Cerebral Infarction
Conditions
Brief summary
The study is designed to assess safety of Vorapaxar when added to standard of care (aspirin) in Japanese subjects with cerebral infarction. The study will assess incidence and tolerability of bleeding, major adverse cardiac events, all adverse events, and effect on expression of markers of inflammation.
Interventions
DRUGVorapaxar 2.5 mg
Oral tablets; once daily for 60 days.
DRUGVorapaxar 1 mg
Oral tablets; once daily for 60 days
DRUGPlacebo
oral tablets; once daily for 60 days
DRUGAspirin 75-150 mg
oral tablets; once daily for 60 days
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women at least 18 years old with last cerebral infarction (excluding cardiogenic cerebral embolism) having occurred from 14 days to less than 1 year after onset (at the time of obtaining consent), with stable nervous system for more than 24 hours and known course of disease. * Participants confirmed to have cerebral infarction lesion by brain computerized tomography (CT) or magnetic resonance imaging (MRI). * Both of in-participant and out-participant * Willing to give appropriate informed consent and complete all study-related procedures and able to adhere to dosing and visit schedules. * Women of child-bearing potential (all postmenopausal women who are \<1 year menopausal or who have not had surgical sterilization or a hysterectomy are considered to be women of child-bearing potential) must agree to use a medically accepted method of contraception while receiving protocol-specified study drug, and for 60 days after completion or discontinuation of the medication.
Exclusion criteria
* Pregnancy and nursing patients (premenopausal women should have a negative pregnancy test result confirmed before enrollment) * Participant with any serious complication or any condition that the investigator feels that would cause a significant hazard to the participant if the study drug is administered. * Known hypersensitivity to any component of the study drug. * Participation in a study or use of an investigational study drug within 30 days before obtaining consent. * Member of the staff personnel directly involved with this study * Family member of the study staff. * History of a bleeding diathesis, or evidence of active abnormal bleeding within 30 days before obtaining consent. * History of cerebral hemorrhage. * Severe hypertension (systolic blood pressure \>200 mmHg or diastolic blood pressure \>110 mmHg). * Major surgery within 2 weeks before obtaining consent. * Known platelet count \<100,000/mm\^3 * Participants confirmed to have cerebral bleeding or any causes of cerebral bleeding by brain CT or MRI. * Participants with transient ischemic attack (TIA), progressive stroke or cardiogenic cerebral embolism. * Known impairment of renal function (serum creatinine \>2.0 mg/dL \[\>176.8 (umol/L\]), dysproteinemia, nephrotic syndrome, or other renal disease * Active or chronic hepatobiliary system or hepatic disease, or aspartate aminotransferase (GOT) or alanine aminotransferate (GPT) activity more than two times greater than the upper limit of the laboratory normal range. * Participants with contraindictation to aspirin. * Scheduled to have PCI (peripheral coronary intervention), peripheral interventional event, carotid endarterectomy, intra- and extra- cranial bypass surgery and intravascular surgery (angioplasty) during the study period. * Combination therapy with unfractionated heparin, tissue plasminogen activator, urokinase, warfarin, factor Xa inhibitor, direct thrombin inhibitor or antiplatelet agents other than aspirin after obtaining consent, or scheduled to have the above combination therapy. * Any serious impairment which would make detection of new ischemic events difficult (eg, bedridden participants, participants with total nursing care, dementia participants, etc.) or consciousness disturbance which may cause aspiration of the study drug.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Non-Major Adverse Cardiac Events (Non-MACE) | Up to Day 121 | An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporarily associated with study drug administration, whether or not considered related to study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization. All MACE events were excluded from this analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Up to Day 60 | Major TIMI bleeding was defined as any intracranial bleeding (excluding micohemorrhages \<10 mm evident on magnetic resonance imaging \[MRI\]), clinical over signs of hemorrhge associated with a drop in hemoglobin \>=5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in a hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI or Minor TIMI bleeding. |
| Number of Participants With MACE or Death | Up to Day 121 | The number of participants experiencing major cardiac events or death was evaluated up to Day 121. Major cardiac events were defined as nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization. |
| Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Up to Day 60 | Participant blood samples were collected to determine the median serum level of hs-CRP. hs-cRP levels reflect the underlying level of inflammation. The higher the level, the greater the disease burden. |
| Mean CD40 Ligand Levels By Study Visit | Up to Day 60 | Participant blood samples were collected to determine the mean serum level of CD40 ligand. CD40 ligand values represent the level of disease activation with a higher level of CD40 ligand indicating a greater underlying risk. |
| Mean Membrane-Bound P-Selectin Levels By Study Visit | Up to Day 60 | Participant blood samples were collected at Baseline, Day 30, and Day 60 to determine the mean level of membrane-bound p-selectin in the serum. Membrane-bound P-selectin levels reflect the underlying level of inflammation. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vorapaxar 1 mg Vorapaxar 1 mg tablets administered orally once daily for 60 days. | 33 |
| Vorapaxar 2.5 mg Vorapaxar 2.5 mg tablets administered orally once daily for 60 days. | 29 |
| Placebo Matching placbo tablets to Vorapaxar administered orally once daily for 60 days. | 28 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 | 1 |
| Overall Study | Protocol-Defined Clinical Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Vorapaxar 1 mg | Vorapaxar 2.5 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 63.0 Years STANDARD_DEVIATION 10 | 65.8 Years STANDARD_DEVIATION 11.6 | 63.7 Years STANDARD_DEVIATION 8.9 | 64.3 Years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Male | 26 Participants | 20 Participants | 23 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 33 | 24 / 29 | 20 / 28 |
| serious Total, serious adverse events | 1 / 33 | 2 / 29 | 3 / 28 |
Outcome results
Primary
Number of Participants Experiencing Non-Major Adverse Cardiac Events (Non-MACE)
An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporarily associated with study drug administration, whether or not considered related to study drug. MACE events were defined as nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization. All MACE events were excluded from this analysis.
Time frame: Up to Day 121
Population: The population consisted of all enrolled participants that received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorapaxar 1 mg | Number of Participants Experiencing Non-Major Adverse Cardiac Events (Non-MACE) | 27 Participants |
| Vorapaxar 2.5 mg | Number of Participants Experiencing Non-Major Adverse Cardiac Events (Non-MACE) | 27 Participants |
| Placebo | Number of Participants Experiencing Non-Major Adverse Cardiac Events (Non-MACE) | 22 Participants |
Secondary
Mean CD40 Ligand Levels By Study Visit
Participant blood samples were collected to determine the mean serum level of CD40 ligand. CD40 ligand values represent the level of disease activation with a higher level of CD40 ligand indicating a greater underlying risk.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants that received at least one dose of study drug and had CD40 ligand data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Day 60 (n=29, 26, 27) | 6.2 mg/L | Standard Error 0.82 |
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Day 14 (n=32, 29, 28) | 6.3 mg/L | Standard Error 0.64 |
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Day 45 (n=29, 27, 28) | 5.9 mg/L | Standard Error 0.77 |
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Baseline (n=33, 29, 28) | 6.5 mg/L | Standard Error 0.62 |
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Day 30 (n=31, 28, 28) | 6.7 mg/L | Standard Error 0.79 |
| Vorapaxar 1 mg | Mean CD40 Ligand Levels By Study Visit | Day 7 (n=32, 28, 27) | 7.2 mg/L | Standard Error 0.71 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Day 30 (n=31, 28, 28) | 7.1 mg/L | Standard Error 0.78 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Day 45 (n=29, 27, 28) | 5.7 mg/L | Standard Error 0.77 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Day 7 (n=32, 28, 27) | 5.8 mg/L | Standard Error 0.74 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Day 60 (n=29, 26, 27) | 5.3 mg/L | Standard Error 0.76 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Baseline (n=33, 29, 28) | 8.3 mg/L | Standard Error 0.77 |
| Vorapaxar 2.5 mg | Mean CD40 Ligand Levels By Study Visit | Day 14 (n=32, 29, 28) | 6.5 mg/L | Standard Error 0.79 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Day 14 (n=32, 29, 28) | 6.6 mg/L | Standard Error 0.66 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Baseline (n=33, 29, 28) | 5.9 mg/L | Standard Error 0.62 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Day 7 (n=32, 28, 27) | 5.6 mg/L | Standard Error 0.6 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Day 60 (n=29, 26, 27) | 6.0 mg/L | Standard Error 0.56 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Day 30 (n=31, 28, 28) | 5.9 mg/L | Standard Error 0.6 |
| Placebo | Mean CD40 Ligand Levels By Study Visit | Day 45 (n=29, 27, 28) | 6.2 mg/L | Standard Error 0.54 |
Secondary
Mean Membrane-Bound P-Selectin Levels By Study Visit
Participant blood samples were collected at Baseline, Day 30, and Day 60 to determine the mean level of membrane-bound p-selectin in the serum. Membrane-bound P-selectin levels reflect the underlying level of inflammation. Intensity levels are reported in arbitrary units 0 (dark) to 1023 (bright). Higher values correspond to greater membrane-bound P-Selectin levels.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants that received at least one dose of study drug and had membrane-bound p-selectin data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 1 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 30 (n=2, 1, 3) | 19.9 Arbitrary Units | Standard Error 4.2 |
| Vorapaxar 1 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Baseline (n=2, 1, 3) | 15.7 Arbitrary Units | Standard Error 0.8 |
| Vorapaxar 1 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 60 (n=2, 1, 3) | 17.8 Arbitrary Units | Standard Error 0.05 |
| Vorapaxar 2.5 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 30 (n=2, 1, 3) | 16.6 Arbitrary Units | — |
| Vorapaxar 2.5 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Baseline (n=2, 1, 3) | 19.5 Arbitrary Units | — |
| Vorapaxar 2.5 mg | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 60 (n=2, 1, 3) | 18.3 Arbitrary Units | — |
| Placebo | Mean Membrane-Bound P-Selectin Levels By Study Visit | Baseline (n=2, 1, 3) | 17.4 Arbitrary Units | Standard Error 1.06 |
| Placebo | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 60 (n=2, 1, 3) | 18.0 Arbitrary Units | Standard Error 0.07 |
| Placebo | Mean Membrane-Bound P-Selectin Levels By Study Visit | Day 30 (n=2, 1, 3) | 17.1 Arbitrary Units | Standard Error 1.1 |
Secondary
Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit
Participant blood samples were collected to determine the median serum level of hs-CRP. hs-cRP levels reflect the underlying level of inflammation. The higher the level, the greater the disease burden.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants who received at least one dose of study drug and had hs-CRP data available.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Baseline (n=33, 29, 28) | 0.65 mg/L | Standard Deviation 1.44 |
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 7 (n=32, 28, 27) | 0.77 mg/L | Standard Deviation 2.33 |
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 14 (32, 29, 28) | 0.93 mg/L | Standard Deviation 2.69 |
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 30 (n=31, 28, 28) | 0.96 mg/L | Standard Deviation 3.95 |
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 45 (n=29, 27, 28) | 0.70 mg/L | Standard Deviation 1.09 |
| Vorapaxar 1 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 60 (n=29, 26, 27) | 0.59 mg/L | Standard Deviation 0.58 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 60 (n=29, 26, 27) | 0.53 mg/L | Standard Deviation 0.63 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Baseline (n=33, 29, 28) | 0.67 mg/L | Standard Deviation 1.66 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 30 (n=31, 28, 28) | 0.55 mg/L | Standard Deviation 1.07 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 45 (n=29, 27, 28) | 0.48 mg/L | Standard Deviation 0.74 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 7 (n=32, 28, 27) | 0.49 mg/L | Standard Deviation 0.73 |
| Vorapaxar 2.5 mg | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 14 (32, 29, 28) | 0.62 mg/L | Standard Deviation 0.79 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 7 (n=32, 28, 27) | 0.41 mg/L | Standard Deviation 0.58 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 14 (32, 29, 28) | 0.44 mg/L | Standard Deviation 0.72 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 60 (n=29, 26, 27) | 0.61 mg/L | Standard Deviation 0.93 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 30 (n=31, 28, 28) | 0.56 mg/L | Standard Deviation 0.95 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Baseline (n=33, 29, 28) | 0.56 mg/L | Standard Deviation 1.06 |
| Placebo | Median High-Sensitivity C-Reactive Protein (Hs-CRP) Levels By Study Visit | Day 45 (n=29, 27, 28) | 0.59 mg/L | Standard Deviation 0.76 |
Secondary
Number of Participants With MACE or Death
The number of participants experiencing major cardiac events or death was evaluated up to Day 121. Major cardiac events were defined as nonfatal stroke, hospitalization due to recurrent ischemia, or urgent coronary revascularization.
Time frame: Up to Day 121
Population: The population consisted of all enrolled participants that received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 1 mg | Number of Participants With MACE or Death | MACE | 1 Participants |
| Vorapaxar 1 mg | Number of Participants With MACE or Death | Death | 0 Participants |
| Vorapaxar 2.5 mg | Number of Participants With MACE or Death | MACE | 1 Participants |
| Vorapaxar 2.5 mg | Number of Participants With MACE or Death | Death | 0 Participants |
| Placebo | Number of Participants With MACE or Death | MACE | 3 Participants |
| Placebo | Number of Participants With MACE or Death | Death | 0 Participants |
Secondary
Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events
Major TIMI bleeding was defined as any intracranial bleeding (excluding micohemorrhages \<10 mm evident on magnetic resonance imaging \[MRI\]), clinical over signs of hemorrhge associated with a drop in hemoglobin \>=5 g/dL, or fatal bleeding (bleeding that directly results in death within 7 days). Minor TIMI bleeding was defined as any clinically overt bleeding resulting in a hemoglobin drop of 3 to \<5 g/dL. Non-TIMI bleeding included all bleeding events not covered under Major TIMI or Minor TIMI bleeding.
Time frame: Up to Day 60
Population: The population consisted of all enrolled participants that received at least one dose of study drug and had TIMI bleeding data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vorapaxar 1 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Minor TIMI Bleeding | 0 Participants |
| Vorapaxar 1 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Major TIMI Bleeding | 0 Participants |
| Vorapaxar 1 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Non-TIMI Bleeding | 5 Participants |
| Vorapaxar 2.5 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Minor TIMI Bleeding | 0 Participants |
| Vorapaxar 2.5 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Major TIMI Bleeding | 0 Participants |
| Vorapaxar 2.5 mg | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Non-TIMI Bleeding | 10 Participants |
| Placebo | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Major TIMI Bleeding | 0 Participants |
| Placebo | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Non-TIMI Bleeding | 6 Participants |
| Placebo | Number of Paticipants Experiencing Thrombolysis in Myocardial Infarction (TIMI) Major, Minor, and Non-TIMI Bleeding Events | Minor TIMI Bleeding | 1 Participants |