Hypertension
Conditions
Brief summary
This study will test the relationship between CBP (central blood pressure) and PBP (peripheral blood pressure) effects after single and multiple doses of Isosorbide mononitrate extended release (ISMN ER) or Amlodipine besylate in participants with hypertension.
Interventions
DRUGPlacebo
Placebo, capsule taken orally once daily during 4 weeks of treatment
DRUGComparator: Amlodipine
Amlodipine 10 mg, taken orally as two 5 mg capsules, single daily dose for 4 weeks
DRUGComparator: ISMN ER
ISMN ER 30 mg capsule, taken orally as single daily dose for 4 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Participant is a male or female between 30 and 65 years of age (inclusive) at the pre-study (screening) * Female participant of childbearing potential must have a negative pregnancy test * Participant has a brachial systolic blood pressure \>130 mm Hg and \<180 mm Hg * Participant has a Body Mass Index (BMI) that is \>20 kg/m\^2 and \<35 kg/m\^2 * Participant has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months
Exclusion criteria
* Female Participant is pregnant or lactating * Participant anticipates the use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) other than acetaminophen * Participant is currently a user (including recreational use) of any illicit drugs, has a history of drug or alcohol abuse within approximately 2 years, or has a positive prestudy urine drug screen * Participant has a condition for which there is a warning, contraindication, or precaution against the use of ISMN ER including: acute myocardial infarction or congestive heart failure, hypotension, volume depletion, and pregnancy * Participant has a history of significant drug allergy or any clinically significant adverse experience of a serious nature related to the administration of either a marketed or an investigational drug, including nitrates, nitrites, Amlodipine, and ISMN ER
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline (0 hrs), 12 hours post-dose (Day 1) | 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. |
| Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment | Baseline (0 hrs), 24 hours after the Day 28 dose | 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. |
| TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment | Baseline (0 hrs), 12 hours post-dose (Day 1) | 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. |
| Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment | Baseline (0 hrs), 24 hours after the Day 28 dose | 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. |
| TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment | Baseline (0 hrs), 12 hours post-dose (Day 1) | 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. |
| Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment | Baseline (0 hrs), 24 hours after the Day 28 dose | 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. |
| TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment | Baseline (0 hrs), 12 hours post-dose (Day 1) | 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. |
| Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment | Baseline (0 hrs), 24 hours after the Day 28 dose | 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. |
| TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment | Baseline (0 hrs), 12 hours post-dose (Day 1) | 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. |
| Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment | Baseline (0 hrs), 24 hours after the Day 28 dose | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 1 | Discontinued For Other Reason | 0 | 0 | 1 | 1 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 7.05 |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 34 | 18 / 38 | 9 / 37 |
| serious Total, serious adverse events | 0 / 34 | 0 / 38 | 0 / 37 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment | -0.7 mm mercury (Hg) | Standard Deviation 9 |
| Amlodipine | Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment | -7.7 mm mercury (Hg) | Standard Deviation 9 |
| Placebo | Change From Baseline (0 Hours) to Week 4 in Central DBP After Multiple Doses of Treatment | 1.1 mm mercury (Hg) | Standard Deviation 9 |
p-value: 0.42895% CI: [-6.1, 2.6]ANOVA
p-value: <0.000595% CI: [-13.1, -4.5]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment | -12.9 mm mercury (Hg) | Standard Deviation 11.6 |
| Placebo | Change From Baseline (0 Hours) to Week 4 in Central SBP After Multiple Doses of Treatment | 3.2 mm mercury (Hg) | Standard Deviation 11.6 |
p-value: 0.18695% CI: [-9.5, 1.8]ANOVA
p-value: <0.000595% CI: [-21.7, -10.5]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment | -4.7 percent | Standard Deviation 6.2 |
| Placebo | Change From Baseline (0 Hours) to Week 4 in Heart-Rate-Corrected AIx After Multiple Doses of Treatment | 1.2 percent | Standard Deviation 6.2 |
p-value: 0.40795% CI: [-1.7, 4.3]ANOVA
p-value: <0.000595% CI: [-8.9, -2.9]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment | -7.5 mm mercury (Hg) | Standard Deviation 8.7 |
| Placebo | Change From Baseline (0 Hours) to Week 4 in Peripheral DBP After Multiple Doses of Treatment | 1.0 mm mercury (Hg) | Standard Deviation 8.7 |
p-value: 0.26795% CI: [-6.6, 1.8]ANOVA
p-value: <0.000595% CI: [-12.7, -4.3]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment | -11.4 mm mercury (Hg) | Standard Deviation 11.2 |
| Placebo | Change From Baseline (0 Hours) to Week 4 in Peripheral SBP After Multiple Doses of Treatment | 3.9 mm mercury (Hg) | Standard Deviation 11.2 |
p-value: 0.11295% CI: [-9.9, 1]ANOVA
p-value: <0.000595% CI: [-20.7, -9.8]ANOVA
Primary
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | 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 | -0.7 percent | Standard Deviation 4.5 |
| Placebo | 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 | 2.1 percent | Standard Deviation 4.5 |
p-value: <0.000595% CI: [-15.3, -10.9]ANOVA
p-value: 0.01695% CI: [-4.9, -0.6]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment | -2.1 mm mercury (Hg) | Standard Deviation 5.9 |
| Placebo | TWA Change From Baseline (0 Hours) to 12 Hours in Central Diastolic Blood Pressure (DBP) After A Single Dose of Treatment | 1.1 mm mercury (Hg) | Standard Deviation 5.9 |
p-value: <0.000595% CI: [-12.1, -6.4]ANOVA
p-value: 0.03595% CI: [-6, -0.3]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment | -3.6 mm mercury (Hg) | Standard Deviation 7.7 |
| Placebo | TWA Change From Baseline (0 Hours) to 12 Hours in Central Systolic Blood Pressure (SBP) After A Single Dose of Treatment | 2.7 mm mercury (Hg) | Standard Deviation 7.7 |
p-value: <0.000595% CI: [-21.2, -10.1]ANOVA
p-value: 0.00195% CI: [-17.4, -6.3]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment | -2.0 mm mercury (Hg) | Standard Deviation 5.7 |
| Placebo | TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral DBP After A Single Dose of Treatment | 1.0 mm mercury (Hg) | Standard Deviation 5.7 |
p-value: <0.000595% CI: [-11.8, -6.2]ANOVA
p-value: 0.03995% CI: [-5.8, -0.2]ANOVA
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ISMN ER | 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 |
| Amlodipine | TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment | -3.1 mm mercury (Hg) | Standard Deviation 7.7 |
| Placebo | TWA Change From Baseline (0 Hours) to 12 Hours in Peripheral SBP After A Single Dose of Treatment | 1.7 mm mercury (Hg) | Standard Deviation 7.7 |
p-value: <0.000595% CI: [-17.5, -10]ANOVA
p-value: 0.01595% CI: [-8.5, -1]ANOVA