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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Panel A: MK-4618 + Met → PBO + Met | Experimental | Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1. |
|
| Panel A: PBO + Met → MK-4618 + Met | Experimental | Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1. |
|
| Panel B: MK-4618 + Amlo → PBO + Amlo | Experimental | Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1. |
|
| Panel B: PBO + Amlo → MK-4618 + Amlo | Experimental | Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| MK-4618 | Drug | Once daily oral dose of MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7 |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 42 days |
| 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. | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 |
| 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. | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Predose and up to 24 hours postdose on Day 7 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| ID | Type | URL | Comment |
|---|---|---|---|
| CSR Synopsis | View IPD |
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| ID | Title | Description |
|---|---|---|
| FG000 | Panel A: MK-4618 + Met → PBO + Met | Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1. |
| FG001 | Panel A: PBO + Met → MK-4618 + Met | Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of metoprolol (Met) for the duration of the study. A 2-week washout period follows Period 1. |
| FG002 | Panel B: MK-4618 + Amlo → PBO + Amlo | Once daily oral dose of MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 1 followed by once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1. |
| FG003 | Panel B: PBO + Amlo → MK-4618 + Amlo | Once daily oral dose of placebo (two tablets) on Days 1 through 7 in Period 1 followed by MK-4618 (two 50-mg tablets) on Days 1 through 7 in Period 2. Participants receive previously prescribed daily dose of amlodipine (Amlo) for the duration of the study. A 2-week washout period follows Period 1. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 |
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| Two-week Washout Period |
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| Treatment Period 2 |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The All Subjects as Treated population included all participants who received >=1 dose of study drug | Posted | Number | Percentage of participants | Up to 42 days |
|
Up to 42 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Panel A: MK-4618 + Met | Once daily oral dose of MK-4618 (two 50-mg tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of metoprolol for the duration of the study. A 2-week washout period follows Period 1. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA version 15.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme, Corp. | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C000608232 | N-(4-((5-(hydroxy(phenyl)methyl)pyrrolidin-2-yl)methyl)phenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo(1,2-a)pyrimidine-6-carboxamide |
| D008790 | Metoprolol |
| D017311 | Amlodipine |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
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|
| Placebo for MK-4618 | Drug | Once daily oral dose of placebo for MK-4618 100 mg (two 50 mg tablets) on Days 1 through 7 |
|
| Metoprolol | Drug | Previously prescribed daily dose of open-label metoprolol for the duration of the study |
|
|
| Amlodipine | Drug | Previously prescribed daily dose of open-label amlodipine for the duration of the study |
|
|
| Discontinued due to blood draws |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| 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. |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Panel A: PBO + Met | Once daily oral dose of placebo (two tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of metoprolol for the duration of the study. A 2-week washout period follows Period 1. |
| OG002 | Panel B: MK-4618 + Amlo | Once daily oral dose of MK-4618 (two 50-mg tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of amlodipine for the duration of the study. A 2-week washout period follows Period 1. |
| OG003 | Panel B: PBO + Amlo | Once daily oral dose of placebo (two tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of amlodipine for the duration of the study. A 2-week washout period follows Period 1. |
|
|
| 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. | The All Subjects as Treated population included all participants who received >=1 dose of study drug. | Posted | Mean | 95% Confidence Interval | mmHg | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 |
|
|
|
|
| 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. | The All Subjects as Treated population included all participants who received >=1 dose of study drug. | Posted | Mean | 95% Confidence Interval | mmHg | Baseline (predose) and up to 24 hours postdose on Day 1 and Day 7 |
|
|
|
|
| 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. | 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. | Posted | Geometric Mean | 90% Confidence Interval | uM*hr | Predose and up to 24 hours postdose on Day 7 |
|
|
|
| 0 |
| 12 |
| 4 |
| 12 |
| EG001 | Panel A: PBO + Met | Once daily oral dose of placebo (two tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of metoprolol for the duration of the study. A 2-week washout period follows Period 1. | 0 | 13 | 7 | 13 |
| EG002 | Panel B: MK-4618 + Amlo | Once daily oral dose of MK-4618 (two 50-mg tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of amlodipine for the duration of the study. A 2-week washout period follows Period 1. | 0 | 12 | 5 | 12 |
| EG003 | Panel B: PBO + Amlo | Once daily oral dose of placebo (two tablets) in Period 1 or 2. Participants receive previously prescribed daily dose of amlodipine for the duration of the study. A 2-week washout period follows Period 1. | 0 | 13 | 8 | 13 |
| Abdominal pain lower | Gastrointestinal disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Application site pain | General disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Application site rash | General disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Vessel puncture site swelling | General disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA version 15.0 | Systematic Assessment |
|
| Weight increased | Investigations | MedDRA version 15.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA version 15.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA version 15.0 | Systematic Assessment |
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| Depressed mood | Psychiatric disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Penile pain | Reproductive system and breast disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA version 15.0 | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA version 15.0 | Systematic Assessment |
|
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
| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| Standing, Day 1 |
|
| Standing, Day 7 |
|
| Semi-recumbent, Day 7 | Mean Difference (Final Values) | 2.29 | 2-Sided | 90 | -4.92 | 9.49 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Met versus PBO + Met is <20 mmHg |
| Standing, Day 1 | Mean Difference (Final Values) | 1.65 | 2-Sided | 90 | -5.31 | 8.62 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Met versus PBO + Met is <20 mmHg |
| Standing, Day 7 | Mean Difference (Final Values) | -1.09 | 2-Sided | 90 | -8.06 | 5.88 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Met versus PBO + Met is <20 mmHg |
| Standing, Day 1 |
|
| Standing, Day 7 |
|
| Semi-recumbent, Day 7 | Mean Difference (Final Values) | -5.91 | 2-Sided | 90 | -10.71 | -1.11 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Amlo versus PBO + Amlo is <20 mmHg |
| Standing, Day 1 | Mean Difference (Final Values) | -6.25 | 2-Sided | 90 | -11.47 | -1.03 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Amlo versus PBO + Amlo is <20 mmHg |
| Standing, Day 7 | Mean Difference (Final Values) | -1.57 | 2-Sided | 90 | -6.79 | 3.65 | The estimated parameter is mean maximum change from baseline for placebo minus MK-4618. Mean and confidence interval for the difference were obtained from linear mixed effects model performed on the maximum increase from baseline values. | Non-Inferiority or Equivalence | Hypothesis: the upper bound of the 90% confidence interval for the difference in maximum change from baseline for MK-4618 + Amlo versus PBO + Amlo is <20 mmHg |