Hypertension
Conditions
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.
Interventions
DRUGMK-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.
DRUGComparator: Candesartan cilexetil
Single dose administration of candesartan, 32 mg oral tablet
DRUGComparator: Pbo
Placebo
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Adverse Events (AEs) | 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. |
| Number of Participants Who Discontinued Treatment Due to an AE | 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
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 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 |
| Change From Baseline in Aortic Augmentation Index (AIx) of MK-5478 and Candesartan | 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. |
| Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 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 |
Participant flow
Recruitment details
A Part II of this study was planned. However, since the efficacy criteria for advancing to Part II were not met in Part I, this study was considered completed with the completion of Part I. Therefore participants were not recruited for Part II.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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 | 2 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Washout 4 | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Pbo → 5 mg → Candesartan → 24 mg → 38 mg | 1 mg → 5 mg → 12 mg → Candesartan → Pbo | 1 mg → Candesartan → Pbo → 24 mg → 38 mg | 1 mg → 5 mg → 12 mg → Pbo → Candesartan | Pbo → 8 mg→ 18 mg → 2 mg Fed → Candesartan | 2 mg→Pbo → Candesartan → Pbo Fed → 38 mg | 2 mg→Candesartan→ Pbo → Candesartan Fed → 38 mg | 2 mg → 8 mg → 18 mg → 2 mg Fed → Pbo | Candesartan→8 mg→ 18 mg → 2 mg Fed → 38 mg | Candesartan → Pbo → 12 mg → 24 mg → 38 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 46.5 Years | 38.5 Years | 46.0 Years | 35.0 Years | 37.5 Years | 44.5 Years | 48.0 Years | 46.5 Years | 45.0 Years | 39.0 Years | 45.5 Years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 3 / 6 | 3 / 6 | 4 / 6 | 4 / 6 | 3 / 6 | 2 / 6 | 2 / 5 | 1 / 6 | 6 / 16 | 9 / 15 | 0 / 2 | 1 / 2 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 16 | 0 / 15 | 0 / 2 | 0 / 2 |
Outcome results
Primary
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.
Time frame: Up to 24 hours after administration of study drug
Population: All participants who received at least one dose of the investigational drug, according to the treatment(s) they actually received; according to study drug taken at time of the event and not by randomly assigned sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-5478 1 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 2 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 5 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 8 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 12 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 18 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 24 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 38 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 2 mg - Fed | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| Candesartan 32 mg | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| Candesartan 32 mg - Fed | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| Candesartan Placebo | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
| MK-5478 Placebo | Number of Participants Who Discontinued Treatment Due to an AE | 0 Participants |
Primary
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.
Time frame: Up to 14 days after administration of last dose of study drug (up to Day 52)
Population: All participants who received at least one dose of the investigational drug, according to the treatment(s) they actually received; according to study drug taken at time of the event and not by randomly assigned sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-5478 1 mg | Number of Participants With One or More Adverse Events (AEs) | 5 Participants |
| MK-5478 2 mg | Number of Participants With One or More Adverse Events (AEs) | 3 Participants |
| MK-5478 5 mg | Number of Participants With One or More Adverse Events (AEs) | 3 Participants |
| MK-5478 8 mg | Number of Participants With One or More Adverse Events (AEs) | 4 Participants |
| MK-5478 12 mg | Number of Participants With One or More Adverse Events (AEs) | 4 Participants |
| MK-5478 18 mg | Number of Participants With One or More Adverse Events (AEs) | 3 Participants |
| MK-5478 24 mg | Number of Participants With One or More Adverse Events (AEs) | 2 Participants |
| MK-5478 38 mg | Number of Participants With One or More Adverse Events (AEs) | 2 Participants |
| MK-5478 2 mg - Fed | Number of Participants With One or More Adverse Events (AEs) | 1 Participants |
| Candesartan 32 mg | Number of Participants With One or More Adverse Events (AEs) | 9 Participants |
| Candesartan 32 mg - Fed | Number of Participants With One or More Adverse Events (AEs) | 0 Participants |
| Candesartan Placebo | Number of Participants With One or More Adverse Events (AEs) | 1 Participants |
| MK-5478 Placebo | Number of Participants With One or More Adverse Events (AEs) | 6 Participants |
Secondary
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
Time frame: Pre-dose and up to 48 hours postdose
Population: In order to keep the study blinded, the scheduled number of treated participants rather than the actual number of treated participants were analyzed; according to the scheduled study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-5478 1 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 0.236 umol.hr/L | Standard Deviation 0.141 |
| MK-5478 2 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 0.494 umol.hr/L | Standard Deviation 0.202 |
| MK-5478 5 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 1.87 umol.hr/L | Standard Deviation 0.538 |
| MK-5478 8 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 1.80 umol.hr/L | Standard Deviation 0.436 |
| MK-5478 12 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 1.36 umol.hr/L | Standard Deviation 0.448 |
| MK-5478 18 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 2.23 umol.hr/L | Standard Deviation 0.582 |
| MK-5478 24 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 3.15 umol.hr/L | Standard Deviation 1.55 |
| MK-5478 38 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 4.50 umol.hr/L | Standard Deviation 0.857 |
| MK-5478 2 mg - Fed | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 0.504 umol.hr/L | Standard Deviation 0.07 |
| Candesartan 32 mg | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 5.89 umol.hr/L | Standard Deviation 1.38 |
| Candesartan 32 mg - Fed | Area Under the Plasma Concentration Versus Time Curve (AUC 0-infinity) of MK-5478 and Candesartan | 4.46 umol.hr/L | Standard Deviation 0.314 |
Secondary
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.
Time frame: Baseline and 1 to 3 hours postdose
Population: Results were not analyzed because none showed a \> 5% decrease in AIx.
Secondary
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
Time frame: Pre-dose and up to 48 hours postdose
Population: In order to keep the study blinded, the scheduled number of treated participants rather than the actual number of treated participants were analyzed; according to the scheduled study drug and not by randomly assigned sequence.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-5478 1 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.0291 µmol/L | Standard Deviation 0.012 |
| MK-5478 2 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.0573 µmol/L | Standard Deviation 0.0206 |
| MK-5478 5 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.254 µmol/L | Standard Deviation 0.0588 |
| MK-5478 8 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.227 µmol/L | Standard Deviation 0.063 |
| MK-5478 12 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.120 µmol/L | Standard Deviation 0.0332 |
| MK-5478 18 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.245 µmol/L | Standard Deviation 0.0634 |
| MK-5478 24 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.321 µmol/L | Standard Deviation 0.206 |
| MK-5478 38 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.532 µmol/L | Standard Deviation 0.154 |
| MK-5478 2 mg - Fed | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.0553 µmol/L | Standard Deviation 0.00891 |
| Candesartan 32 mg | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.476 µmol/L | Standard Deviation 0.194 |
| Candesartan 32 mg - Fed | Maximum Plasma Concentration (Cmax) of MK-5478 and Candesartan | 0.451 µmol/L | Standard Deviation 0.0641 |