Trial Outcomes & Findings for The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED) (NCT NCT01130168)

Results Overview

The augmentation index (AIx) is a measure of systemic arterial stiffness, and is the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Single dose effects on AIx were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. This value was used for all AIx analyses.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

38 participants

Primary outcome timeframe

Baseline (0 hrs), 12 hours post-dose (Day 1)

Results posted on

2015-10-09

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo/ISMN ER/Amlodipine (Sequence 1) Participants received a dose-matched Placebo capsule orally for 4 weeks during Period 1, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 2, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 3, with a 2-week washout between each period. Experimental: ISMN ER/Amlodipine/Placebo	ISMN ER/Amlodipine/Placebo (Sequence 2) Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 2, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 3, with a 2-week washout between each period	Amlodipine/Placebo/ISMN ER (Sequence 3) Participants received Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 3, with a 2-week washout between each period	ISMN ER/Placebo/Amlodipine (Sequence 4) Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 3, with a 2-week washout between each period.	Placebo/Amlodipine/ISMN ER (Sequence 5) Participants received a dose-matched Placebo capsule orally for 4 weeks during Period 1, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 2, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 3, with a 2-week washout between each period.	Amlodipine/ISMN ER/Placebo (Sequence 6) Participants received Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 1, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 2, followed by a dose-matched Placebo capsule for 4 weeks during Period, with a 2-week washout between each period.
Period 1 STARTED	6	7	6	8	5	6
Period 1 COMPLETED	6	6	5	5	5	6
Period 1 NOT COMPLETED	0	1	1	3	0	0
Period 2 STARTED	6	6	5	5	5	6
Period 2 COMPLETED	6	6	5	5	5	6
Period 2 NOT COMPLETED	0	0	0	0	0	0
Period 3 STARTED	6	6	5	5	5	6
Period 3 COMPLETED	6	6	5	5	5	6
Period 3 NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	ISMN ER/Amlodipine/Placebo (Sequence 2) Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 2, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 3, with a 2-week washout between each period	Amlodipine/Placebo/ISMN ER (Sequence 3) Participants received Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by a ISMN ER 30 mg capsule orally for 4 weeks during Period 3, with a 2-week washout between each period	ISMN ER/Placebo/Amlodipine (Sequence 4) Participants received a ISMN ER 30 mg capsule orally for 4 weeks during Period 1, followed by a dose-matched Placebo capsule orally for 4 weeks during Period 2, followed by Amlodipine 10 mg (two 5 mg capsules) orally for 4 weeks during Period 3, with a 2-week washout between each period.
Period 1 Withdrawal by Subject	1	0	1
Period 1 Discontinued For Other Reason	0	1	1
Period 1 Adverse Event	0	0	1

Baseline Characteristics

The Effects of Antihypertensive Agents on Central Blood Pressure in Healthy Participants and Participants With Hypertension (MK-0000-166) (COMPLETED)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=33 Participants
Age, Continuous	49 years STANDARD_DEVIATION 7.05 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants
Sex: Female, Male Male	22 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (0 hrs), 12 hours post-dose (Day 1)

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the single dose AIx analysis.

The augmentation index (AIx) is a measure of systemic arterial stiffness, and is the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Single dose effects on AIx were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. This value was used for all AIx analyses.

Outcome measures

Outcome measures
Measure	ISMN ER n=32 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Time-weighted Average (TWA) Change From Baseline (0 Hours) to 12 Hours in Heart-Rate-Corrected Augmentation Index (AIx) After A Single Dose of Treatment	-11.1 percent Standard Deviation 4.5 • Interval -22.0 to 4.0	-0.7 percent Standard Deviation 4.5 • Interval -13.0 to 8.0	2.1 percent Standard Deviation 4.5 • Interval -6.0 to 10.0

PRIMARY outcome

Timeframe: Baseline (0 hrs), 24 hours after the Day 28 dose

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for two participants in the ISM ER treatment group, therefore these participants were excluded from the multiple dose AIx analysis.

The augmentation index (AIx) is a measure of systemic arterial stiffness, and is the ratio of augmented aortic pressure (Δ P) to central pulse pressure expressed as a percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Because heart rate (HR) affects AIx, AIx was corrected to a HR of 75 beats per minute (bpm) as follows: HR-corrected AIx = -0.39 x (75 - HR) + AIx. This value was used for all AIx analyses.

Outcome measures

Outcome measures
Measure	ISMN ER n=31 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment	2.5 percent Standard Deviation 6.2	-4.7 percent Standard Deviation 6.2	1.2 percent Standard Deviation 6.2

PRIMARY outcome

Timeframe: Baseline (0 hrs), 12 hours post-dose (Day 1)

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the single dose SBP analysis.

Central SBP was measured by the SphygmoCor® device. Single dose effects on central SBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.

Outcome measures

Outcome measures
Measure	ISMN ER n=32 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment	-14.7 mm mercury (Hg) Standard Deviation 7.7	-3.6 mm mercury (Hg) Standard Deviation 7.7	2.7 mm mercury (Hg) Standard Deviation 7.7

PRIMARY outcome

Timeframe: Baseline (0 hrs), 24 hours after the Day 28 dose

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the multiple dose SBP analysis.

Central SBP was measured by the SphygmoCor® device. Central SBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.

Outcome measures

Outcome measures
Measure	ISMN ER n=32 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment	-0.7 mm mercury (Hg) Standard Deviation 11.6	-12.9 mm mercury (Hg) Standard Deviation 11.6	3.2 mm mercury (Hg) Standard Deviation 11.6

PRIMARY outcome

Timeframe: Baseline (0 hrs), 12 hours post-dose (Day 1)

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the single dose DBP analysis.

Central DBP was measured by the SphygmoCor® device. Single dose effects on central DBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.

Outcome measures

Outcome measures
Measure	ISMN ER n=32 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment	-8.2 mm mercury (Hg) Standard Deviation 5.9	-2.1 mm mercury (Hg) Standard Deviation 5.9	1.1 mm mercury (Hg) Standard Deviation 5.9

PRIMARY outcome

Timeframe: Baseline (0 hrs), 24 hours after the Day 28 dose

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses. Unreliable SphygmoCor® data were collected for one participant in the ISM ER treatment group, therefore this participant was excluded from the multiple dose DBP analysis.

Central DBP was measured by the SphygmoCor® device. Central DBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.

Outcome measures

Outcome measures
Measure	ISMN ER n=32 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment	-0.7 mm mercury (Hg) Standard Deviation 9.0	-7.7 mm mercury (Hg) Standard Deviation 9.0	1.1 mm mercury (Hg) Standard Deviation 9.0

PRIMARY outcome

Timeframe: Baseline (0 hrs), 12 hours post-dose (Day 1)

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses.

Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Single dose effects on peripheral SBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.

Outcome measures

Outcome measures
Measure	ISMN ER n=33 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment	-12.1 mm mercury (Hg) Standard Deviation 7.7	-3.1 mm mercury (Hg) Standard Deviation 7.7	1.7 mm mercury (Hg) Standard Deviation 7.7

PRIMARY outcome

Timeframe: Baseline (0 hrs), 24 hours after the Day 28 dose

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses.

Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Peripheral SBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.

Outcome measures

Outcome measures
Measure	ISMN ER n=33 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment	-0.6 mm mercury (Hg) Standard Deviation 11.2	-11.4 mm mercury (Hg) Standard Deviation 11.2	3.9 mm mercury (Hg) Standard Deviation 11.2

PRIMARY outcome

Timeframe: Baseline (0 hrs), 12 hours post-dose (Day 1)

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses.

Peripheral DBP was measured by Brachial Sphygmomanometer (standard cuff). Single dose effects on peripheral DBP were estimated as a time-weighted average change from baseline over the 12-hour post single dose observation period.

Outcome measures

Outcome measures
Measure	ISMN ER n=33 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment	-8.0 mm mercury (Hg) Standard Deviation 5.7	-2.0 mm mercury (Hg) Standard Deviation 5.7	1.0 mm mercury (Hg) Standard Deviation 5.7

PRIMARY outcome

Timeframe: Baseline (0 hrs), 24 hours after the Day 28 dose

Population: 33 participants completed all study periods and provided more than 1 period of BP data, and were thus evaluable for the BP analyses.

Peripheral SBP was measured by Brachial Sphygmomanometer (standard cuff). Peripheral DBP was measured at baseline and at 24 hours post dose on Day 28 (Week 4) and expressed as a change from baseline.

Outcome measures

Outcome measures
Measure	ISMN ER n=33 Participants Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=33 Participants Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	Placebo n=33 Participants Placebo was administered as a single once daily dose during 4 weeks of treatment.
Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment	-1.4 mm mercury (Hg) Standard Deviation 8.7	-7.5 mm mercury (Hg) Standard Deviation 8.7	1.0 mm mercury (Hg) Standard Deviation 8.7

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

ISMN ER

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Amlodipine

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Placebo n=34 participants at risk Placebo was administered as a single once daily dose during 4 weeks of treatment.	ISMN ER n=38 participants at risk Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	Amlodipine n=37 participants at risk Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
Gastrointestinal disorders Nausea	0.00% 0/34 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	5.3% 2/38 • Number of events 2 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	5.4% 2/37 • Number of events 2 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.
Gastrointestinal disorders Vomiting	2.9% 1/34 • Number of events 1 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	2.6% 1/38 • Number of events 1 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	5.4% 2/37 • Number of events 2 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.
General disorders Oedema Peripheral	0.00% 0/34 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	0.00% 0/38 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	5.4% 2/37 • Number of events 2 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.
Nervous system disorders Headache	17.6% 6/34 • Number of events 6 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	42.1% 16/38 • Number of events 16 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	16.2% 6/37 • Number of events 6 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.
Nervous system disorders Tension Headache	5.9% 2/34 • Number of events 2 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	2.6% 1/38 • Number of events 1 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.	0.00% 0/37 Adverse event data were unavailable for 4 participants in the Placebo treatment group and for 1 participant in the Amlodipine treatment group due to discontinuations during Period 1.

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. SPONSOR review can be expedited to meet publication timelines
Publication restrictions are in place

Restriction type: OTHER