Hypertension
Conditions
Keywords
High blood pressure
Brief summary
This was designed as a two part study comprising sequential double-dummy, placebo controlled 3-period randomized crossover studies. The study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of different doses and dose regimens of MK-8266. Only Part I of the study was completed.
Interventions
DRUGTreatment A
MK-8266 1.3 mg orally twice daily (BID, 1 mg in the morning and 0.3 mg 8 hours later) plus placebo to match Treatment B on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.
DRUGTreatment B
MK-8266 0.1 mg orally administered every 2 hours as frequent divided dosing (FDD, total dose of 0.9 mg) plus placebo to match Treatment A on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.
DRUGTreatment C
Placebo to match MK-8266 Treatments A and B orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
DRUGTreatment D
MK-8266 orally twice daily (1 mg in the morning and 0.4 mg 8 hours later) plus placebo to match Treatment E on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.
DRUGTreatment E
MK-8266 0.2 mg orally every 2 hours (total dose of 1.4 mg) plus placebo to match Treatment D on Days 1 through 3. On Day 4, single dose of 1 mg MK-8266.
DRUGTreatment F
Placebo to match MK-8266 Treatments D and E orally daily on Days 1 through 3. On Day 4, single dose of placebo to match MK-8266.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
21 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Participant has essential hypertension who is in grade 1 or 2 hypertension according to the European Society of Hypertension (ESH) as delineated in the European Society of Cardiology (ESC) 2007 guidelines, i.e. systolic blood pressure values of 140-179 and diastolic blood pressure values of 90-109 on at least 3 occasions prior to the study. * Otherwise healthy participants with grade 1 or 2 arterial hypertension who are treated with a single antihypertensive drug and meet the above blood pressure criteria may be enrolled at the discretion of the investigator * Participant is generally in good health with the exception of hypertension * Participant is a nonsmoker and/or has not used nicotine or nicotine-containing products for 6 months
Exclusion criteria
* Participant has a history of any illness that might confound the results of the study or pose and additional risk to the participant if they take part in the study * Participant has a history of stroke, chronic seizures, or major neurological disorder * Participant has a disability that can interfere with rising from a semi-recumbent position to the standing position * Participant has a personal or family history of a bleeding or clotting disorder * Participant has a history of frequent nosebleeds or recurrent or active gingivitis * Participant has a history of cancer, except 1) certain skin cancers; 2) cancer successfully treated more than 10 years prior to the study that has not recurred; or, 3) participants who are unlikely to have a recurrence during the study * Participant has a history of cardiac disease including but not limited to heart valve disease or evidence of secondary cardiac damage * Participant is categorized as class II or greater according to the New York Heart Association (NYHA) functional classification for heart failure * Participant is unable to refrain from use of prescription or non-prescription drugs or herbal remedies (such as St. John's Wort) during the study * Participant anticipates using phosphodiesterase (PDE5) inhibitors \[sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®)\] during the study * Participant consumes excessive amounts of alcohol (more than 3 drinks per day) or caffeine (more than 6 servings a day) * Participant has had major surgery, donated or lost 1 unit of blood, or participated in another investigational within 4 weeks prior to the study * Participant has a history of multiple and/or severe allergies, or has had an anaphylactic reaction or intolerance to any drugs or food
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events (AEs) | MK-8266 1.3 mg BID and 0.9 mg FDD groups: Up to Day 4 in each period; MK-8266 1 mg QD group: the last AE was reported on day 10 after the last dose; Placebo group: Up to 10-14 days after the last dose of placebo | The number of participants with one or more clinical or laboratory AEs was assessed. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. |
| Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3 | Pre-dose and 0.5, 1, 2, 4, and 8 hours after dosing on Day 1, and pre-dose and 4 and 8 hours after dosing on Day 3 of each period | The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided. |
| Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4 | Predose and 2, 4, and 8 hours after dosing on Day 4 of each period | The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided. |
| Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3 | Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3 | The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided. |
| Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4 | Predose and 2, 4, and 8 hours after dosing on Day 4 of each period | The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided. |
| Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3 | Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3 | The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 1 and Day 3. |
| Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4 | Predose and 2, 4, and 8 hours after dosing on Day 4 of each period | The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 4. |
| Change From Baseline in Heart Rate (HR) | Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3 | The effect of MK-8266 and placebo on changes in HR were assessed, as measured by time weighted average change from baseline in HR over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for HR are shown in the Baseline Characteristics section. |
| Change From Baseline in Diastolic Blood Pressure (DBP) | Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3 | The effect of MK-8266 and placebo on changes in diastolic blood pressure (DBP) were assessed, as measured by time weighted average change from baseline in DBP over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for DBP are shown in the Baseline Characteristics section. |
Participant flow
Recruitment details
The same participants in Part 1 were to continue in Part 2, pending the planned evaluation of Part 1 pharmacodynamic results. Based on the Part 1 results, no participants continued to Part 2.
Participants by arm
| Arm | Count |
|---|---|
| All Participants, All Sequences A: MK-8266 1.3 mg BID, B: MK-8266 0.9 mg FDD, C: Placebo | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1: Period 1 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 1: Period 1 | Fulfilled Stopping Criteria | 1 | 0 | 2 | 0 | 1 | 1 |
| Part 1: Period 1 | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 | 0 |
| Part 1: Period 2 | Fulfilled Stopping Criteria | 0 | 0 | 1 | 0 | 0 | 0 |
| Part 1: Period 3 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 1: Period 3 | Protocol Deviation | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 1: Period 3 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants, All Sequences |
|---|---|
| Age, Continuous | 49.1 Years STANDARD_DEVIATION 6.7 |
| Diastolic Blood Pressure (DBP) | 93.36 mmHg STANDARD_DEVIATION 5.08 |
| Heart Rate (HR) | 78.00 Beats per minute STANDARD_DEVIATION 8.77 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 | 0 / 26 | 0 / 27 |
| other Total, other adverse events | 9 / 25 | 16 / 26 | 8 / 26 | 9 / 27 |
| serious Total, serious adverse events | 0 / 25 | 0 / 26 | 0 / 26 | 0 / 27 |
Outcome results
Primary
Adverse Events (AEs)
The number of participants with one or more clinical or laboratory AEs was assessed. An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product.
Time frame: MK-8266 1.3 mg BID and 0.9 mg FDD groups: Up to Day 4 in each period; MK-8266 1 mg QD group: the last AE was reported on day 10 after the last dose; Placebo group: Up to 10-14 days after the last dose of placebo
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8266 1.3 mg BID | Adverse Events (AEs) | 9 Participants |
| MK-8266 0.9 mg FDD | Adverse Events (AEs) | 16 Participants |
| MK-8266 1 mg QD | Adverse Events (AEs) | 8 Participants |
| Placebo | Adverse Events (AEs) | 9 Participants |
Primary
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4
The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.
Time frame: Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Population: All participants who received at least one dose of the investigational drug and had assessment of AUC(0-8 hours)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8266 1.3 mg BID | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4 | 135 nM*hr | Standard Deviation 46.6 |
| MK-8266 0.9 mg FDD | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Day 4 | 139 nM*hr | Standard Deviation 43.2 |
Primary
Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3
The AUC(0-8 hours) of MK-8266 was assessed. The arithmetic mean and standard deviation values of AUC(0-8 hours), based on the raw scale, are provided.
Time frame: Pre-dose and 0.5, 1, 2, 4, and 8 hours after dosing on Day 1, and pre-dose and 4 and 8 hours after dosing on Day 3 of each period
Population: All participants who received at least one dose of the investigational drug and had assessment of AUC(0-8 hours)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8266 1.3 mg BID | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3 | Day 1 | 83.4 nM*hr | Standard Deviation 22.2 |
| MK-8266 1.3 mg BID | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3 | Day 3 | 120 nM*hr | Standard Deviation 41.7 |
| MK-8266 0.9 mg FDD | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3 | Day 1 | 23.7 nM*hr | Standard Deviation 5.96 |
| MK-8266 0.9 mg FDD | Area Under the MK-8266 Concentration Versus Time Curve AUC(0-8 Hours) on Days 1 and 3 | Day 3 | 69.3 nM*hr | Standard Deviation 25.8 |
Primary
Change From Baseline in Diastolic Blood Pressure (DBP)
The effect of MK-8266 and placebo on changes in diastolic blood pressure (DBP) were assessed, as measured by time weighted average change from baseline in DBP over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for DBP are shown in the Baseline Characteristics section.
Time frame: Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3
Population: All participants who received at least one dose of the investigational drug and had DBP measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-8266 1.3 mg BID | Change From Baseline in Diastolic Blood Pressure (DBP) | -3.21 mmHg | Standard Deviation 3.77 |
| MK-8266 0.9 mg FDD | Change From Baseline in Diastolic Blood Pressure (DBP) | -3.04 mmHg | Standard Deviation 5.3 |
| MK-8266 1 mg QD | Change From Baseline in Diastolic Blood Pressure (DBP) | -0.28 mmHg | Standard Deviation 4.68 |
p-value: 0.021290% CI: [-5.3, -0.57]Linear mixed effects model
p-value: 0.029990% CI: [-5.16, -0.36]Linear mixed effects model
p-value: 0.450690% CI: [-2.54, 2.19]Linear mixed effects model
Primary
Change From Baseline in Heart Rate (HR)
The effect of MK-8266 and placebo on changes in HR were assessed, as measured by time weighted average change from baseline in HR over 0-24 hours postdose (TWA\^0-24 hr) on Day 3. Baseline values for HR are shown in the Baseline Characteristics section.
Time frame: Pre-dose (Baseline) and every 30 minutes for the first 4 hours, followed by hourly up to 24 hours after dosing on Day 3
Population: All participants who received at least one dose of the investigational drug and had HR measurements
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MK-8266 1.3 mg BID | Change From Baseline in Heart Rate (HR) | 2.78 Beats per minute | Standard Deviation 6.67 |
| MK-8266 0.9 mg FDD | Change From Baseline in Heart Rate (HR) | 5.84 Beats per minute | Standard Deviation 3.94 |
| MK-8266 1 mg QD | Change From Baseline in Heart Rate (HR) | 1.68 Beats per minute | Standard Deviation 3.67 |
p-value: 0.132590% CI: [-0.54, 2.74]Linear mixed effects model
p-value: <0.00190% CI: [2.53, 5.79]Linear mixed effects model
p-value: 0.001690% CI: [-4.7, -1.42]Linear mixed effects model
Primary
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3
The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3
Population: All participants who received at least one dose of the investigational drug and had assessment for Cmax
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8266 1.3 mg BID | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3 | Day 1 | 17.4 mg/mL | Standard Deviation 4.01 |
| MK-8266 1.3 mg BID | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3 | Day 3 | 20.5 mg/mL | Standard Deviation 6.11 |
| MK-8266 0.9 mg FDD | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3 | Day 1 | 8.63 mg/mL | Standard Deviation 2.85 |
| MK-8266 0.9 mg FDD | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 1 and Day 3 | Day 3 | 11.0 mg/mL | Standard Deviation 3.73 |
Primary
Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4
The Cmax of MK-8266 was assessed. The arithmetic mean and standard deviation values of Cmax, based on the raw scale, are provided.
Time frame: Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Population: All participants who received at least one dose of the investigational drug and had assessment for Cmax
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8266 1.3 mg BID | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4 | 23.1 nM | Standard Deviation 7.28 |
| MK-8266 0.9 mg FDD | Maximum Plasma Concentration (Cmax) of MK-8266 on Day 4 | 23.3 nM | Standard Deviation 6.86 |
Primary
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3
The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 1 and Day 3.
Time frame: Pre-dose and 0.5, 1, 2, 4, 8, 12, 14, 15, and 16 hours after dosing on Days 1 and 3
Population: All participants who received at least one dose of the investigational drug and had assessment for Tmax
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MK-8266 1.3 mg BID | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3 | Day 1 | 4.0 Hours |
| MK-8266 1.3 mg BID | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3 | Day 3 | 4.0 Hours |
| MK-8266 0.9 mg FDD | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3 | Day 1 | 16.0 Hours |
| MK-8266 0.9 mg FDD | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 1 and Day 3 | Day 3 | 16.0 Hours |
Primary
Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4
The Tmax of MK-8266 was assessed. Descriptive statistics are provided for the minimum, median and maximum values for the Tmax of MK-8266 on Day 4.
Time frame: Predose and 2, 4, and 8 hours after dosing on Day 4 of each period
Population: All participants who received at least one dose of the investigational drug and had assessment for Tmax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-8266 1.3 mg BID | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4 | 4.0 Hours |
| MK-8266 0.9 mg FDD | Time to Maximum Plasma Concentration (Tmax) of MK-8266 on Day 4 | 4.0 Hours |