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

Phase 1

Completed

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

• Registration Number: NCT01096160
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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

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 Timeline

• Study Start: 2010-03-01
• Study First Submitted: 2010-03-26
• Study First Submitted QC: 2010-03-29
• Study First Posted: 2010-03-30
• Primary Completion: 2010-11-01
• Study Completion: 2010-11-01
• Results First Submitted: 2018-02-21
• Status Verified: 2019-06
• Results First Submitted QC: 2019-06-24
• Last Update Submitted: 2019-06-24
• Results First Posted: 2019-08-12
• Last Update Posted: 2019-08-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 40

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Panel A: MK-8266 BID, 1 mg/Placebo	MK-8226 BID, 1 mg	MK-8266 1 mg (0.7 mg in the morning \[AM\] + 0.3 mg in the evening \[PM\]), or as matching placebo BID.
Panel B: MK-8266 BID, 1.8 mg/Placebo	Placebo BID (Panel B)	MK-8266 1.8 mg (1 mg in the AM + 0.8 mg in the PM), or as matching placebo BID.
Panel D: MK-8266 TID, 2.4 mg/Placebo	Placebo TID (Panel D)	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.
Panel B: MK-8266 BID, 1.8 mg/Placebo	MK-8266 BID, 1.8 mg	MK-8266 1.8 mg (1 mg in the AM + 0.8 mg in the PM), or as matching placebo BID.
Panel A: MK-8266 BID, 1 mg/Placebo	Placebo BID (Panel A)	MK-8266 1 mg (0.7 mg in the morning \[AM\] + 0.3 mg in the evening \[PM\]), or as matching placebo BID.
Panel C: MK-8266 TID, 1.8 mg/Placebo	MK-8266 TID, 1.8 mg	MK-8266 TID, 1.8 mg (0.6 mg every 6 hours \[q6hr\]), or as matching placebo TID.
Panel C: MK-8266 TID, 1.8 mg/Placebo	Placebo TID (Panel C)	MK-8266 TID, 1.8 mg (0.6 mg every 6 hours \[q6hr\]), or as matching placebo TID.
Panel E: MK-8266 TID, 2.4 mg/Placebo	MK-8266 TID, 2.4 mg	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.
Panel D: MK-8266 TID, 2.4 mg/Placebo	MK-8266 TID, 2.4 mg	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.
Panel E: MK-8266 TID, 2.4 mg/Placebo	Placebo TID (Panel E)	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.

Primary Outcome Measures

Name	Time	Method
Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up	Up to 24 days	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.
Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE	Up to 10 days	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.
Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo	Baseline and Day 10	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.
Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo	Day 10 (24 hours postdose)	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.

Secondary Outcome Measures

Name	Time	Method
Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo	Day 10	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.
Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo	Baseline and Day 10 (5 hours postdose)	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.
Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo	Baseline and Day 10 (5 hours postdose)	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.
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo	Baseline and Day 10	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.