Trial Outcomes & Findings for A Study of the Effect of MK-8457 on Blood Pressure in Hypertensive Participants (MK-8457-004-AM1) (NCT NCT01446003)

Last Updated: 2019-02-05

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

31 participants

Primary outcome timeframe

Baseline and Day 10

Results posted on

2019-02-05

Participant Flow

Participant milestones

Participant milestones
Measure	MK-8457-Placebo Sequence 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.	Placebo-MK-8457 Sequence 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.
Period 1 STARTED	16	15
Period 1 COMPLETED	14	15
Period 1 NOT COMPLETED	2	0
Period 2 STARTED	14	15
Period 2 COMPLETED	13	15
Period 2 NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	MK-8457-Placebo Sequence 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.	Placebo-MK-8457 Sequence 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.
Period 1 Protocol Violation	2	0
Period 2 Adverse Event	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=31 Participants
Age, Continuous	52.3 Years STANDARD_DEVIATION 5.9 • n=5 Participants
Age, Customized Between 18 and 65 years	30 Participants n=5 Participants
Age, Customized >=65 years	1 Participants n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Day 10

Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (change in 24-hour mean ambulatory SBP).

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=29 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo n=28 Participants 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.
Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP)	-0.47 mmHg Interval -2.6 to 1.66	-2.49 mmHg Interval -4.66 to -0.31

PRIMARY outcome

Timeframe: Up to 70 days

Population: The safety population consisted of all participants who received at least one dose of the investigational drug.

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo n=29 Participants 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.
Number of Participants Who Experienced at Least One Adverse Event (AE)	8 Participant Interval -2.6 to 1.66	9 Participant Interval -4.66 to -0.31

PRIMARY outcome

Timeframe: Up to 70 days

Population: The safety population consisted of all participants who received at least one dose of the investigational drug.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo n=29 Participants 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.
Number of Participants Who Discontinued the Study Medication Due to an AE	1 Participant Interval -2.6 to 1.66	0 Participant Interval -4.66 to -0.31

SECONDARY outcome

Timeframe: Baseline and Day 10

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=29 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo n=28 Participants 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.
Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP)	0.22 mmHg Interval -1.33 to 1.78	-1.35 mmHg Interval -2.93 to 0.23

SECONDARY outcome

Timeframe: Up to 4 hours postdose on Days 1 and 10

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=29 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo n=28 Participants 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.
Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours SBP - AM (n=29,28)	17.80 mmHg 95% Confidence Interval 13.36 • Interval 12.36 to 23.23	9.90 mmHg 95% Confidence Interval 10.05 • Interval 4.37 to 15.43
Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours DBP - AM (n=29,28)	16.90 mmHg 95% Confidence Interval 8.17 • Interval 13.14 to 20.66	11.64 mmHg 95% Confidence Interval 8.26 • Interval 7.8 to 15.48
Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours SBP - PM (n=29,27)	12.68 mmHg 95% Confidence Interval 12.28 • Interval 8.63 to 16.72	13.61 mmHg 95% Confidence Interval 11.31 • Interval 9.4 to 17.83
Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours DBP - PM (n=29,27)	10.89 mmHg 95% Confidence Interval 11.52 • Interval 8.02 to 13.76	12.58 mmHg 95% Confidence Interval 10.89 • Interval 9.6 to 15.56

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo 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.
Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 Day 1 (n=31)	29600 nM*hr Geometric Coefficient of Variation 36	—
Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 Day 10 (n=30)	56200 nM*hr Geometric Coefficient of Variation 44	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo 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.
Maximum Concentration (Cmax) of MK-8457 Day 1 (n=31)	5680 nM Geometric Coefficient of Variation 31	—
Maximum Concentration (Cmax) of MK-8457 Day 10 (n=30)	8630 nM Geometric Coefficient of Variation 38	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo 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.
Time to Maximum Concentration (Tmax) of MK-8457 Day 1 (n=31)	1 hr Interval 0.75 to 2.0	—
Time to Maximum Concentration (Tmax) of MK-8457 Day 10 (n=30)	1 hr Interval 0.5 to 3.0	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	MK-8457 100 mg BID n=31 Participants Participants received MK-8457 100 mg BID for 10 days followed by Placebo for 10 days. Each treatment was separated by a 10-day washout.	Placebo 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.
Trough Plasma Concentration (Ctrough) of MK-8457 Day 1 (n=31)	999 nM Geometric Coefficient of Variation 56	—
Trough Plasma Concentration (Ctrough) of MK-8457 Day 10 (n=30)	2540 nM Geometric Coefficient of Variation 56	—

Adverse Events

MK-8457 100 mg BID

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission.
Publication restrictions are in place

Restriction type: OTHER

Measure	MK-8457 100 mg BID n=31 participants at risk Participants received MK-8457 100 mg BID for 10 days	Placebo n=29 participants at risk Participants received Placebo for MK-8457 for 10 days
Blood and lymphatic system disorders Lymphadenopathy	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Ear and labyrinth disorders Tinnitus	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Gastrointestinal disorders Bloating	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Gastrointestinal disorders Diarrhoea	6.5% 2/31 • Number of events 2 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Gastrointestinal disorders Nausea	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	6.9% 2/29 • Number of events 2 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
General disorders Energy decreased	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
General disorders Flu-like symptoms	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
General disorders Swelling of fingers	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
General disorders Venipuncture site pain	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Infections and infestations Viral upper respiratory tract infection	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Investigations White blood cell count abnormal	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Musculoskeletal and connective tissue disorders Knee pain	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Nervous system disorders Headache	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Nervous system disorders Lightheadedness	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/31 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	3.4% 1/29 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.
Vascular disorders Deep vein thrombosis	3.2% 1/31 • Number of events 1 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.	0.00% 0/29 • Up to 70 days The safety population consisted of all participants who received at least one dose of the investigational drug.