Hypertension
Conditions
Brief summary
This study will evaluate the safety and tolerability of MK-4618 when coadministered with antihypertensive agents and will evaluate changes in blood pressure following co-administration of MK-4618 with a beta blocker and a vasodilator. The primary hypothesis of the study is that MK-4618 does not result in a clinically meaningful change in systolic blood pressure relative to placebo when co-administered with a beta-blocker or with amlodipine.
Interventions
DRUGMK-4618
Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7
DRUGPlacebo for MK-4618
Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7
DRUGMetoprolol
Previously prescribed daily dose of open-label metoprolol for the duration of the study
DRUGAmlodipine
Previously prescribed daily dose of open-label amlodipine for the duration of the study
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or female not of childbearing potential * Not a nursing mother * Must be on stable dose of a beta blocker (Panel A only) or amlodipine (Panel B only) for the treatment of hypertension for at least 6 weeks prior to enrollment. Must take the designated daily dose of metoprolol or amlodipine for the duration of the study * In good health other than hypertension * Nonsmoker * Participant has a resting systolic blood pressure \<150 and \>95 mmHg and a diastolic blood pressure \<95 and \>75 mmHg at prestudy clinical evaluation
Exclusion criteria
* Any illness that might confound the results of the study or pose a risk by participation * History of orthostatic hypotension (decrease in blood pressure upon standing accompanied by symptoms of lightheadedness or dizziness) * History of cancer, excepting certain skin or cervical cancers or cancers that were treated successfully 10 or more years prior to screening * Condition for which there is a warning, contraindication, or precaution against the use of extended release metoprolol (Panel A) or amlodipine (Panel B) * Consumes excessive amounts of alcohol or caffeine daily * Has multiple and/or severe allergies (including latex allergy) or has had an anaphylactic reaction or significant intolerance to drugs or food * Uses illicit drugs or has a history of drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Clinical or Laboratory Adverse Experience | Up to 42 days | An adverse experience was 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. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product is also an adverse experience. The percentage of participants with a clinical or laboratory adverse experience was recorded. |
| Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 | Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement. |
| Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 | Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618 | Predose and up to 24 hours postdose on Day 7 | Blood samples were collected on Day 7 predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose for the determination of plasma MK-4618 concentration. The hypothesis for this outcome is that the steady-state AUC0-24hr for MK-4618 is \>=0.47 uM\*hr. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panel A Participants Once daily oral dose of MK-4618 (two 50-mg tablets) or placebo (two tablets) on Days 1 through 7 in Period 1 followed by the crossover treatment in Period 2. Participants receive previously prescribed daily dose of metoprolol for the duration of the study. A 2-week washout period follows Period 1. | 13 |
| Panel B Participants Once daily oral dose of MK-4618 (two 50-mg tablets) or placebo (two tablets) on Days 1 through 7 in Period 1 followed by the crossover treatment in Period 2. Participants receive previously prescribed daily dose of amlodipine for the duration of the study. A 2-week washout period follows Period 1. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 0 | 1 | 0 | 0 |
| Treatment Period 1 | Discontinued due to blood draws | 0 | 0 | 0 | 1 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Panel A Participants | Panel B Participants | Total |
|---|---|---|---|
| Age, Continuous | 53.8 Years | 55.2 Years | 54.5 Years |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 12 | 7 / 13 | 5 / 12 | 8 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 13 | 0 / 12 | 0 / 13 |
Outcome results
Primary
Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A
Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement.
Time frame: Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7
Population: The All Subjects as Treated population included all participants who received \>=1 dose of study drug.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Semi-recumbent, Day 1 | 16.03 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Semi-recumbent, Day 7 | 14.38 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Standing, Day 1 | 14.79 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Standing, Day 7 | 6.12 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Standing, Day 7 | 7.21 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Semi-recumbent, Day 1 | 17.25 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Standing, Day 1 | 13.14 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A | Semi-recumbent, Day 7 | 12.10 mmHg |
Comparison: Semi-recumbent, Day 190% CI: [-8.42, 5.98]
Comparison: Semi-recumbent, Day 790% CI: [-4.92, 9.49]
Comparison: Standing, Day 190% CI: [-5.31, 8.62]
Comparison: Standing, Day 790% CI: [-8.06, 5.88]
Primary
Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B
Semi-recumbent and standing systolic blood pressure was measured predose and at intervals up to 24 hours postdose on Day 1 and Day 7. The baseline value is the average of measurements taken in the hour before dosing. Participants were to rest quietly in a semi-recumbent position for at least 10 minutes before each semi-recumbent measurement.
Time frame: Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7
Population: The All Subjects as Treated population included all participants who received \>=1 dose of study drug.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Semi-recumbent, Day 1 | 14.69 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Semi-recumbent, Day 7 | 10.52 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Standing, Day 1 | 6.50 mmHg |
| Panel A: MK-4618 + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Standing, Day 7 | 6.33 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Standing, Day 7 | 7.90 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Semi-recumbent, Day 1 | 12.74 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Standing, Day 1 | 12.75 mmHg |
| Panel A: PBO + Met | Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B | Semi-recumbent, Day 7 | 16.43 mmHg |
Comparison: Semi-recumbent, Day 190% CI: [-2.85, 6.75]
Comparison: Semi-recumbent, Day 790% CI: [-10.71, -1.11]
Comparison: Standing, Day 190% CI: [-11.47, -1.03]
Comparison: Standing, Day 790% CI: [-6.79, 3.65]
Primary
Percentage of Participants With a Clinical or Laboratory Adverse Experience
An adverse experience was 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. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product is also an adverse experience. The percentage of participants with a clinical or laboratory adverse experience was recorded.
Time frame: Up to 42 days
Population: The All Subjects as Treated population included all participants who received \>=1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel A: MK-4618 + Met | Percentage of Participants With a Clinical or Laboratory Adverse Experience | 33.3 Percentage of participants |
| Panel A: PBO + Met | Percentage of Participants With a Clinical or Laboratory Adverse Experience | 53.8 Percentage of participants |
| Panel B: MK-4618 + Amlo | Percentage of Participants With a Clinical or Laboratory Adverse Experience | 41.7 Percentage of participants |
| Panel B: PBO + Amlo | Percentage of Participants With a Clinical or Laboratory Adverse Experience | 61.5 Percentage of participants |
Secondary
Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618
Blood samples were collected on Day 7 predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose for the determination of plasma MK-4618 concentration. The hypothesis for this outcome is that the steady-state AUC0-24hr for MK-4618 is \>=0.47 uM\*hr.
Time frame: Predose and up to 24 hours postdose on Day 7
Population: The Per Protocol population included participants who complied with the protocol sufficiently to ensure that the data will likely exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Panel A: MK-4618 + Met | Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618 | 2.60 uM*hr |
| Panel A: PBO + Met | Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618 | 4.60 uM*hr |