hypertension.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: MK-8226 BID, 1 mg; Drug: Placebo BID (Panel A); Drug: MK-8266 BID, 1.8 mg; Drug: Placebo BID (Panel B); Drug: MK-8266 TID, 1.8 mg; Drug: Placebo TID (Panel C); Drug: MK-8266 TID, 2.4 mg; Drug: MK-8266 TID, 2.4 mg; Drug: Placebo TID (Panel D); Drug: Placebo TID (Panel E)

Detailed Description

This study evaluated AEs, discontinuation due to AEs, and effects on hemodynamic parameters, including systolic blood pressure (SBP) and aortic augmentation index (AIx), following multiple oral doses of MK-8266. Five serial panels, each consisting of eight participants (40 participants in Panels A, B, C, D, and E), were randomized to receive either MK-8266 or matching placebo twice daily (BID) or three times daily (TID) for 10 consecutive days. Although the original plan was to evaluate MK-8266 treatment in Panels D and E using both BID and TID regimens, the study actually evaluated identical TID regimens in these panels.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Participant is male with essential hypertension (high blood pressure)
• Participant is in good general health (with the exception of hypertension)
• Participant has a Body Mass Index (BMI) <= 33 kg/m^2 at the Screening visit
• Participant has a platelet count >= 150,000 cu/mL at the Screening visit
• Participant has a positive AIx at the Screening visit

Exclusion Criteria:

• Participant has a history of stroke, chronic seizure, or major neurological disease
• Participant has a functional disability that can interfere with rising from a seated position to the standing position
• Participant has any history of a bleeding or clotting disorder
• Participant has a history of cancer
• Participant is unable to refrain from or anticipates the use of any prescription or non-prescription medication
• Participant consumes excessive amounts of alcohol or caffeinated beverages daily

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel A: MK-8266 BID, 1 mg/Placebo; MK-8266 1 mg (0.7 mg in the morning [AM] + 0.3 mg in the evening [PM]), or as matching placebo BID.	Drug: MK-8226 BID, 1 mg; MK-8266 1 mg administered as oral capsules (0.7 mg + 0.3 mg), BID for 10 consecutive days. Panel A was completed prior to initiation of Panel B.; Other Names: MK-8266; Drug: Placebo BID (Panel A); Placebo administered as oral capsules BID for 10 consecutive days. Panel A was completed prior to initiation of Panel B.
Experimental: Panel B: MK-8266 BID, 1.8 mg/Placebo; MK-8266 1.8 mg (1 mg in the AM + 0.8 mg in the PM), or as matching placebo BID.	Drug: MK-8266 BID, 1.8 mg; MK-8266 1.8 mg administered as oral capsules (1 mg + 0.8 mg), BID for 10 consecutive days. Panel B was completed prior to initiation of Panel C.; Other Names: MK-8266; Drug: Placebo BID (Panel B); Placebo administered as oral capsules BID for 10 consecutive days. Panel B was completed prior to initiation of Panel C.
Experimental: Panel C: MK-8266 TID, 1.8 mg/Placebo; MK-8266 TID, 1.8 mg (0.6 mg every 6 hours [q6hr]), or as matching placebo TID.	Drug: MK-8266 TID, 1.8 mg; MK-8266 1.8 mg administered as oral capsules (0.6 mg), TID for 10 consecutive days. Panel C was completed prior to initiation of Panel D.; Other Names: MK-8266; Drug: Placebo TID (Panel C); Placebo administered as oral capsules TID for 10 consecutive days. Panel C was completed prior to initiation of Panel D.
Experimental: Panel D: MK-8266 TID, 2.4 mg/Placebo; MK-8266 TID (Panel D), 2.4 mg (0.8 mg q6hr), or as matching placebo TID. Panel D was completed prior to initiation of Panel E.	Drug: MK-8266 TID, 2.4 mg; MK-8266 TID (Panel D), 2.4 mg administered as oral capsules (0.8 mg), TID for 10 consecutive days. Panel D was completed prior to initiation of Panel E.; Other Names: MK-8266; Drug: MK-8266 TID, 2.4 mg; MK-8266 TID (Panel E), 2.4 mg administered as oral capsules (0.8 mg), TID for 10 consecutive days. Panel E was initiated after completion of Panel D.; Other Names: MK-8266; Drug: Placebo TID (Panel D); Placebo administered as oral capsules TID for 10 consecutive days. Panel D was completed prior to initiation of Panel E.
Experimental: Panel E: MK-8266 TID, 2.4 mg/Placebo; MK-8266 TID (Panel E), 2.4 mg (0.8 mg q6hr), or as matching placebo TID. Panel E was initiated after completion of Panel D.	Drug: MK-8266 TID, 2.4 mg; MK-8266 TID (Panel D), 2.4 mg administered as oral capsules (0.8 mg), TID for 10 consecutive days. Panel D was completed prior to initiation of Panel E.; Other Names: MK-8266; Drug: MK-8266 TID, 2.4 mg; MK-8266 TID (Panel E), 2.4 mg administered as oral capsules (0.8 mg), TID for 10 consecutive days. Panel E was initiated after completion of Panel D.; Other Names: MK-8266; Drug: Placebo TID (Panel E); Placebo administered as oral capsules TID for 10 consecutive days. Panel E was initiated after completion of Panel D.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up	Assessment of the number of participants with at least one clinical or laboratory AE in those receiving multiple oral doses of MK-8266. 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.	Up to 24 days
Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE	Assessment of the number of participants receiving MK-8266 who discontinued therapy due to an AE over 10 days of treatment. 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. The number of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Days 0-10.	Up to 10 days
Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo	Assessment of the change from baseline in SBP, obtained using a validated, semi-automated oscillometric device. Evaluated for MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis.	Baseline and Day 10
Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo	Assessment of HR (beats/min) on Day 10 (24-hours postdose) with MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA^0-24hrs). Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Baseline HR values are shown in the Baseline Characteristics section for Panels A, B, C, D, E.	Day 10 (24 hours postdose)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo	Assessment of the central, ascending aortic blood pressure augmentation index (AIx), based on measurement of central pulse pressure at selected time points on Day 10, as measured by applanation tonometry of the radial artery. This outcome measure assessed the time weighted average change over 24 hours postdose (TWA^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment.	Day 10
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo	Assessment of whole blood samples for cGMP analysis, based on samples obtained predose as well as 4 and 24 hours postdose on Day 1 and Day 10, and predose only on Day 4. The change from baseline in cGMP was assessed at 24 hours postdose on Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment.	Baseline and Day 10
Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo	The percent inhibition of ADP-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of ADP (2.5 µM) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10 only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo.	Baseline and Day 10 (5 hours postdose)
Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo	The percent inhibition of collagen-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of collagen (2 µg/mL) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10, only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo.	Baseline and Day 10 (5 hours postdose)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2010
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: March 26, 2010
• First Submitted That Met QC Criteria: March 29, 2010
• First Posted (Estimate): March 30, 2010

Study Record Updates

• Last Update Posted (Actual): August 12, 2019
• Last Update Submitted That Met QC Criteria: June 24, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: 8266-002; 2010-018654-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf