The Effects of Antihypertensive Agents on Central Blood P... | NCT01130168

ID	Type	Description	Link
2010_537

The Effects of Antihypertensive Agents on Central Blood P... | NCT01130168 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo/ISMN ER/Amlodipine (Sequence 1)	Experimental	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.	Drug: Placebo Drug: Comparator: Amlodipine Drug: Comparator: ISMN ER
ISMN ER/Amlodipine/Placebo (Sequence 2)	Experimental	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.	Drug: Placebo Drug: Comparator: Amlodipine Drug: Comparator: ISMN ER
Amlodipine/Placebo/ISMN ER (Sequence 3)	Experimental	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.	Drug: Placebo Drug: Comparator: Amlodipine Drug: Comparator: ISMN ER
ISMN ER/Placebo/Amlodipine (Sequence 4)	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	Placebo, capsule taken orally once daily during 4 weeks of treatment	Amlodipine/ISMN ER/Placebo (Sequence 6) Amlodipine/Placebo/ISMN ER (Sequence 3)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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	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.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment	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.	Baseline (0 hrs), 24 hours after the Day 28 dose
TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment	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.	Baseline (0 hrs), 12 hours post-dose (Day 1)
Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment	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.

Name	Affiliation	Role
Medical Monitor	Merck Sharp & Dohme LLC	Study Director

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Withdrawal by Subject		FG0000 subjects FG0011 subjects FG0020 subjects FG0031 subjects FG0040 subjects FG0050 subjects
Discontinued For Other Reason		FG0000 subjects FG0010 subjects FG0021 subjects FG0031 subjects FG004
Adverse Event		FG0000 subjects FG0010 subjects FG0020 subjects FG0031 subjects FG004

Period 2

Type	Comment	Milestone Data
STARTED		FG0006 subjects FG0016 subjects FG0025 subjects FG0035 subjects FG0045 subjects FG0056 subjects
COMPLETED		FG0006 subjects FG0016 subjects FG0025 subjects FG0035 subjects FG004
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004

Period 3

Type	Comment	Milestone Data
STARTED		FG0006 subjects FG0016 subjects FG0025 subjects FG0035 subjects FG0045 subjects FG0056 subjects
COMPLETED		FG0006 subjects FG0016 subjects FG0025 subjects FG0035 subjects FG004
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004

ID	Title	Description
BG000	All Participants

Units	Counts
Participants	BG00033

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Age data were not reported for 5 participants who were excluded from analysis.

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	OG000-11.1± 4.5(-22.0 to 4.0) OG001-0.7± 4.5(-13.0 to 8.0) OG0022.1± 4.5(-6.0 to 10.0)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-13.1			2-Sided	95	-15.3	-10.9				No	Superiority or Other
OG001 OG002		ANOVA		0.016

Primary

Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment

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.

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.

Posted

Least Squares Mean

Standard Deviation

percent

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Primary

TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment

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.

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.

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Primary

Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment

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.

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.

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Primary

TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment

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.

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.

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Primary

Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment

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.

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.

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Primary

TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment

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.

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

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Units	Counts

Primary

Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment

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.

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

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Units	Counts
Participants

Primary

TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment

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.

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

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Units	Counts

Primary

Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment

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.

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

Posted

Least Squares Mean

Standard Deviation

mm mercury (Hg)

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

ID	Title	Description
OG000	ISMN ER	ISMN ER was administered as a 30 mg single daily dose over 4 weeks.
OG001	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.
OG002	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Placebo was administered as a single once daily dose during 4 weeks of treatment.	34	7	34
EG001	ISMN ER	Isosorbide mononitrate extended release (ISMN ER) was administered as a 30 mg single daily dose over 4 weeks.	38	18	38
EG002	Amlodipine	Amlodipine was administered as a 10 mg single daily dose over 4 weeks.	37	9	37

Other Adverse Events

Term	Organ System	Source Vocabulary	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA (14.0)	EG0000 events0 affected34 at risk EG0012 events2 affected38 at risk EG0022 events2 affected37 at risk
Vomiting	Gastrointestinal disorders	MedDRA (14.0)	EG0001 events1 affected34 at risk EG0011 events1 affected38 at risk EG0022 events2 affected37 at risk
Oedema Peripheral	General disorders	MedDRA (14.0)	EG0000 events0 affected34 at risk EG0010 events0 affected38 at risk EG0022 events2 affected37 at risk
Headache	Nervous system disorders	MedDRA (14.0)	EG0006 events6 affected34 at risk EG00116 events16 affected38 at risk EG0026 events6 affected37 at risk
Tension Headache	Nervous system disorders	MedDRA (14.0)	EG0002 events2 affected34 at risk EG0011 events1 affected38 at risk EG0020 affected37 at risk

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.407		Mean Difference (Final Values)	1.3			2-Sided	95	-1.7	4.3				No	Superiority or Other
OG001 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-5.9			2-Sided	95	-8.9	-2.9				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-17.4			2-Sided	95	-21.2	-10.1				No	Superiority or Other
OG001 OG002		ANOVA		0.001		Mean Difference (Final Values)	-6.3			2-Sided	95	-17.4	-6.3				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.186		Mean Difference (Final Values)	-3.8			2-Sided	95	-9.5	1.8				No	Superiority or Other
OG001 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-16.1			2-Sided	95	-21.7	-10.5				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		<0.0005		Median Difference (Final Values)	-9.2			2-Sided	95	-12.1	-6.4				No	Superiority or Other
OG001 OG002		ANOVA		0.035		Mean Difference (Final Values)	-3.5			2-Sided	95	-6.0	-0.3				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.428		Mean Difference (Final Values)	-1.8			2-Sided	95	-6.1	2.6				No	Superiority or Other
OG001 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-8.8			2-Sided	95	-13.1	-4.5				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-13.7			2-Sided	95	-17.5	-10.0				No	Superiority or Other
OG001 OG002		ANOVA		0.015		Mean Difference (Final Values)	-4.8			2-Sided	95	-8.5	-1.0				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.112		Mean Difference (Final Values)	-4.4			2-Sided	95	-9.9	1.0				No	Superiority or Other
OG001 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-15.3			2-Sided	95	-20.7	-9.8				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-9.0			2-Sided	95	-11.8	-6.2				No	Superiority or Other
OG001 OG002		ANOVA		0.039		Mean Difference (Final Values)	-3.0			2-Sided	95	-5.8	-0.2				No	Superiority or Other

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANOVA		0.267		Mean Difference (Final Values)	-2.4			2-Sided	95	-6.6	1.8				No	Superiority or Other
OG001 OG002		ANOVA		<0.0005		Mean Difference (Final Values)	-8.5			2-Sided	95	-12.7	-4.3				No	Superiority or Other

ID	Term
D014652	Vascular Diseases
D002318	Cardiovascular Diseases