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Safety and Tolerability of MK-5478 in Participants With Hypertension (5478-001)

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: NCT01025843
Recruitment Status : Completed
First Posted : December 4, 2009
Results First Posted : February 26, 2016
Last Update Posted : September 21, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Description
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Brief Summary:
This is a two part introductory clinical trial with MK-5478. Part I will evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of MK-5478 in young, healthy males. Part II will evaluate the safety, tolerability and pharmacodynamic effects of MK-5478 in participants with hypertension. The primary hypothesis is that single oral doses of MK-5478 are sufficiently safe and well tolerated.

Condition or disease Intervention/treatment Phase
Hypertension Drug: MK-5478 Drug: Comparator: Candesartan cilexetil Drug: Comparator: Pbo Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Single Dose Study to Evaluate the Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of MK5478 in Subjects and in Patients With Hypertension
Actual Study Start Date : December 1, 2009
Actual Primary Completion Date : May 1, 2010
Actual Study Completion Date : May 1, 2010

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pbo → 5 mg → Candesartan → 24 mg → 38 mg
Placebo in Period 1; 5 mg MK-5478 in Period 2; Candesartan in Period 3; 24 mg MK-5478 in Period 4; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 1 mg → 5 mg → 12 mg → Candesartan → Pbo
1 mg MK-5478 in Period 1; 5 mg MK-5478 in Period 2; 12 mg MK-5478 in Period 3; Candesartan in Period 4; and Placebo in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 1 mg → Candesartan → Pbo → 24 mg → 38 mg
1 mg MK-5478 in Period 1; Candesartan in Period 2: Placebo in Period 3; 24 mg MK-5478 in Period 4; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 1 mg → 5 mg → 12 mg → Pbo → Candesartan
1 mg MK-5478 in Period 1; 5 mg MK-5478 in Period 2; 12 mg MK-5478 in Period 3; Placebo in Period 4; and Candesartan in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: Pbo→ 8 mg→ 18 mg → 2 mg fed→Candesartan
Placebo in Period 1; 8 mg MK-5478 in Period 2; 18 mg MK-5478 in Period 3; 2 mg MK-5478 in Period 4 with a high fat meal; and Candesartan in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 2 mg→Pbo → Candesartan → Pbo fed→38 mg
2 mg MK-5478 in Period 1; Placebo in Period 2; Candesartan in Period 3; Placebo in Period 4 with a high fat meal; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 2 mg→Candesartan→Pbo→Candesartan fed→38 mg
2 mg MK-5478 in Period 1; Candesartan in Period 2; Placebo in Period 3; Candesartan in Period 4 with a high fat meal; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: 2 mg → 8 mg → 18 mg → 2 mg fed → Pbo
2 mg MK-5478 in Period 1; 8 mg MK-5478 in Period 2; 18 mg MK-5478 in Period 3; 2 mg MK-5478 in Period 4 with a high fat meal; and Placebo in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: Candesartan→8 mg→ 18 mg →2 mg fed→38 mg
Candesartan in Period 1; 8 mg MK-5478 in Period 2; 18 mg MK-5478 in Period 3; 2 mg MK-5478 in Period 4 with a high fat meal; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo
Experimental: Candesartan→Pbo → 12 mg → 24 mg→38 mg
Candesartan in Period 1; Placebo in Period 2; 12 mg MK-5478 in Period 3; 24 mg MK-5478 in Period 4; and 38 mg MK-5478 in Period 5. There was a minimum 7 days washout between periods.
 Drug: MK-5478
In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.

Drug: Comparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
Other Name: Atacand/Amias

Drug: Comparator: Pbo
Placebo


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants With One or More Adverse Events (AEs) [ Time Frame: Up to 14 days after administration of last dose of study drug (up to Day 52) ]
    An AE is 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.

  2. Number of Participants Who Discontinued Treatment Due to an AE [ Time Frame: Up to 24 hours after administration of study drug ]
    An AE is 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, is also an AE.


Secondary Outcome Measures :
  1. Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan [ Time Frame: Pre-dose and up to 48 hours postdose ]
    Blood was collected at the following time points: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, and 48 hours post-dose in order to measure AUC 0-infinity of MK-5478 and Candesartan

  2. Change From Baseline in Aortic Augmentation Index (AIx) of MK-5478 and Candesartan [ Time Frame: Baseline and 1 to 3 hours postdose ]
    Central blood pressure (CBP) parameters will be measured and used to derive the aortic augmentation index (AIx). The AIx quantifies the contribution of back-reflected outgoing systolic pressure waves to late-systolic central blood pressure, which increases with decreasing aortic compliance. AIx is measured by pulse wave analysis using the SphygmoCor System supplied by AtCor Medical. Results with a > 5% decrease in AIx were planned for analysis; results with a < 5% decrease in AIx were not analysed.

  3. Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan [ Time Frame: Pre-dose and up to 48 hours postdose ]
    Blood was collected at the following time points: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, and 48 hours post-dose in order to measure the Cmax of MK-5478 and Candesartan


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Part I:

  • Is a male between 18 to 50 years of age
  • Is in good health
  • Is a non-smoker

Part II:

  • Is male of non-child bearing potential between 18 and 50 years of age
  • Has hypertension (high blood pressure)

Exclusion Criteria:

Part I and Part II:

  • Has a history of stroke, seizures or major neurological disorder
  • Has a history of cancer
  • Has a history of any cardiovascular disease
  • Is unable to refrain from the use of any prescription or non-prescription drugs
  • Consumes excessive amounts of alcohol or caffeine
  • Has had major surgery, donated blood or participated in another investigational study in the past 4 weeks
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01025843


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
More Information
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01025843    
Other Study ID Numbers: 5478-001
2009-016048-38 ( EudraCT Number )
First Posted: December 4, 2009    Key Record Dates
Results First Posted: February 26, 2016
Last Update Posted: September 21, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Additional relevant MeSH terms:
Layout table for MeSH terms
Hypertension
Vascular Diseases
Cardiovascular Diseases
Candesartan
Candesartan cilexetil
 Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action