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

Study Overview
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Brief Summary
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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.

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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: MK-5478
* Drug: Comparator: Candesartan cilexetil
* Drug: Comparator: Pbo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pbo → 5 mg → Candesartan → 24 mg → 38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 1 mg → 5 mg → 12 mg → Candesartan → Pbo<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 1 mg → Candesartan → Pbo → 24 mg → 38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 1 mg → 5 mg → 12 mg → Pbo → Candesartan<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: Pbo→ 8 mg→ 18 mg → 2 mg fed→Candesartan<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 2 mg→Pbo → Candesartan → Pbo fed→38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 2 mg→Candesartan→Pbo→Candesartan fed→38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: 2 mg → 8 mg → 18 mg → 2 mg fed → Pbo<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: Candesartan→8 mg→ 18 mg →2 mg fed→38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|
| Experimental: Candesartan→Pbo → 12 mg → 24 mg→38 mg<br>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<br>* In Part I: Single dose administration of MK-5478 oral capsules, total doses of 1, 2, 5, 8, 12, 18, 24 or 38 mg.<br>Drug: Comparator: Candesartan cilexetil<br>* Single dose administration of candesartan, 32 mg oral tablet<br>* Other names: Atacand/Amias;Drug: Comparator: Pbo<br>* Placebo<br>|

What is the study measuring?
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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 |