Hypertension
Conditions
Brief summary
This study is being done to evaluate the antihypertensive efficacy and tolerability of MK-7145 in participants with mild-to-moderate hypertension. The primary hypotheses for the study were as follows: 1. Multiple dose administration of 6-mg MK-7145 results in a reduction in systolic blood pressure (SBP) in male participants with mild to moderate hypertension that is superior to placebo, as measured by time weighted average change from baseline over 24 hours postdose (TWA0-24hrs) on dosing Day 28 2. Multiple dose administration of 6-mg MK-7145 results in a reduction in SBP in male participants with mild to moderate hypertension that is similar to hydrochlorothiazide (HCTZ), as measured by TWA0-24hrs on dosing Day 28 3. The effect of MK-7145 and HCTZ on natriuresis (UNaV) as well as SBP and diastolic blood pressure (DBP), both as measured by TWA0-24hrs, will be estimated 4. Multiple dose administration of MK-7145 for 4 weeks will be generally safe and well-tolerated.
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of essential hypertension * Body mass index (BMI) ≤35 kg/m\^2 * Participant in general good health * No history of clinically significant arrhythmias or clinically significant abnormality on electrocardiogram (ECG) * No history of clinically significant cardiac disease * Treatment-naïve or taking up to 2 antihypertensive therapeutic agents * Non-smoker and/or has not used nicotine or nicotine-containing products for at least 6 months
Exclusion criteria
* Participant has low plasma potassium * History of stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * History of osteoporosis * Active or history of nephrocalcinosis, nephrolithiasis or hypercalciuria * Orthostatic change in vital sign measurements while going from a semi-recumbent to standing position accompanied by symptoms * Functional disability that can interfere with rising from a semi-recumbent position to the standing position * History of malignant neoplastic disease. Exceptions: (1) adequately treated non-melanomatous skin carcinoma; (2) other malignancies which have been successfully treated \>10 years prior to the prestudy (screening) visit, (3) unlikely to sustain a recurrence * Participant is unable to refrain from the use of prescription and non-prescription drugs such as high-dose aspirin (≥325 mg/day), strong/moderate Cytochrome P450 3A4 (CYP3A4) inhibitors (such as ritonavir, indinavir, nelfinavir, erythromycin, telithromycin, clarithromycin, chloramphenicol, fluconazole, ketoconazole, itraconazole, nefazodone, aprepitant, verapamil, or diltiazem) as well as strong/moderate CYP3A4 inducers (such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, rifampicin, modafinil, St Johns Wort, cyproterone, or progestin) beginning approximately 2 weeks (or 5 half-lives), prior to administration of the initial dose of study drug until the post study visit * Current use of non-steroidal anti-inflammatory drugs (NSAIDs) other than low dose aspirin, aluminum- or magnesium-containing antacids, sucralfate, metal cations such as iron, multivitamins containing iron or zinc that cannot be discontinued at least 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug until the post study visit * Consumption of excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer \[284 mL/10 ounces\], wine \[125 mL/4 ounces\], or distilled spirits \[25 mL/1 ounce\]) per day * Participant consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day * Major surgery, donation or lost 1 unit of blood (approximately 500 mL), or participation in another investigational study within 4 weeks prior to the prestudy (screening) * History of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Regular use of any illicit drugs or history of drug abuse within approximately 6 months * Dehydration or volume-depletion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1 | Baseline (Day-1) and Day 1 | Urine sodium (Na) levels were measured over 24-hours on Day -1 (baseline) and on Day 1. The total amount of Na excreted in the urine for Day-1 (baseline) and Day1 were calculated and the difference between the 2 values was recorded. |
| Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP) | Baseline and Day 28 | Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average systolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded. |
| Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP) | Baseline and Day 28 | Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average diastolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded. |
| Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE) | Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE that was reported as at least possibly-related to the study was summarized by study drug taken at the time of the AE. |
| Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) | Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE during the study was summarized by study drug taken at the time of the AE. |
| Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE) | up to 4 weeks of each treatment period | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who had the administration of the study drug discontinued during the study was summarized by study drug taken at the time of the AE. Participants may or may not have completed the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28 | Baseline (Day -1) and Day 28 | Urine potassium (K+) levels were measured over 24-hours on Day -1 and on Day 28. The total amount of K+ excreted in the urine for Day-1 (baseline) and Day 28 were calculated and the difference between the 2 values was recorded. |
Participant flow
Pre-assignment details
Participants were randomly assigned to 1 of 12 treatment sequences Each 4-week treatment period was separated by a wash-out of approximately 4 weeks
Participants by arm
| Arm | Count |
|---|---|
| Treatment A → Treatment C Participants received 6 mg MK-7145 for 4 weeks and then after a 4 week washout, received HCTZ 25 mg, daily, for 4 weeks | 7 |
| Treatment C → Treatment A Participants received HCTZ 25 mg daily for 4 weeks and then after a 4-week washout, received 6 mg MK-7145 daily for 4 weeks. | 7 |
| Treatment A → Treatment D Participants received 6 mg MK-7145 daily for 4 weeks and then after a 4-week washout, received Placebo MK-7145 daily for 4 weeks. | 3 |
| Treatment D → Treatment A Participants received Placebo MK-7145 daily for 4 weeks and then after a 4-week washout, received 6 mg MK-7145 daily for 4 weeks. | 3 |
| Treament D → Treatment C Participants received Placebo MK-7145 daily for 4 weeks and then after a 4-week washout, received HCTZ 25 mg placebo daily for 4 weeks. | 3 |
| Treatment C → Treatment D Participants received HCTZ 25 mg daily for 4 weeks and then after a 4-week washout, received Placebo MK-7145 daily for 4 weeks. | 4 |
| Treatment A → Treatment B Participants received 6 mg MK-7145 daily for 4 weeks and then after a 4-week washout, received 3 mg MK-7145 daily for 4 weeks. | 4 |
| Treatment B → Treatment A Participants received 3 mg MK-7145 daily for 4 weeks and then after a 4-week washout, received 6 mg MK-7145 daily for 4 weeks. | 4 |
| Treatment B → Treatment C Participants received 3 mg MK-7145 daily for 4 weeks and then after a 4-week washout, received HCTZ 25 mg daily for 4 weeks. | 3 |
| Treatment C → Treatment B Participants received HCTZ 25 mg daily for 4 weeks and then after a 4-week washout, received 3 mg MK-7145 daily for 4 weeks. | 2 |
| Treatment B → Treatment D Participants received 3 mg MK-7145 daily for 4 weeks and then after a 4-week washout, received Placebo MK-715 daily for 4 weeks. | 3 |
| Treatment D → Treament B Participants received Placebo MK-7145 daily for 4 weeks and then after a 4-week washout, received 3 mg MK-7145 daily for 4 weeks. | 3 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Period 2 | met protocol specified stopping criteria | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 |
| Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Treatment A → Treatment C | Treatment C → Treatment A | Treatment A → Treatment D | Treatment D → Treatment A | Treament D → Treatment C | Treatment C → Treatment D | Treatment A → Treatment B | Treatment B → Treatment A | Treatment B → Treatment C | Treatment C → Treatment B | Treatment B → Treatment D | Treatment D → Treament B | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.1 years STANDARD_DEVIATION 8.1 | 56.1 years STANDARD_DEVIATION 10.9 | 58.3 years STANDARD_DEVIATION 4.5 | 60.7 years STANDARD_DEVIATION 3.2 | 59.3 years STANDARD_DEVIATION 8.3 | 54.8 years STANDARD_DEVIATION 14.7 | 60.0 years STANDARD_DEVIATION 6.7 | 52.0 years STANDARD_DEVIATION 9.6 | 48.3 years STANDARD_DEVIATION 12.6 | 60.5 years STANDARD_DEVIATION 6.4 | 50.0 years STANDARD_DEVIATION 1 | 49.0 years STANDARD_DEVIATION 9.2 | 54.4 years STANDARD_DEVIATION 9.2 |
| 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 | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 19 | 19 / 28 | 15 / 26 | 9 / 19 |
| serious Total, serious adverse events | 0 / 19 | 1 / 28 | 2 / 26 | 0 / 19 |
Outcome results
Primary
Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP)
Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average diastolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded.
Time frame: Baseline and Day 28
Population: All participants who received at least 1 dose of study drug, complied with protocol sufficiently and had available data for endpoint. Participants are grouped by study drug taken at the time of the evaluation and not by randomly assigned sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7145 3 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP) | -4.5 mmHg |
| MK-7145 6 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP) | -4.3 mmHg |
| HCTZ 25 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP) | -1.5 mmHg |
| Placebo | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Diastolic Blood Pressure (DBP) | -1.1 mmHg |
90% CI: [-6.1, -0.3]
90% CI: [-5.5, -0.2]
90% CI: [-6, -0.1]
90% CI: [-6.5, -0.2]
90% CI: [-3.3, 2.7]
Primary
Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP)
Each participant had their blood pressure monitored by continuous 24-hour ambulatory blood pressure monitoring (ABPM) on Days -1 and 28 of each treatment period. The average systolic blood pressure over the 24-hour monitoring period was calculated for baseline (Day -1) and Day 28. The difference between baseline and Day 28 was calculated and recorded.
Time frame: Baseline and Day 28
Population: All participants who received at least 1 dose of study drug, complied with protocol sufficiently and had available data for endpoint. Participants are grouped by study drug taken at the time of the evaluation and not by randomly assigned sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7145 3 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP) | -9.5 mmHg |
| MK-7145 6 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP) | -10.2 mmHg |
| HCTZ 25 mg | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP) | -4.8 mmHg |
| Placebo | Change From Baseline in Time-weighted Average Over 24 Hours Post Dose (TWA [0-24]) in Systolic Blood Pressure (SBP) | -2.8 mmHg |
Comparison: Type I error rate of alpha=0.10 (1-sided) is specified for testing of the hypothesis.80% CI: [-10.6, -4.1]
Comparison: Type I error rate of alpha=0.05 (1-sided) is specified for testing of the hypothesis.90% CI: [-9.2, -1.6]
90% CI: [-9, -0.5]
90% CI: [-11.2, -2.2]
90% CI: [-6.2, 2.3]
Primary
Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1
Urine sodium (Na) levels were measured over 24-hours on Day -1 (baseline) and on Day 1. The total amount of Na excreted in the urine for Day-1 (baseline) and Day1 were calculated and the difference between the 2 values was recorded.
Time frame: Baseline (Day-1) and Day 1
Population: All participants who received at least 1 dose of study drug, complied with protocol sufficiently and had available data for endpoint. Participants are grouped by study drug taken at the time of the evaluation and not by randomly assigned sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7145 3 mg | Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1 | 0.4 mmol/day |
| MK-7145 6 mg | Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1 | 46.0 mmol/day |
| HCTZ 25 mg | Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1 | 64.1 mmol/day |
| Placebo | Change From Baseline in Urine Sodium at 24 Hours Post-dose on Day 1 | -30.5 mmol/day |
Comparison: Type I error rate of alpha=0.10 (1-sided) is specified for testing of the hypothesis.80% CI: [49.2, 103.8]
90% CI: [-100.8, -26.7]
90% CI: [-49.1, 12.9]
90% CI: [-7, 68.7]
90% CI: [58.8, 130.4]
Primary
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE during the study was summarized by study drug taken at the time of the AE.
Time frame: Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period)
Population: All participants who received at least 1 dose of study drug. AEs are reported by study drug taken at the time of the event and not by randomly assigned sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-7145 3 mg | Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) | 84.2 Percentage of Participants |
| MK-7145 6 mg | Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) | 78.6 Percentage of Participants |
| HCTZ 25 mg | Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) | 73.1 Percentage of Participants |
| Placebo | Percentage of Participants Who Experienced at Least 1 Adverse Event (AE) | 47.4 Percentage of Participants |
Primary
Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who experienced an AE that was reported as at least possibly-related to the study was summarized by study drug taken at the time of the AE.
Time frame: Up to 14 days post last dose of each treatment period (total of 6 weeks for each treatment period)
Population: All participants who received at least 1 dose of study drug. AEs are reported by study drug taken at the time of the event and not by randomly assigned sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-7145 3 mg | Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE) | 52.6 Percentage of Participants |
| MK-7145 6 mg | Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE) | 42.9 Percentage of Participants |
| HCTZ 25 mg | Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE) | 42.3 Percentage of Participants |
| Placebo | Percentage of Participants Who Experienced at Least 1 Drug-related Adverse Event (AE) | 26.3 Percentage of Participants |
Primary
Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the 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 was temporally associated with the use of the product, was also an AE. The percentage of participants who had the administration of the study drug discontinued during the study was summarized by study drug taken at the time of the AE. Participants may or may not have completed the study.
Time frame: up to 4 weeks of each treatment period
Population: All participants who received at least 1 dose of study drug. AEs are reported by study drug taken at the time of the event and not by randomly assigned sequence.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-7145 3 mg | Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE) | 0 Percentage of Participants |
| MK-7145 6 mg | Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE) | 10.7 Percentage of Participants |
| HCTZ 25 mg | Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE) | 7.7 Percentage of Participants |
| Placebo | Percentage of Participants Who Had Study Discontinued During the Study Due to an Adverse Event (AE) | 5.3 Percentage of Participants |
Secondary
Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28
Urine potassium (K+) levels were measured over 24-hours on Day -1 and on Day 28. The total amount of K+ excreted in the urine for Day-1 (baseline) and Day 28 were calculated and the difference between the 2 values was recorded.
Time frame: Baseline (Day -1) and Day 28
Population: All participants who received at least 1 dose of study drug, complied with protocol sufficiently and had available data for endpoint. Participants are grouped by study drug taken at the time of the evaluation and not by randomly assigned sequence.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-7145 3 mg | Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28 | 0.3 mmol/day |
| MK-7145 6 mg | Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28 | -6.5 mmol/day |
| HCTZ 25 mg | Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28 | -2.7 mmol/day |
| Placebo | Change From Baseline in Urine Potassium at 24 Hours Post-dose on Day 28 | -7.6 mmol/day |
80% CI: [-2.3, 18.2]
80% CI: [-8.5, 10.7]
90% CI: [-9.6, 15.6]
90% CI: [-15, 7.2]
90% CI: [-7.7, 17.6]