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Co-Administration of MK-4618 With Antihypertensive Agents (MK-4618-010)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01337674
Recruitment Status : Completed
First Posted : April 19, 2011
Results First Posted : February 2, 2016
Last Update Posted : December 24, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Hypertension
Interventions Drug: MK-4618
Drug: Placebo for MK-4618
Drug: Metoprolol
Drug: Amlodipine
Enrollment 26
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Panel A: MK-4618 + Met → PBO + Met Panel A: PBO + Met → MK-4618 + Met Panel B: MK-4618 + Amlo → PBO + Amlo Panel B: PBO + Amlo → MK-4618 + Amlo
Hide Arm/Group Description 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. 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. 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. 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.
Period Title: Treatment Period 1
Started 6 7 [1] 6 7 [1]
Completed 6 6 6 6
Not Completed 0 1 0 1
Reason Not Completed
Adverse Event             0             1             0             0
Discontinued due to blood draws             0             0             0             1
[1]
The discontinued participant was replaced
Period Title: Two-week Washout Period
Started 6 6 6 6
Completed 6 6 6 6
Not Completed 0 0 0 0
Period Title: Treatment Period 2
Started 6 6 6 6
Completed 6 6 5 6
Not Completed 0 0 1 0
Reason Not Completed
Withdrawal by Subject             0             0             1             0
Arm/Group Title Panel A Participants Panel B Participants Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 13 13 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 13 participants 13 participants 26 participants
53.8
(42 to 68)
55.2
(41 to 77)
54.5
(41 to 77)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants 13 participants 26 participants
Female
4
  30.8%
8
  61.5%
12
  46.2%
Male
9
  69.2%
5
  38.5%
14
  53.8%
1.Primary Outcome
Title Percentage of Participants With a Clinical or Laboratory Adverse Experience
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Subjects as Treated population included all participants who received >=1 dose of study drug
Arm/Group Title Panel A: MK-4618 + Met Panel A: PBO + Met Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Hide Arm/Group Description:
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.
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.
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.
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.
Overall Number of Participants Analyzed 12 13 12 13
Measure Type: Number
Unit of Measure: Percentage of participants
33.3 53.8 41.7 61.5
2.Primary Outcome
Title Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel A
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Subjects as Treated population included all participants who received >=1 dose of study drug.
Arm/Group Title Panel A: MK-4618 + Met Panel A: PBO + Met
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 12 13
Mean (95% Confidence Interval)
Unit of Measure: mmHg
Semi-recumbent, Day 1
16.03
(9.46 to 22.61)
17.25
(10.93 to 23.57)
Semi-recumbent, Day 7
14.38
(7.81 to 20.96)
12.10
(5.78 to 18.42)
Standing, Day 1
14.79
(7.43 to 22.15)
13.14
(6.01 to 20.26)
Standing, Day 7
6.12
(-1.24 to 13.49)
7.21
(0.09 to 14.34)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Panel A: MK-4618 + Met, Panel A: PBO + Met
Comments Semi-recumbent, Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.22
Confidence Interval (2-Sided) 90%
-8.42 to 5.98
Estimation Comments 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.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Panel A: MK-4618 + Met, Panel A: PBO + Met
Comments Semi-recumbent, Day 7
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.29
Confidence Interval (2-Sided) 90%
-4.92 to 9.49
Estimation Comments 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.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Panel A: MK-4618 + Met, Panel A: PBO + Met
Comments Standing, Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.65
Confidence Interval (2-Sided) 90%
-5.31 to 8.62
Estimation Comments 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.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Panel A: MK-4618 + Met, Panel A: PBO + Met
Comments Standing, Day 7
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.09
Confidence Interval (2-Sided) 90%
-8.06 to 5.88
Estimation Comments 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.
3.Primary Outcome
Title Maximum Change From Baseline in Semi-recumbent and Standing Systolic Blood Pressure: Panel B
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
The All Subjects as Treated population included all participants who received >=1 dose of study drug.
Arm/Group Title Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 12 13
Mean (95% Confidence Interval)
Unit of Measure: mmHg
Semi-recumbent, Day 1
14.69
(9.65 to 19.72)
12.74
(7.87 to 17.61)
Semi-recumbent, Day 7
10.52
(5.48 to 15.55)
16.43
(11.56 to 21.30)
Standing, Day 1
6.50
(1.27 to 11.73)
12.75
(7.70 to 17.79)
Standing, Day 7
6.33
(1.10 to 11.57)
7.90
(2.85 to 12.95)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Panel B: MK-4618 + Amlo, Panel B: PBO + Amlo
Comments Semi-recumbent, Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.95
Confidence Interval (2-Sided) 90%
-2.85 to 6.75
Estimation Comments 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.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Panel B: MK-4618 + Amlo, Panel B: PBO + Amlo
Comments Semi-recumbent, Day 7
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.91
Confidence Interval (2-Sided) 90%
-10.71 to -1.11
Estimation Comments 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.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Panel B: MK-4618 + Amlo, Panel B: PBO + Amlo
Comments Standing, Day 1
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -6.25
Confidence Interval (2-Sided) 90%
-11.47 to -1.03
Estimation Comments 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.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Panel B: MK-4618 + Amlo, Panel B: PBO + Amlo
Comments Standing, Day 7
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.57
Confidence Interval (2-Sided) 90%
-6.79 to 3.65
Estimation Comments 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.
4.Secondary Outcome
Title Steady-state Area Under the Plasma Concentration Versus Time Curve (AUC0-24hr) for MK-4618
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Panel A: MK-4618 + Met Panel B: MK-4618 + Amlo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 12 12
Geometric Mean (90% Confidence Interval)
Unit of Measure: uM*hr
2.60
(2.09 to 3.24)
4.60
(3.69 to 5.74)
Time Frame Up to 42 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Panel A: MK-4618 + Met Panel A: PBO + Met Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Hide Arm/Group Description 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. 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. 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. 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.
All-Cause Mortality
Panel A: MK-4618 + Met Panel A: PBO + Met Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Panel A: MK-4618 + Met Panel A: PBO + Met Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/12 (0.00%)      0/13 (0.00%)      0/12 (0.00%)      0/13 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Panel A: MK-4618 + Met Panel A: PBO + Met Panel B: MK-4618 + Amlo Panel B: PBO + Amlo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/12 (33.33%)      7/13 (53.85%)      5/12 (41.67%)      8/13 (61.54%)    
Blood and lymphatic system disorders         
Anaemia  1  0/12 (0.00%)  0 1/13 (7.69%)  1 0/12 (0.00%)  0 0/13 (0.00%)  0
Gastrointestinal disorders         
Abdominal pain lower  1  0/12 (0.00%)  0 0/13 (0.00%)  0 1/12 (8.33%)  1 0/13 (0.00%)  0
Toothache  1  0/12 (0.00%)  0 0/13 (0.00%)  0 1/12 (8.33%)  1 0/13 (0.00%)  0
General disorders         
Application site pain  1  0/12 (0.00%)  0 1/13 (7.69%)  1 0/12 (0.00%)  0 0/13 (0.00%)  0
Application site rash  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Asthenia  1  0/12 (0.00%)  0 1/13 (7.69%)  1 0/12 (0.00%)  0 0/13 (0.00%)  0
Chest pain  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Vessel puncture site swelling  1  0/12 (0.00%)  0 0/13 (0.00%)  0 1/12 (8.33%)  1 0/13 (0.00%)  0
Injury, poisoning and procedural complications         
Fall  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Investigations         
Weight increased  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Musculoskeletal and connective tissue disorders         
Back pain  1  0/12 (0.00%)  0 1/13 (7.69%)  1 0/12 (0.00%)  0 0/13 (0.00%)  0
Pain in extremity  1  1/12 (8.33%)  1 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Nervous system disorders         
Dizziness  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Headache  1  1/12 (8.33%)  2 5/13 (38.46%)  6 2/12 (16.67%)  4 2/13 (15.38%)  2
Psychiatric disorders         
Depressed mood  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Renal and urinary disorders         
Dysuria  1  0/12 (0.00%)  0 0/13 (0.00%)  0 1/12 (8.33%)  1 0/13 (0.00%)  0
Reproductive system and breast disorders         
Penile pain  1  1/12 (8.33%)  1 0/13 (0.00%)  0 0/12 (0.00%)  0 0/13 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Cough  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Nasal congestion  1  0/12 (0.00%)  0 0/13 (0.00%)  0 0/12 (0.00%)  0 1/13 (7.69%)  1
Oropharyngeal pain  1  0/12 (0.00%)  0 1/13 (7.69%)  1 0/12 (0.00%)  0 0/13 (0.00%)  0
Vascular disorders         
Flushing  1  1/12 (8.33%)  1 0/13 (0.00%)  0 0/12 (0.00%)  0 0/13 (0.00%)  0
Hot flush  1  1/12 (8.33%)  1 0/13 (0.00%)  0 0/12 (0.00%)  0 0/13 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA version 15.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme, Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01337674    
Other Study ID Numbers: 4618-010
First Submitted: April 15, 2011
First Posted: April 19, 2011
Results First Submitted: October 30, 2015
Results First Posted: February 2, 2016
Last Update Posted: December 24, 2018