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

A Single Dose Study to Evaluate the Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of MK5478 in Subjects and in Patients With Hypertension

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: MK-5478; Drug: Comparator: Candesartan cilexetil; Drug: Comparator: Pbo

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

10

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: Atacand/Amias; Drug: Comparator: Pbo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With One or More Adverse Events (AEs)	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.	Up to 14 days after administration of last dose of study drug (up to Day 52)
Number of Participants Who Discontinued Treatment Due to an AE	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.	Up to 24 hours after administration of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan	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	Pre-dose and up to 48 hours postdose
Change From Baseline in Aortic Augmentation Index (AIx) of MK-5478 and Candesartan	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.	Baseline and 1 to 3 hours postdose
Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan	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	Pre-dose and up to 48 hours postdose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2009
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: December 2, 2009
• First Submitted That Met QC Criteria: December 2, 2009
• First Posted (Estimate): December 4, 2009

Study Record Updates

• Last Update Posted (Actual): September 21, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Candesartan; Candesartan cilexetil
• Other Study ID Numbers: 5478-001; 2009-016048-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis