A Rising Single Dose Study of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics of MK-8892 (MK-8892-001)

Pulmonary Arterial Hypertension Clinical Trial

Official title:

A Single Rising Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8892

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01798849
• Other study ID #: 8892-001
• Secondary ID: 2012-005472-34
• Status: Completed
• Phase: Phase 1
• Start date: March 15, 2013
• Est. completion date: July 17, 2013

Study information

• Verified date: May 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: July 17, 2013
• Est. primary completion date: July 17, 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• MK-8892

• Placebo for MK-8892

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	up to 7 weeks
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.	up to 7 weeks
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.	Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
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.	up to 7 weeks
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.	up to 7 weeks
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.	Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period)
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.	Predose and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
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.	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)
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.	Predose (baseline) and 2, 4, 12, and 24 hours postdose (for each Dosing Period of Each Panel)
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.	Predose (baseline) and 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose (for each Dosing Period of Each Panel)
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.	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)
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.	Predose to 24 hours Postdose (for each Dosing Period of Each Panel)
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.	Predose, 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose
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.	Predose and 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours postdose