Hypertension
Conditions
Brief summary
This study will evaluate the effect of treatment with multiple doses of MK-8457 on systolic blood pressure in participants with mild to moderate hypertension in addition to safety and tolerability. The study hypothesis is that MK-8457 does not increase systolic blood pressure to a clinically significant extent, as measured by 24-hour mean ambulatory systolic blood pressure change from baseline after 10 days of dosing.
Interventions
DRUGMK-8457
10 x 10-mg capsule BID for 10 days
DRUGPlacebo for MK-8457
10 x 10-mg capsule BID for 10 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* If female, must be of non-childbearing potential * If male with female partner(s) of child-bearing potential must agree to use a medically acceptable method of contraception during the study and for 90 days after the last dose of study drug * Body mass index (BMI) ≤35 kg/m\^2 * Mild-to-moderate hypertension requiring treatment with one or more antihypertensive agents * Receiving stable treatment for hypertension for at least 8 weeks prior to the start of dosing and continuing therapy for duration of study * No clinically significant arrhythmias or clinically significant abnormality on electrocardiogram * Nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months
Exclusion criteria
* Any illness that might confound the results of the study or poses an additional risk * History of stroke, chronic seizures, or major neurological disorder * Clinically significant endocrine, gastrointestinal, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * Clinically significant cardiovascular disease or has active angina * History of malignant neoplastic disease * Taking 325 mg aspirin daily * Taking 3 or more medications for the treatment of hypertension * Unable to refrain from or anticipates the use of any non-steroidal anti-inflammatory drugs (NSAIDs) * Consumes excessive amounts of alcohol and/or coffee, tea, cola, or other caffeinated beverages * Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 4 weeks * Significant multiple and/or severe allergies * Regular user of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 2 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | Baseline and Day 10 | SBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour least squares (LS) mean ambulatory SBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour SBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Up to 70 days | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Number of Participants Who Discontinued the Study Medication Due to an AE | Up to 70 days | An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of MK-8457 | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 | Maximum plasma concentrations of MK-8521 were determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. |
| Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | Baseline and Day 10 | DBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour LS mean ambulatory DBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour DBP for each participant on Day -1. Increased values represent an increase in hypertensive severity. |
| Trough Plasma Concentration (Ctrough) of MK-8457 | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; pre-AM dose on Day 5 or 6 | The lowest plasma concentration reached by the drug prior to the next administration was determined for Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group was not included; this endpoint evaluated only the MK-8457 group. |
| Time to Maximum Concentration (Tmax) of MK-8457 | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10 | Tmax was determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group. |
| Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | Up to 4 hours postdose on Days 1 and 10 | The effect of drug on resting blood pressure was estimated using maxMAΔ. The maxMAΔ in blood pressure was calculated as the maximum moving average change from baseline to Day 10 of 3 consecutive 15-minute blood pressure measurements across the first 4 hours after the morning (AM) and evening (PM) doses. In this method, the LS means of three consecutive time points over the 4 hour period were determined and the maximum LS mean was used for the endpoint. Blood pressure was determined using continuous monitoring at rest. Increased values represent an increase in hypertensive severity. |
| Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10 | AUC0-12hr is an estimate of total plasma exposure to study drug over the dosing interval (12hr). Plasma concentrations of MK-8457 were determined on Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group is not included; this endpoint evaluated only the MK-8457 group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Protocol Violation | 2 | 0 |
| Period 2 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 52.3 Years STANDARD_DEVIATION 5.9 |
| Age, Customized >=65 years | 1 Participants |
| Age, Customized Between 18 and 65 years | 30 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 31 | 9 / 29 |
| serious Total, serious adverse events | 0 / 31 | 0 / 29 |
Outcome results
Primary
Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP)
SBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour least squares (LS) mean ambulatory SBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour SBP for each participant on Day -1. Increased values represent an increase in hypertensive severity.
Time frame: Baseline and Day 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (change in 24-hour mean ambulatory SBP).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8457 100 mg BID | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | -0.47 mmHg |
| Placebo | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Systolic Blood Pressure (SBP) | -2.49 mmHg |
Comparison: If the upper limit of the 90% confidence interval lies below the bound 5 mmHg, the hypothesis that change from baseline in ambulatory 24-hour mean SBP in participants with mild to moderate hypertension following 10 days of multiple dosing of MK-8457 is similar to placebo will be supported.90% CI: [-0.52, 4.56]Linear mixed effect models
Primary
Number of Participants Who Discontinued the Study Medication Due to an AE
An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 70 days
Population: The safety population consisted of all participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8457 100 mg BID | Number of Participants Who Discontinued the Study Medication Due to an AE | 1 Participant |
| Placebo | Number of Participants Who Discontinued the Study Medication Due to an AE | 0 Participant |
Primary
Number of Participants Who Experienced at Least One Adverse Event (AE)
An AE is defined as any unfavorable and unintended medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 70 days
Population: The safety population consisted of all participants who received at least one dose of the investigational drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8457 100 mg BID | Number of Participants Who Experienced at Least One Adverse Event (AE) | 8 Participant |
| Placebo | Number of Participants Who Experienced at Least One Adverse Event (AE) | 9 Participant |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457
AUC0-12hr is an estimate of total plasma exposure to study drug over the dosing interval (12hr). Plasma concentrations of MK-8457 were determined on Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group is not included; this endpoint evaluated only the MK-8457 group.
Time frame: pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (AUC0-12hr).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8457 100 mg BID | Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | Day 1 (n=31) | 29600 nM*hr | Geometric Coefficient of Variation 36 |
| MK-8457 100 mg BID | Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC0-12hr) of MK-8457 | Day 10 (n=30) | 56200 nM*hr | Geometric Coefficient of Variation 44 |
Secondary
Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP)
DBP was measured using ambulatory blood pressure monitoring (ABPM) on Day -1 and Day 10 of each treatment period. The 24-hour LS mean ambulatory DBP change from baseline was then determined for Day 10, the last day of multiple dose treatment. Baseline is defined as the average 24-hour DBP for each participant on Day -1. Increased values represent an increase in hypertensive severity.
Time frame: Baseline and Day 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (change in 24-hour mean ambulatory DBP).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK-8457 100 mg BID | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | 0.22 mmHg |
| Placebo | Change From Baseline to Day 10 in 24-hour Mean Ambulatory Diastolic Blood Pressure (DBP) | -1.35 mmHg |
90% CI: [0.19, 2.96]Linear mixed effects model
Secondary
Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours
The effect of drug on resting blood pressure was estimated using maxMAΔ. The maxMAΔ in blood pressure was calculated as the maximum moving average change from baseline to Day 10 of 3 consecutive 15-minute blood pressure measurements across the first 4 hours after the morning (AM) and evening (PM) doses. In this method, the LS means of three consecutive time points over the 4 hour period were determined and the maximum LS mean was used for the endpoint. Blood pressure was determined using continuous monitoring at rest. Increased values represent an increase in hypertensive severity.
Time frame: Up to 4 hours postdose on Days 1 and 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (maxMAΔ in blood pressure).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8457 100 mg BID | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | SBP - AM (n=29,28) | 17.80 mmHg | 95% Confidence Interval 13.36 |
| MK-8457 100 mg BID | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | DBP - PM (n=29,27) | 10.89 mmHg | 95% Confidence Interval 11.52 |
| MK-8457 100 mg BID | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | SBP - PM (n=29,27) | 12.68 mmHg | 95% Confidence Interval 12.28 |
| MK-8457 100 mg BID | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | DBP - AM (n=29,28) | 16.90 mmHg | 95% Confidence Interval 8.17 |
| Placebo | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | SBP - AM (n=29,28) | 9.90 mmHg | 95% Confidence Interval 10.05 |
| Placebo | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | DBP - PM (n=29,27) | 12.58 mmHg | 95% Confidence Interval 10.89 |
| Placebo | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | DBP - AM (n=29,28) | 11.64 mmHg | 95% Confidence Interval 8.26 |
| Placebo | Change From Baseline to Day 10 in Maximum Moving Average (maxMAΔ) Blood Pressure Measured Over 4 Hours | SBP - PM (n=29,27) | 13.61 mmHg | 95% Confidence Interval 11.31 |
Comparison: Treatment comparison of maxMAΔ in SBP from baseline to Day 10 after AM dosing90% CI: [2.44, 13.35]Linear mixed effects model
Comparison: Treatment comparison of maxMAΔ in SBP from baseline to Day 10 after PM dosing90% CI: [-5.68, 3.81]Linear mixed effects model
Comparison: Treatment comparison of maxMAΔ in DBP from baseline to Day 10 after AM dosing90% CI: [0.81, 9.71]Linear mixed effects model
Comparison: Treatment comparison of maxMAΔ in DBP from baseline to Day 10 after PM dosing90% CI: [-4.55, 1.17]Linear mixed effects model
Secondary
Maximum Concentration (Cmax) of MK-8457
Maximum plasma concentrations of MK-8521 were determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group.
Time frame: pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Cmax).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8457 100 mg BID | Maximum Concentration (Cmax) of MK-8457 | Day 1 (n=31) | 5680 nM | Geometric Coefficient of Variation 31 |
| MK-8457 100 mg BID | Maximum Concentration (Cmax) of MK-8457 | Day 10 (n=30) | 8630 nM | Geometric Coefficient of Variation 38 |
Secondary
Time to Maximum Concentration (Tmax) of MK-8457
Tmax was determined for the AM dose on Day 1 and Day 10. The placebo group was not included; this endpoint evaluated only the MK-8457 group.
Time frame: pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; 24 hrs post-AM dose on Day 10
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Tmax).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MK-8457 100 mg BID | Time to Maximum Concentration (Tmax) of MK-8457 | Day 1 (n=31) | 1 hr |
| MK-8457 100 mg BID | Time to Maximum Concentration (Tmax) of MK-8457 | Day 10 (n=30) | 1 hr |
Secondary
Trough Plasma Concentration (Ctrough) of MK-8457
The lowest plasma concentration reached by the drug prior to the next administration was determined for Day 1 (after initial dosing) and Day 10 (after multiple dosing). The placebo group was not included; this endpoint evaluated only the MK-8457 group.
Time frame: pre-AM dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hrs post AM dose on Days 1 and 10; pre-AM dose on Day 5 or 6
Population: The per-protocol population consisting of participants who comply with the protocol sufficiently to ensure that data were likely to exhibit the effects of treatment according to the underlying scientific model used for analysis (Ctrough).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8457 100 mg BID | Trough Plasma Concentration (Ctrough) of MK-8457 | Day 1 (n=31) | 999 nM | Geometric Coefficient of Variation 56 |
| MK-8457 100 mg BID | Trough Plasma Concentration (Ctrough) of MK-8457 | Day 10 (n=30) | 2540 nM | Geometric Coefficient of Variation 56 |