Pulmonary Arterial Hypertension
Conditions
Brief summary
This study will evaluate safety, tolerability and effects on central diastolic blood pressure (cDBP) of MK-8892 given as single oral doses in healthy male participants (Panel A and B) and in male participants with mild-to-moderate hypertension (Panel C).
Detailed description
Up to three planned panels of either 8 healthy participants (Panels A and B) or 8 participants with mild to moderate hypertension (Panel C) will be enrolled. In Panels A and B, 8 participants will alternately receive single rising doses of MK-8892 or placebo. All doses will be administered in the fasted state, except Panel A, Period 5 in which a standard high-fat breakfast provided approximately 30 minutes prior to dosing. Panel A will begin first. At least 3 days will elapse before participants in the alternate panel (Panel B) will receive the next higher dose. In Panel C, 8 mild to moderate hypertensive male participants will receive single rising doses of MK-8892 or placebo. Panel C may begin after the first 4 periods of Panels A and B have completed dosing. For all panels, there will be at least 7 days washout between treatment periods for any given participant. Participants may only be enrolled in one panel of the study. Subsequent doses in any panel will be administered only after careful evaluation of safety, tolerability, and pharmacodynamic effects of a given dose. All participants in periods of all panels (with exception of 2.0 mg fasted/fed periods) will be randomly assigned to either study drug or placebo, i.e a participant could be assigned to receive study drug in one period and placebo in another. As per the protocol allocation plan, the same participants will receive 2.0 mg MK-8892 in a fasted and fed state.The 2.0 mg MK-8892 fed/fasted data will be utilized for pharmacokinetic comparison and only the 2.0 mg MK-8892 fasted data will utilized for the analysis of the pharmacodynamics endpoints. In addition, during any of the treatment periods if a participant demonstrates change in any one of the protocol-defined parameters lasting ≥1 hour, dose escalation in that participant will be halted and the participant may be withdrawn from the study or rechallenged at same dose or at a lower dose. Paricipants that meet criteria listed will be followed up until parameters no longer meet stopping rule criteria.
Interventions
DRUGMK-8892
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 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Systolic blood pressure (SBP) \> 110 and ≤ 140 mmHg for Panels A and B, SBP values of 140-175 mmHg and diastolic blood pressure (DBP) of 90-105 mmHg on at least three different occasions at the prestudy (screening) visit for Panel C. Participants being treated with medication for their hypertension may be included as long as they are titrated off of their medication * Body Mass Index (BMI) ≥ 18 kg/m\^2 and ≤ 32 kg/m\^2 * Healthy (with the exception of hypertensive subjects in Panel C) * No clinically significant abnormality on electrocardiogram (ECG) * No history of clinically significant cardiac disease * No history of heart failure * Nonsmoker and/or has not used nicotine or nicotine-containing products for at least 6 months
Exclusion criteria
* Mentally or legally incapacitated * History of stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal, cardiovascular (except mild to moderate hypertension), hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * Functional disability that can interfere with rising from a sitting position to the standing position * History of cancer (malignancy) * History of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or nonprescription drugs or food * Positive for hepatitis B, hepatitis C, or Human Immunodeficiency Virus (HIV) * Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 4 weeks * Has participated in another investigational trial within 4 weeks * Unable to refrain from or anticipates the use of any medication during the study * Anticipates using medication for erectile dysfunction during the study * Uses or anticipates using organic nitrates during the study (e.g. nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, pentaerythritol) * Anticipates using cytochrome P450 inhibitors (e.g. ketoconazole) or inducers (e.g. rifampin) during the study * Consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages per day * Consumes excessive amounts, defined as greater than 6 servings of coffee, tea, cola, or other caffeinated beverages per day * Regular user (including recreational user) of illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | up to 7 weeks | An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. Adverse events were summarized by dose taken at the time of the event. |
| Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | up to 7 weeks | An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not considered related to the medicinal product. The percentage of participants that were discontinued from the study due to an AE was summarized. Adverse events were summarized by dose taken at the time of the event. |
| Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel) | Central diastolic blood pressure measurements were obtained at predose and at 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose via applanation tonometry of the radial artery. The average central diastolic blood pressure over the 24-hour monitoring period was calculated for each dose of each panel by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease. |
| Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | up to 7 weeks | An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. Adverse events were summarized by dose taken at the time of the event. |
| Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | up to 7 weeks | An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that were discontinued from the study due to an AE was summarized. Adverse events were summarized by dose taken at the time of the event. |
| Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period) | Central diastolic blood pressure measurements were obtained at predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose via applanation tonometry of the radial artery. The average central diastolic blood pressure over the 24-hour monitoring period was calculated for each dose of each panel by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | Predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel) | Peripheral diastolic blood pressure was measured using a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease. |
| Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | Predose (baseline) and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose (for each Dosing Period of Each Panel) | Heart rate was measured predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose by a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease. |
| Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | Predose (baseline) and 2, 4, 12, and 24 hours postdose (for each Dosing Period of Each Panel) | AIx was measured by applanation tonometry of the radial artery. The central pressure waveform was determined from the peripheral pressure waveform by a transfer function. Augmentation index is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. |
| Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel) | Peripheral blood pressure assessments were obtained at predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose by using a validated automatic measuring device. Peripheral diastolic blood pressure was measured a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease. |
| Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | Predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose (for each Dosing Period of Each Panel) | Heart rate was measured predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose by a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease. |
| TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | Predose to 24 hours Postdose (for each Dosing Period of Each Panel) | AIx was measured by applanation tonometry of the radial artery. The central pressure waveform was determined from the peripheral pressure waveform by a transfer function. Augmentation index is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease. |
| Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | Predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose | Blood samples taken at Predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr. |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last. |
| Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf. |
| Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax. |
| Time to Cmax (Tmax) of MK-8892 - Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Tmax. |
| Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2. |
| Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr. |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last. |
| Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf. |
| Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax. |
| Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Tmax. |
| Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2. |
| Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of 2.0 mg MK-8892-Healthy Participants-Fasted/Fed | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal. |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal. |
| Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal. |
| Maximum Concentration (Cmax) of 2.0 mg MK-8892 - Healthy Participants- Fasted/Fed | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal. |
| Apparent Terminal Half-life (t1/2) of 2.0 mg MK-8892 - Healthy Participants -Fasted/Fed | Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose | Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2.A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal. |
Participant flow
Pre-assignment details
In Panels A and B, 8 healthy male participants alternately received single rising doses of MK-8892 or placebo.In Panel C, 8 mild to moderate hypertensive male participants received single rising doses of MK-8892 determined by results of Panels A and B or placebo. Each period in a panel was separated by a 7-day washout.
Participants by arm
| Arm | Count |
|---|---|
| Panel A-Healthy Within each of the 5 rising dose treatment periods, 6 participants received a single dose of MK-8892 0.5 mg, 2.0 mg, 6.0 mg, or 14 mg, and 2 participants received placebo. Dosing periods alternated with Panel B. | 8 |
| Panel B-Healthy Within each of the 4 rising dose treatment periods, 6 participants received a single dose of MK-8892 1.0 mg, 4.0 mg, 9.0 mg or 12 mg, and 2 participants received placebo. Dosing periods alternated with Panel A. | 8 |
| Panel C-Mild/Moderate Hypertension Within each of the 5 single dose treatment periods, 6 participants with mild to moderate hypertension received a single dose of MK-8892 0.5 mg, 1.0 mg, 2.0 mg or 6.0 mg, and 2 participants received placebo. Dosages were determined by the results of Panels A and B. | 9 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Panel A-Healthy | Panel B-Healthy | Panel C-Mild/Moderate Hypertension | Total |
|---|---|---|---|---|
| Age, Continuous | 42.8 years STANDARD_DEVIATION 9.5 | 37.1 years STANDARD_DEVIATION 15.1 | 50.6 years STANDARD_DEVIATION 5.3 | 43.8 years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 9 Participants | 25 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 | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 16 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 8 |
| other Total, other adverse events | 3 / 6 | 4 / 6 | 3 / 6 | 6 / 6 | 6 / 6 | 5 / 6 | 6 / 6 | 6 / 6 | 7 / 16 | 3 / 6 | 2 / 6 | 4 / 6 | 7 / 9 | 6 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 16 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 8 |
Outcome results
Primary
Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants
Central diastolic blood pressure measurements were obtained at predose and at 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose via applanation tonometry of the radial artery. The average central diastolic blood pressure over the 24-hour monitoring period was calculated for each dose of each panel by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease.
Time frame: Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
Population: Healthy participants (Panels A and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -1.83 mm Hg | Standard Error 1.71 |
| 1.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -2.27 mm Hg | Standard Error 1.69 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -4.21 mm Hg | Standard Error 1.7 |
| 4.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -4.25 mm Hg | Standard Error 1.71 |
| 6.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -6.22 mm Hg | Standard Error 1.7 |
| 9.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -6.64 mm Hg | Standard Error 1.69 |
| 12.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -6.94 mm Hg | Standard Error 1.69 |
| 14.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -8.89 mm Hg | Standard Error 1.7 |
| Placebo-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP)- Healthy Participants | -1.33 mm Hg | Standard Error 1.26 |
p-value: 0.73295% CI: [-3.42, 2.43]Mixed effect model
p-value: 0.53195% CI: [-3.94, 2.06]Mixed effects model
p-value: 0.05695% CI: [-5.83, 0.08]Mixed effects model
p-value: 0.06395% CI: [-6, 0.17]Mixed effects model
p-value: 0.00295% CI: [-7.79, -1.99]Mixed effects model
p-value: 0.00195% CI: [-8.32, -2.31]Mixed effects model
p-value: 0.00195% CI: [-8.62, -2.6]Mixed effects model
p-value: <0.000195% CI: [-10.5, -4.63]Mixed effects model
Primary
Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants
Central diastolic blood pressure measurements were obtained at predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose via applanation tonometry of the radial artery. The average central diastolic blood pressure over the 24-hour monitoring period was calculated for each dose of each panel by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease.
Time frame: Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period)
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | -3.56 mm Hg | Standard Error 1.87 |
| 1.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | -4.76 mm Hg | Standard Error 1.85 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | -7.55 mm Hg | Standard Error 1.85 |
| 4.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | -7.86 mm Hg | Standard Error 1.59 |
| 6.0 mg MK-8892-Healthy | Change in 24-hour Time-weighted Average (TWA0-24hr) for Central Diastolic Blood Pressure (cDBP) - Hypertensive Participants | -1.22 mm Hg | Standard Error 1.67 |
p-value: 0.16595% CI: [-5.7, 1.02]Mixed effects model
p-value: 0.03895% CI: [-6.86, -0.21]Mixed effects model
p-value: 095% CI: [-9.55, -3.1]Mixed effects model
p-value: <0.000195% CI: [-9.35, -3.92]Mixed effects model
Primary
Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. Adverse events were summarized by dose taken at the time of the event.
Time frame: up to 7 weeks
Population: All healthy participants (Panels A and B) who received at least 1 dose of the study drug. As pre-specified in the protocol, safety data were pooled for the MK 8892 2.0 mg fed and fasted arms only and were not planned to be provided separately.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 50.0 Percentage of Participants |
| 1.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 66.7 Percentage of Participants |
| 2.0 mg MK-8892-Healthy (Pooled) | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 50.0 Percentage of Participants |
| 4.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 100.0 Percentage of Participants |
| 6.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 100.0 Percentage of Participants |
| 9.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 83.3 Percentage of Participants |
| 12.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 100.0 Percentage of Participants |
| 14.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 100.0 Percentage of Participants |
| Placebo-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs)- Healthy Participants | 43.8 Percentage of Participants |
Primary
Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized. Adverse events were summarized by dose taken at the time of the event.
Time frame: up to 7 weeks
Population: All hypertensive participants (Panel C) who received at least 1 dose of the study drug in a fasted state.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | 50.0 Percentage of Participants |
| 1.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | 33.3 Percentage of Participants |
| 2.0 mg MK-8892-Healthy (Pooled) | Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | 66.7 Percentage of Participants |
| 4.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | 77.8 Percentage of Participants |
| 6.0 mg MK-8892-Healthy | Percentage of Participants Who Report 1 or More Adverse Events (AEs) - Hypertensive Participants | 75.0 Percentage of Participants |
Primary
Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that were discontinued from the study due to an AE was summarized. Adverse events were summarized by dose taken at the time of the event.
Time frame: up to 7 weeks
Population: All hypertensive participants (Panel C) who received at least 1 dose of the study drug in a fasted state.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | 0.0 Percentage of Participants |
| 1.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | 0.0 Percentage of Participants |
| 2.0 mg MK-8892-Healthy (Pooled) | Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | 0.0 Percentage of Participants |
| 4.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | 0.0 Percentage of Participants |
| 6.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Due to an AE - Hypertensive Participants | 0.0 Percentage of Participants |
Primary
Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not considered related to the medicinal product. The percentage of participants that were discontinued from the study due to an AE was summarized. Adverse events were summarized by dose taken at the time of the event.
Time frame: up to 7 weeks
Population: All healthy participants (Panels A and B) who received at least 1 dose of the study drug. As pre-specified in the protocol, safety data were pooled for the MK 8892 2.0 mg fed and fasted arms only and were not planned to be provided separately.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 1.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 2.0 mg MK-8892-Healthy (Pooled) | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 4.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 6.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 9.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 12.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| 14.0 mg MK-8892-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
| Placebo-Healthy | Percentage of Participants Who Were Discontinued From the Study Due to an AE- Healthy Participants | 0.0 Percentage of Participants |
Secondary
Apparent Terminal Half-life (t1/2) of 2.0 mg MK-8892 - Healthy Participants -Fasted/Fed
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2.A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panel A) who were administered 2.0 mg MK-8892 in both fasted and fed state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of 2.0 mg MK-8892 - Healthy Participants -Fasted/Fed | 20.1 Hours |
| 1.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of 2.0 mg MK-8892 - Healthy Participants -Fasted/Fed | 20.5 Hours |
Secondary
Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 17.9 Hours | Geometric Coefficient of Variation 28 |
| 1.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 20.6 Hours | Geometric Coefficient of Variation 40 |
| 2.0 mg MK-8892-Healthy (Pooled) | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 20.1 Hours | Geometric Coefficient of Variation 44 |
| 4.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 17.7 Hours | Geometric Coefficient of Variation 43 |
| 6.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 15.6 Hours | Geometric Coefficient of Variation 45 |
| 9.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 20.9 Hours | Geometric Coefficient of Variation 28 |
| 12.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 23.7 Hours | Geometric Coefficient of Variation 23 |
| 14.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892 - Healthy Participants | 21.1 Hours | Geometric Coefficient of Variation 41 |
Secondary
Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the t1/2.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Includes protocol-defined 6.0 mg rechallenge.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | 23.5 Hours | Geometric Coefficient of Variation 30 |
| 1.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | 24.5 Hours | Geometric Coefficient of Variation 28 |
| 2.0 mg MK-8892-Healthy (Pooled) | Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | 21.6 Hours | Geometric Coefficient of Variation 34 |
| 4.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | 28.8 Hours | Geometric Coefficient of Variation 49 |
| 6.0 mg MK-8892-Healthy | Apparent Terminal Half-life (t1/2) of MK-8892- Hypertensive Participants | 26.3 Hours | Geometric Coefficient of Variation 57 |
Secondary
Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of 2.0 mg MK-8892-Healthy Participants-Fasted/Fed
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
Population: Healthy participants (Panel A) who were administered 2.0 mg MK-8892 in both fasted and fed state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of 2.0 mg MK-8892-Healthy Participants-Fasted/Fed | 218.2 nM·hr |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of 2.0 mg MK-8892-Healthy Participants-Fasted/Fed | 278.2 nM·hr |
Secondary
Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants
Blood samples taken at Predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr.
Time frame: Predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 67 nM·hr | Geometric Coefficient of Variation 27 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 128 nM·hr | Geometric Coefficient of Variation 32 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 218 nM·hr | Geometric Coefficient of Variation 11 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 464 nM·hr | Geometric Coefficient of Variation 28 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 694 nM·hr | Geometric Coefficient of Variation 14 |
| 9.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 793 nM·hr | Geometric Coefficient of Variation 31 |
| 12.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 1202 nM·hr | Geometric Coefficient of Variation 25 |
| 14.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Healthy Participants | 1306 nM·hr | Geometric Coefficient of Variation 18 |
Secondary
Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose of each dosing period to determine the AUC0-24hr.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Includes protocol-defined 6.0 mg rechallenge.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | 79 nM·hr | Geometric Coefficient of Variation 27 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | 158 nM·hr | Geometric Coefficient of Variation 14 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | 285 nM·hr | Geometric Coefficient of Variation 17 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | 806 nM·hr | Geometric Coefficient of Variation 24 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8892 - Hypertensive Participants | 714 nM·hr | Geometric Coefficient of Variation 22 |
Secondary
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panel A) who were administered 2.0 mg MK-8892 in both fasted and fed state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | 390.0 nM·hr |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | 518.5 nM·hr |
Secondary
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 113 nM·hr | Geometric Coefficient of Variation 37 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 232 nM·hr | Geometric Coefficient of Variation 63 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 391 nM·hr | Geometric Coefficient of Variation 34 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 757 nM·hr | Geometric Coefficient of Variation 50 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 1195 nM·hr | Geometric Coefficient of Variation 30 |
| 9.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 1342 nM·hr | Geometric Coefficient of Variation 41 |
| 12.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 2443 nM·hr | Geometric Coefficient of Variation 39 |
| 14.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892 - Healthy Participants | 2702 nM·hr | Geometric Coefficient of Variation 31 |
Secondary
Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-inf.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Includes protocol-defined 6.0 mg rechallenge.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | 164.0 nM·hr | Geometric Coefficient of Variation 53 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | 346.0 nM·hr | Geometric Coefficient of Variation 32 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | 557.0 nM·hr | Geometric Coefficient of Variation 28 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | 1947.0 nM·hr | Geometric Coefficient of Variation 48 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration Time-curve From Hour 0 to Infinity (AUC0-inf) of MK-8892- Hypertensive Participants | 1760.0 nM·hr | Geometric Coefficient of Variation 38 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panel A) who were administered 2.0 mg MK-8892 in both fasted and fed state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | 368.5 nM·hr | Geometric Coefficient of Variation 29.2 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of 2.0 mg MK-8892 - Healthy Participants-Fasted/Fed | 494.6 nM·hr | Geometric Coefficient of Variation 29.2 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 103.3 nM·hr | Geometric Coefficient of Variation 40 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 216.8 nM·hr | Geometric Coefficient of Variation 58.7 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 368.5 nM·hr | Geometric Coefficient of Variation 29.2 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 724.7 nM·hr | Geometric Coefficient of Variation 42.9 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 1157.6 nM·hr | Geometric Coefficient of Variation 26.4 |
| 9.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 1293.3 nM·hr | Geometric Coefficient of Variation 39.4 |
| 12.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 2286.3 nM·hr | Geometric Coefficient of Variation 35.7 |
| 14.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Healthy Participants | 2527.7 nM·hr | Geometric Coefficient of Variation 25.5 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the AUC0-last.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Hypertensive participants (Panel C) who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | 150.2 nM·hr | Geometric Coefficient of Variation 45.9 |
| 1.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | 317.3 nM·hr | Geometric Coefficient of Variation 25.9 |
| 2.0 mg MK-8892-Healthy (Pooled) | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | 522.3 nM·hr | Geometric Coefficient of Variation 24 |
| 4.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | 1700.2 nM·hr | Geometric Coefficient of Variation 38.5 |
| 6.0 mg MK-8892-Healthy | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Plasma Concentration Time Point (AUC0-last) of MK-8892 - Hypertensive Participants | 1538.8 nM·hr | Geometric Coefficient of Variation 23.5 |
Secondary
Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants
AIx was measured by applanation tonometry of the radial artery. The central pressure waveform was determined from the peripheral pressure waveform by a transfer function. Augmentation index is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours.
Time frame: Predose (baseline) and 2, 4, 12, and 24 hours postdose (for each Dosing Period of Each Panel)
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -1.73 Percentage | Standard Error 2.3 |
| 1.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -2.31 Percentage | Standard Error 2.32 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -2.82 Percentage | Standard Error 2.31 |
| 4.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -0.26 Percentage | Standard Error 2.38 |
| 6.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -4.23 Percentage | Standard Error 2.29 |
| 9.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -3.85 Percentage | Standard Error 2.31 |
| 12.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -1.84 Percentage | Standard Error 2.3 |
| 14.0 mg MK-8892-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -4.81 Percentage | Standard Error 2.32 |
| Placebo-Healthy | Change in TWA0-24hr for Augmentation Index (AIx) - Healthy Participants | -0.07 Percentage | Standard Error 2.06 |
p-value: 0.90195% CI: [-3.22, 2.84]Mixed effect model
p-value: 0.20295% CI: [-4.24, 0.93]Mixed effect model
p-value: 0.11595% CI: [-5.03, 0.57]Mixed effect model
p-value: 0.04395% CI: [-5.4, -0.09]Mixed effect model
p-value: 0.00295% CI: [-6.74, -1.57]Mixed effect model
p-value: 0.00895% CI: [-6.48, -1.06]Mixed effect model
p-value: 0.20195% CI: [-4.51, 0.98]Mixed effect model
p-value: 0.00195% CI: [-7.37, -2.11]Mixed effect model
Secondary
Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants
Heart rate was measured predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose by a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease.
Time frame: Predose (baseline) and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose (for each Dosing Period of Each Panel)
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 0.46 beats per minute (bpm) | Standard Error 1.36 |
| 1.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 5.55 beats per minute (bpm) | Standard Error 1.32 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 4.71 beats per minute (bpm) | Standard Error 1.42 |
| 4.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 7.44 beats per minute (bpm) | Standard Error 1.93 |
| 6.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 9.29 beats per minute (bpm) | Standard Error 2.22 |
| 9.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 8.85 beats per minute (bpm) | Standard Error 1.93 |
| 12.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 10.34 beats per minute (bpm) | Standard Error 1.09 |
| 14.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 16.29 beats per minute (bpm) | Standard Error 2.21 |
| Placebo-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Healthy Participants | 2.23 beats per minute (bpm) | Standard Error 1.11 |
p-value: 0.21295% CI: [-4.59, 1.05]Mixed effect model
p-value: 0.0595% CI: [0, 6.64]Mixed effect model
p-value: 0.01695% CI: [0.49, 4.47]Mixed effect model
p-value: 0.00795% CI: [1.51, 8.92]Mixed effect model
p-value: 0.00195% CI: [3.03, 11.1]Mixed effect model
p-value: 0.00295% CI: [2.54, 10.71]Mixed effect model
p-value: <0.000195% CI: [5.45, 10.76]Mixed effect model
p-value: <0.000195% CI: [10.54, 17.57]Mixed effect model
Secondary
Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants
Heart rate was measured predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose by a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease.
Time frame: Predose and every 30 minutes from 0.5-4 hours postdose; hourly from 4-12 hours postdose; every 2 hours from 12-16 hours postdose; and at 24 postdose (for each Dosing Period of Each Panel)
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | -0.92 bpm | Standard Error 1.59 |
| 1.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | -0.74 bpm | Standard Error 1.88 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | 0.87 bpm | Standard Error 1.92 |
| 4.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | 7.68 bpm | Standard Error 1.51 |
| 6.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Heart Rate (HR) - Hypertensive Participants | -1.46 bpm | Standard Error 1.62 |
p-value: 0.63895% CI: [-1.8, 2.87]Mixed effect model
p-value: 0.61695% CI: [-2.2, 3.63]Mixed effect model
p-value: 0.04195% CI: [0.11, 4.56]Mixed effect model
p-value: <0.000195% CI: [6.98, 11.3]Mixed effect model
Secondary
Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants
Peripheral diastolic blood pressure was measured using a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. A negative number indicates a decrease.
Time frame: Predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -4.34 mm Hg | Standard Error 1.73 |
| 1.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -2.43 mm Hg | Standard Error 0.83 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -3.69 mm Hg | Standard Error 1.1 |
| 4.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -4.50 mm Hg | Standard Error 1.49 |
| 6.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -6.56 mm Hg | Standard Error 1.06 |
| 9.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -7.04 mm Hg | Standard Error 0.99 |
| 12.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -7.35 mm Hg | Standard Error 0.71 |
| 14.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -9.89 mm Hg | Standard Error 1.68 |
| Placebo-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Healthy Participants | -1.67 mm Hg | Standard Error 0.82 |
p-value: 0.12895% CI: [-6.14, 0.8]Mixed effect model
p-value: 0.30595% CI: [-2.24, 0.72]Mixed effect model
p-value: 0.0795% CI: [-4.23, 0.17]Mixed effects model
p-value: 0.03695% CI: [-5.48, -0.19]Mixed effects model
p-value: <0.000195% CI: [-6.4, -3.37]Mixed effects model
p-value: <0.000195% CI: [-7.29, -3.46]Mixed effects model
p-value: <0.000195% CI: [-6.7, -4.65]Mixed effect model
p-value: <0.000195% CI: [-11.95, -4.5]Mixed effect model
Secondary
Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants
Peripheral blood pressure assessments were obtained at predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose by using a validated automatic measuring device. Peripheral diastolic blood pressure was measured a validated automatic measuring device. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease.
Time frame: Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | -3.40 mm Hg | Standard Error 1.13 |
| 1.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | -4.17 mm Hg | Standard Error 1.63 |
| 2.0 mg MK-8892-Healthy (Pooled) | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | -7.29 mm Hg | Standard Error 1.4 |
| 4.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | -9.16 mm Hg | Standard Error 1.43 |
| 6.0 mg MK-8892-Healthy | Change in TWA0-24hrs for Peripheral Diastolic Blood Pressure (pDBP) - Hypertensive Participants | -0.87 mm Hg | Standard Error 1.4 |
p-value: 0.04295% CI: [-4.97, -0.1]Mixed effect model
p-value: 0.0195% CI: [-5.71, -0.88]Mixed effect model
p-value: <0.000195% CI: [-8.94, -3.89]Mixed effect model
p-value: <0.000195% CI: [-11.32, -5.25]Mixed effect model
Secondary
Maximum Concentration (Cmax) of 2.0 mg MK-8892 - Healthy Participants- Fasted/Fed
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax. A mixed effects model with Cohort (Healthy or hypertensive) as a fixed term, participant as a random effect was used for summary data. For participants that participated in Period 5, study drug was administered after a standard high-fat breakfast provided approximately 30 minutes prior to dosing. The meal was consumed in a 20-minute period with start and stop times being recorded. Participants were administered a single dose of MK-8892 or matching placebo Within 10 minutes of completing the meal.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panel A) who were administered 2.0 mg MK-8892 in both fasted and fed state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Maximum Concentration (Cmax) of 2.0 mg MK-8892 - Healthy Participants- Fasted/Fed | 17.9 nM |
| 1.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of 2.0 mg MK-8892 - Healthy Participants- Fasted/Fed | 20.5 nM |
Secondary
Maximum Concentration (Cmax) of MK-8892 - Healthy Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 4.8 nM | Geometric Coefficient of Variation 32 |
| 1.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 8.5 nM | Geometric Coefficient of Variation 23 |
| 2.0 mg MK-8892-Healthy (Pooled) | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 17.9 nM | Geometric Coefficient of Variation 19 |
| 4.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 35.6 nM | Geometric Coefficient of Variation 26 |
| 6.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 49.0 nM | Geometric Coefficient of Variation 21 |
| 9.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 52.8 nM | Geometric Coefficient of Variation 38 |
| 12.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 72.8 nM | Geometric Coefficient of Variation 23 |
| 14.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892 - Healthy Participants | 87.3 nM | Geometric Coefficient of Variation 16 |
Secondary
Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Cmax.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Includes protocol-defined 6.0 mg rechallenge.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | 4.9 nM | Geometric Coefficient of Variation 21 |
| 1.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | 9.8 nM | Geometric Coefficient of Variation 13 |
| 2.0 mg MK-8892-Healthy (Pooled) | Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | 17.6 nM | Geometric Coefficient of Variation 30 |
| 4.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | 48.9 nM | Geometric Coefficient of Variation 15 |
| 6.0 mg MK-8892-Healthy | Maximum Concentration (Cmax) of MK-8892- Hypertensive Participants | 47.1 nM | Geometric Coefficient of Variation 33 |
Secondary
Time to Cmax (Tmax) of MK-8892 - Healthy Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Tmax.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Healthy participants (Panels and B) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 1.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 2.0 mg MK-8892-Healthy (Pooled) | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 4.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 6.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 9.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 5 hours |
| 12.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 4 hours |
| 14.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892 - Healthy Participants | 2 hours |
Secondary
Time to Cmax (Tmax) of MK-8892- Hypertensive Participants
Blood samples taken at Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose of each dosing period to determine the Tmax.
Time frame: Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint. Includes protocol-defined 6.0 mg rechallenge.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.5 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | 3 Hours |
| 1.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | 4 Hours |
| 2.0 mg MK-8892-Healthy (Pooled) | Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | 6 Hours |
| 4.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | 4 Hours |
| 6.0 mg MK-8892-Healthy | Time to Cmax (Tmax) of MK-8892- Hypertensive Participants | 4 Hours |
Secondary
TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants
AIx was measured by applanation tonometry of the radial artery. The central pressure waveform was determined from the peripheral pressure waveform by a transfer function. Augmentation index is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. The time-weighted average change from baseline was calculated by adjusting each time-point by the baseline, aggregating the area under the curve (AUC) by the trapezoidal method and then dividing the AUC by 24 hours. Negative number indicates a decrease.
Time frame: Predose to 24 hours Postdose (for each Dosing Period of Each Panel)
Population: Hypertensive participants (Panel C) who were administered study drug in a fasted state, who complied with the protocol sufficiently to ensure that these data were likely to exhibit the effects of the treatment, according to the underlying scientific model and had data available for endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg MK-8892-Healthy | TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | -2.30 Percentage | Standard Error 2.01 |
| 1.0 mg MK-8892-Healthy | TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | -2.57 Percentage | Standard Error 2.01 |
| 2.0 mg MK-8892-Healthy (Pooled) | TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | -3.94 Percentage | Standard Error 2.01 |
| 4.0 mg MK-8892-Healthy | TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | -5.43 Percentage | Standard Error 1.8 |
| 6.0 mg MK-8892-Healthy | TWA0-24hr for Augmentation Index (AIx) - Hypertensive Participants | -1.65 Percentage | Standard Error 1.86 |
p-value: 0.67795% CI: [-3.81, 2.52]Mixed effect model
p-value: 0.55495% CI: [-4.08, 2.24]Mixed effect model
p-value: 0.13795% CI: [-5.35, 0.78]Mixed effect model
p-value: 0.00695% CI: [-6.37, -1.19]Mixed effect model