Hypertension
Conditions
Keywords
Hypertension
Brief summary
This study evaluated adverse events (AEs), study discontinuation due to AEs, and pharmacodynamics of MK-8266 in male participants with mild to moderate hypertension.
Detailed description
This study evaluated AEs, discontinuation due to AEs, and effects on hemodynamic parameters, including systolic blood pressure (SBP) and aortic augmentation index (AIx), following multiple oral doses of MK-8266. Five serial panels, each consisting of eight participants (40 participants in Panels A, B, C, D, and E), were randomized to receive either MK-8266 or matching placebo twice daily (BID) or three times daily (TID) for 10 consecutive days. Although the original plan was to evaluate MK-8266 treatment in Panels D and E using both BID and TID regimens, the study actually evaluated identical TID regimens in these panels.
Interventions
DRUGMK-8226 BID, 1 mg
MK-8266 1 mg administered as oral capsules (0.7 mg + 0.3 mg), BID for 10 consecutive days. Panel A was completed prior to initiation of Panel B.
DRUGMK-8266 BID, 1.8 mg
MK-8266 1.8 mg administered as oral capsules (1 mg + 0.8 mg), BID for 10 consecutive days. Panel B was completed prior to initiation of Panel C.
DRUGMK-8266 TID, 1.8 mg
MK-8266 1.8 mg administered as oral capsules (0.6 mg), TID for 10 consecutive days. Panel C was completed prior to initiation of Panel D.
DRUGMK-8266 TID, 2.4 mg
MK-8266 TID (Panel D), 2.4 mg administered as oral capsules (0.8 mg), TID for 10 consecutive days. Panel D was completed prior to initiation of Panel E.
DRUGPlacebo BID (Panel A)
Placebo administered as oral capsules BID for 10 consecutive days. Panel A was completed prior to initiation of Panel B.
DRUGPlacebo BID (Panel B)
Placebo administered as oral capsules BID for 10 consecutive days. Panel B was completed prior to initiation of Panel C.
DRUGPlacebo TID (Panel C)
Placebo administered as oral capsules TID for 10 consecutive days. Panel C was completed prior to initiation of Panel D.
DRUGPlacebo TID (Panel D)
Placebo administered as oral capsules TID for 10 consecutive days. Panel D was completed prior to initiation of Panel E.
DRUGPlacebo TID (Panel E)
Placebo administered as oral capsules TID for 10 consecutive days. Panel E was initiated after completion of Panel D.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Participant is male with essential hypertension (high blood pressure) * Participant is in good general health (with the exception of hypertension) * Participant has a Body Mass Index (BMI) \<= 33 kg/m\^2 at the Screening visit * Participant has a platelet count \>= 150,000 cu/mL at the Screening visit * Participant has a positive AIx at the Screening visit
Exclusion criteria
* Participant has a history of stroke, chronic seizure, or major neurological disease * Participant has a functional disability that can interfere with rising from a seated position to the standing position * Participant has any history of a bleeding or clotting disorder * Participant has a history of cancer * Participant is unable to refrain from or anticipates the use of any prescription or non-prescription medication * Participant consumes excessive amounts of alcohol or caffeinated beverages daily
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | Up to 24 days | Assessment of the number of participants with at least one clinical or laboratory AE in those receiving multiple oral doses of MK-8266. 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. |
| Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | Up to 10 days | Assessment of the number of participants receiving MK-8266 who discontinued therapy due to an AE over 10 days of treatment. 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. The number of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Days 0-10. |
| Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline and Day 10 | Assessment of the change from baseline in SBP, obtained using a validated, semi-automated oscillometric device. Evaluated for MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA\^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. |
| Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | Day 10 (24 hours postdose) | Assessment of HR (beats/min) on Day 10 (24-hours postdose) with MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA\^0-24hrs). Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Baseline HR values are shown in the Baseline Characteristics section for Panels A, B, C, D, E. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | Day 10 | Assessment of the central, ascending aortic blood pressure augmentation index (AIx), based on measurement of central pulse pressure at selected time points on Day 10, as measured by applanation tonometry of the radial artery. This outcome measure assessed the time weighted average change over 24 hours postdose (TWA\^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment. |
| Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline and Day 10 | Assessment of whole blood samples for cGMP analysis, based on samples obtained predose as well as 4 and 24 hours postdose on Day 1 and Day 10, and predose only on Day 4. The change from baseline in cGMP was assessed at 24 hours postdose on Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment. |
| Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline and Day 10 (5 hours postdose) | The percent inhibition of ADP-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of ADP (2.5 µM) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10 only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo. |
| Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo | Baseline and Day 10 (5 hours postdose) | The percent inhibition of collagen-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of collagen (2 µg/mL) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10, only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panel A: MK-8266 BID, 1 mg MK-8266 BID 1 mg, administered as oral capsules (0.7 mg AM + 0.3 mg PM) for 10 days, or as matching placebo | 6 |
| Panel A: Placebo BID Matching placebo capsules, administered orally for 10 days | 2 |
| Panel B: MK-8266 BID, 1.8 mg MK-8266 BID 1 mg, administered as oral capsules (1 mg AM + 0.8 mg PM) for 10 days | 6 |
| Panel B: Placebo BID Matching placebo capsules, administered orally for 10 days | 2 |
| Panel C: MK-8266 TID, 1.8 mg MK-8266 TID 1.8 mg, administered as oral capsules (0.6 mg q6hr) for 10 days | 6 |
| Panel C: Placebo TID Matching placebo capsules, administered orally for 10 days | 2 |
| Panel D: MK-8266 TID, 2.4 mg MK-8266 TID 2.4 mg, administered as oral capsules (0.8 mg q6hr) for 10 days | 6 |
| Panel D: Placebo TID Matching placebo capsules, administered orally for 10 days | 2 |
| Panel E: MK-8266 TID, 2.4 mg MK-8266 TID 2.4 mg, administered as oral capsules (0.8 mg q6hr) for 10 days | 6 |
| Panel E: Placebo TID Matching placebo capsules, administered orally for 10 days | 2 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Met stopping criteria per protocol | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Panel A: MK-8266 BID, 1 mg | Panel A: Placebo BID | Panel B: MK-8266 BID, 1.8 mg | Panel B: Placebo BID | Panel C: MK-8266 TID, 1.8 mg | Panel C: Placebo TID | Panel D: MK-8266 TID, 2.4 mg | Panel D: Placebo TID | Panel E: MK-8266 TID, 2.4 mg | Panel E: Placebo TID | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 1.5 | 47.5 years STANDARD_DEVIATION 4.9 | 45.5 years STANDARD_DEVIATION 7.8 | 52.0 years STANDARD_DEVIATION 1.4 | 46.5 years STANDARD_DEVIATION 3.4 | 54.0 years STANDARD_DEVIATION 1.4 | 46.2 years STANDARD_DEVIATION 5.5 | 46.5 years STANDARD_DEVIATION 7.8 | 47.2 years STANDARD_DEVIATION 5.2 | 48.5 years STANDARD_DEVIATION 0.7 | 47.6 years STANDARD_DEVIATION 4.9 |
| Baseline HR | 70 Beats per minute | 90 Beats per minute | 79 Beats per minute | 89 Beats per minute | 74 Beats per minute | 69 Beats per minute | 72 Beats per minute | 88 Beats per minute | 74 Beats per minute | 81 Beats per minute | 73 Beats per minute |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 6 Participants | 2 Participants | 6 Participants | 2 Participants | 6 Participants | 2 Participants | 6 Participants | 2 Participants | 40 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 |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 5 / 6 | 0 / 2 | 5 / 6 | 1 / 2 | 3 / 6 | 1 / 2 | 4 / 6 | 1 / 2 | 5 / 6 | 2 / 2 |
| serious Total, serious adverse events | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 2 |
Outcome results
Primary
Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo
Assessment of the change from baseline in SBP, obtained using a validated, semi-automated oscillometric device. Evaluated for MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA\^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis.
Time frame: Baseline and Day 10
Population: All participants who received at least one dose of the investigational drug and had SBP assessments at Baseline and on Day 10
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 141.5 Millimeters of mercury (mmHg) | Standard Deviation 8.96 |
| Panel A: MK-8266 BID (1 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | -5.09 Millimeters of mercury (mmHg) | Standard Deviation 7.04 |
| Panel A: Placebo | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 132.6 Millimeters of mercury (mmHg) | Standard Deviation 6.66 |
| Panel A: Placebo | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | -2.18 Millimeters of mercury (mmHg) | Standard Deviation 6.8 |
| Panel B: MK-8266 BID (1.8 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 148.6 Millimeters of mercury (mmHg) | Standard Deviation 23.77 |
| Panel B: MK-8266 BID (1.8 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | -4.78 Millimeters of mercury (mmHg) | Standard Deviation 7.64 |
| Panel B: Placebo | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 0.77 Millimeters of mercury (mmHg) | Standard Deviation 6.62 |
| Panel B: Placebo | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 134.5 Millimeters of mercury (mmHg) | Standard Deviation 8.98 |
| Panel C: MK-8266 TID (1.8 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 146.7 Millimeters of mercury (mmHg) | Standard Deviation 12.07 |
| Panel C: MK-8266 TID (1.8 mg) | Change From Baseline in Systolic Blood Pressure (SBP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | -3.18 Millimeters of mercury (mmHg) | Standard Deviation 7.72 |
p-value: 0.119490% CI: [-17.1, 2.92]Linear mixed effects model
p-value: 0.022490% CI: [-23.7, -2.48]Linear mixed effects model
p-value: 0.479190% CI: [-10.3, 10.91]Linear mixed effects model
Comparison: Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Panel D was completed prior to initiation of Panel E.p-value: 0.070590% CI: [-17.4, 1.01]Linear mixed effcts model
Primary
Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo
Assessment of HR (beats/min) on Day 10 (24-hours postdose) with MK-8266 relative to placebo in participants, as measured by the time weighted average change over 24 hours postdose (TWA\^0-24hrs). Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Baseline HR values are shown in the Baseline Characteristics section for Panels A, B, C, D, E.
Time frame: Day 10 (24 hours postdose)
Population: All participants who received at least one dose of the investigational drug and had HR assessments 24 hours postdose on Day 10.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 65.89 Beats per minute | Standard Deviation 5.59 |
| Panel A: Placebo | Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 69.32 Beats per minute | Standard Deviation 7.87 |
| Panel B: MK-8266 BID (1.8 mg) | Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 62.30 Beats per minute | Standard Deviation 5.28 |
| Panel B: Placebo | Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 66.10 Beats per minute | Standard Deviation 5.38 |
| Panel C: MK-8266 TID (1.8 mg) | Heart Rate (HR) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 62.04 Beats per minute | Standard Deviation 5.98 |
p-value: 0.116190% CI: [-1.51, 9.22]Linear mixed effects model
p-value: 0.018990% CI: [1.6, 12.97]Linear mixed effects model
p-value: 0.468990% CI: [-5.42, 5.95]Linear mixed effects model
Comparison: Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Panel D was completed prior to initiation of Panel E.p-value: 0.086990% CI: [-0.89, 9.01]Linear mixed effects model
Primary
Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE
Assessment of the number of participants receiving MK-8266 who discontinued therapy due to an AE over 10 days of treatment. 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. The number of participants in any treatment group who discontinued therapy due to an AE was primarily assessed for Days 0-10.
Time frame: Up to 10 days
Population: All participants who received at least one dose of the investigational drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel A: Placebo | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel B: MK-8266 BID (1.8 mg) | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 1 Count of Participants |
| Panel B: Placebo | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel C: MK-8266 TID (1.8 mg) | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel C: Placebo | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel D: MK-8266 TID (2.4 mg) | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel D: Placebo | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel E: MK-8266 TID (2.4 mg) | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 0 Count of Participants |
| Panel E: Placebo | Participants Receiving MK-8266 or Placebo Who Discontinued Treatment Due to an AE | 1 Count of Participants |
Primary
Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up
Assessment of the number of participants with at least one clinical or laboratory AE in those receiving multiple oral doses of MK-8266. 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: Up to 24 days
Population: All participants who received at least one dose of the investigational drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 5 Count of Participants |
| Panel A: Placebo | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 0 Count of Participants |
| Panel B: MK-8266 BID (1.8 mg) | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 5 Count of Participants |
| Panel B: Placebo | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 1 Count of Participants |
| Panel C: MK-8266 TID (1.8 mg) | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 3 Count of Participants |
| Panel C: Placebo | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 1 Count of Participants |
| Panel D: MK-8266 TID (2.4 mg) | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 4 Count of Participants |
| Panel D: Placebo | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 1 Count of Participants |
| Panel E: MK-8266 TID (2.4 mg) | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 5 Count of Participants |
| Panel E: Placebo | Participants Receiving MK-8266 or Placebo Who Experienced At Least One Adverse Event (AE) During Treatment and Postdose Follow-up | 2 Count of Participants |
Secondary
Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo
Assessment of the central, ascending aortic blood pressure augmentation index (AIx), based on measurement of central pulse pressure at selected time points on Day 10, as measured by applanation tonometry of the radial artery. This outcome measure assessed the time weighted average change over 24 hours postdose (TWA\^0-24hrs) on dosing Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment.
Time frame: Day 10
Population: All participants who received at least one dose of the investigational drug and had AIx assessment on Day 10
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 8.81 mmHg | Standard Deviation 4.86 |
| Panel A: Placebo | Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 7.45 mmHg | Standard Deviation 2.59 |
| Panel B: MK-8266 BID (1.8 mg) | Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 13.50 mmHg | Standard Deviation 8.95 |
| Panel B: Placebo | Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 11.89 mmHg | Standard Deviation 7 |
| Panel C: MK-8266 TID (1.8 mg) | Aortic Augmentation Index (AIx) on Day 10 Following Multiple Oral Doses of MK-8266 or Placebo | 18.68 mmHg | Standard Deviation 6.68 |
p-value: 0.00390% CI: [-15.7, -4.09]Linear mixed effects model
p-value: 0.00290% CI: [-17.3, -5.1]Linear mixed effects model
p-value: 0.0890% CI: [-11.3, 0.95]Linear mixed effcts model
Comparison: Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Panel D was completed prior to initiation of Panel E.p-value: 0.01990% CI: [-12.1, -1.46]Linear mixed effcts model
Secondary
Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo
Assessment of whole blood samples for cGMP analysis, based on samples obtained predose as well as 4 and 24 hours postdose on Day 1 and Day 10, and predose only on Day 4. The change from baseline in cGMP was assessed at 24 hours postdose on Day 10. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this assessment.
Time frame: Baseline and Day 10
Population: All participants who received at least one dose of the investigational drug and had cGMP assessments at Baseline and on Day 10
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 1.61 nanomoles (nM) | Standard Deviation 0.77 |
| Panel A: MK-8266 BID (1 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 1.34 nanomoles (nM) | Standard Deviation 2.74 |
| Panel A: Placebo | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 0.74 nanomoles (nM) | Standard Deviation 0.5 |
| Panel A: Placebo | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 1.74 nanomoles (nM) | Standard Deviation 4.62 |
| Panel B: MK-8266 BID (1.8 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 1.69 nanomoles (nM) | Standard Deviation 1.15 |
| Panel B: MK-8266 BID (1.8 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 0.43 nanomoles (nM) | Standard Deviation 0.66 |
| Panel B: Placebo | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 0.81 nanomoles (nM) | Standard Deviation 2.78 |
| Panel B: Placebo | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 2.68 nanomoles (nM) | Standard Deviation 1.29 |
| Panel C: MK-8266 TID (1.8 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Baseline value | 0.54 nanomoles (nM) | Standard Deviation 0.21 |
| Panel C: MK-8266 TID (1.8 mg) | Change From Baseline in Cyclic Guanosine Monophosphate (cGMP) Following Multiple Oral Doses of MK-8266 or Placebo | Change from Baseline at Day 10 | 1.05 nanomoles (nM) | Standard Deviation 1.16 |
p-value: 0.31890% CI: [0.53, 3.05]Linear mixed effects model
p-value: 0.1790% CI: [0.66, 4.17]Linear mixed effects model
p-value: 0.05490% CI: [0.16, 1.02]Linear mixed effcts model
Comparison: Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this analysis. Panel D was completed prior to initiation of Panel E.p-value: 0.29790% CI: [0.35, 1.73]Linear mixed effcts model
Secondary
Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo
The percent inhibition of ADP-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of ADP (2.5 µM) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10 only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo.
Time frame: Baseline and Day 10 (5 hours postdose)
Population: All participants who received at least one dose of the investigational drug and had assessment of ADP-induced platelet aggregation on Day 10
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo | -12.3 Percent inhibition | Standard Deviation 29.81 |
| Panel A: Placebo | Percent Inhibition of Platelet Aggregation Induced by Adenosine Diphosphate (ADP) Following Multiple Oral Doses of MK-8266 or Placebo | -12.4 Percent inhibition | Standard Deviation 18.89 |
Secondary
Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo
The percent inhibition of collagen-induced platelet aggregation from Baseline to 5 hours postdose on Day 10 was assessed and is summarized here. Platelet aggregation was initiated by addition of collagen (2 µg/mL) to the participant's blood sample. Aggregation was followed for 5 minutes after addition of the agonist, and the maximum percent of light transmission (extent of aggregation) obtained during this period, as well as the instrument-calculated slope (rate of aggregation), were reported. Post treatment platelet aggregation is expressed as a percent of each participant's pretreatment level of aggregation. Panel D and Panel E had identical treatments (MK-8266 0.8 mg TID), which were combined for this summary. The data are very limited. On Day 10, only 8 participants received MK-8266 0.8 mg TID and 3 participants received placebo.
Time frame: Baseline and Day 10 (5 hours postdose)
Population: All participants who received at least one dose of the investigational drug and had assessment of collagen-induced platelet aggregation on Day 10
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panel A: MK-8266 BID (1 mg) | Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo | -17.7 Percent inhibition | Standard Deviation 26.3 |
| Panel A: Placebo | Percent Inhibition of Platelet Aggregation Induced by Collagen Following Multiple Oral Doses of MK-8266 or Placebo | -8.87 Percent inhibition | Standard Deviation 33.76 |