TIA or Minor Ischemic Stroke
TIA BIOMARKER STUDY
Single blood draw into PAXgene tubes.
- Suspected TIA or minor stroke (NIHSS 4 or less), mimics okay and encouraged – you don’t have to be sure its a TIA or stroke, just sure enough to plan a work-up
- Age 40 or older.
- Blood draw within 72 hours of TIA/minor stroke onset.
- Intracerebral hemorrhage, subarachnoid hemorrhage or other intracerebral lesion by CT or MRI other than positive DWI-MRI
- Lymphoma / leukemia
- Blood dyscrasia
- Infection requiring antibiotics within 14d prior to TIA or up to 72h after TIA
- Immunosuppressive therapy
- Current illicit drug use
- Blood transfusion within the past 1 month
- Major surgery or trauma requiring hospitalization within the past 6 months
- Cancer requiring chemotherapy, radiation or surgery within the past year
- TIA caused by angiography or surgery
- Treatment with IV-tPA
Acute Ischemic Stroke
- Age ≥45 years.
- Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
- Modified Rankin Scale (MRS) score ≤4.
- Ability to be randomized no later than 120 days after stroke onset.
- ESUS, defined as all of the following:
- Stroke that is not lacunar.
- Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis of the artery supplying the area of ischemia. Patients must undergo vascular imaging of the extracranial and intracranial vessels using either catheter angiography, CT angiogram (CTA), MR angiogram (MRA), or ultrasound, as considered appropriate by the treating physician and local principal investigator.
- No major-risk cardioembolic source of embolism, including AF, intracardiac thrombus, mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular ejection fraction <30%, valvular vegetations, or infective endocarditis). Patent foramen ovale is not an exclusion.
- No other specific cause of stroke identified, such as arteritis, dissection, migraine, vasospasm, drug abuse, or hypercoagulability.
- History of AF, AF on 12-lead ECG, or any AF of any duration during heart-rhythm monitoring prior to randomization.
- Clear indication for treatment-dose anticoagulant therapy, such as venous thromboembolism or a mechanical heart valve.
- Left ventricular ejection fraction <30%.
- Definite indication for antiplatelet agent (e.g., aspirin or clopidogrel after implantation of a coronary artery stent).
- History of spontaneous intracranial hemorrhage.
- Chronic kidney disease with serum creatinine ≥2.5 mg/dL.
- Active hepatitis or hepatic insufficiency with Child-Pugh score B or C (see MOP for definition).
- Clinically significant bleeding diathesis.
- Anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 109/L) that is chronic in the judgment of the investigator.
- GI bleeding within the past year considered clinically significant by the investigator.
- Pregnancy risk: − Female patient who is known to be pregnant.
- Female patient who is sexually active and premenopausal without a negative pregnancy test performed after stroke onset.
- Female patient who is sexually active and premenopausal, and who does not commit to adequate birth control.
- Male patient who is sexually active with a premenopausal female partner, and who does not commit to adequate birth control.
- Known allergy or intolerance to aspirin or apixaban.
- Concomitant participation in another clinical trial involving a drug or acute stroke intervention.
- Considered by the investigator to have a condition that precludes follow-up or safe participation in the trial.
- Inability to obtain written, informed consent from patient or surrogate for trial participation.
BMS – AXIOMATIC
- Signed Written Informed Consent
- Participants ≥40 years of age (or LAR) from whom ICF has been obtained
- Type of Participant and Target Disease Characteristics
- Ischemic stroke:
- A neurological deficit attributable to a non-lacunar acute brain infarction detected by MRI and relevant to the clinical symptoms
- NIHSS ≤5
- Acute brain infarction distal to an intracranial or cervical arterial atherosclerotic plaque or aortic arch atheroma >4 mm in thickness, ulceration or thrombus documented by imaging (Doppler ultrasound, CTA, MRA or catheter angiography)
- Modified Rankin Score (mRS)<3 before the index event
- Acute onset neurological deficit attributable to focal ischemia of the brain by history or examination, with complete resolution of the deficit and no brain infarction on MRI
- ABCD2 Score ≥6 or motor symptoms
- Symptoms attributable to an intracranial or cervical arterial atherosclerotic plaque or aortic arch atheroma >4 mm in thickness, ulceration or thrombus documented by imaging (Doppler ultrasound, CTA, MRA or catheter angiography)
- Ischemic stroke:
- The participant must be able to be evaluated by study-specific MRI within 48 hours of index event and prior to randomization. Therefore, participants cannot have any contraindications to MRI.
- No contraindication to clopidogrel or aspirin and suitable for treatment with aspirin 100 mg per day for at least 90 days
- WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.
- Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment
- Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment. In addition, male participants
must be willing to refrain from sperm donation during this time.
- Predicted inability to swallow study medication
- Women who are pregnant or breastfeeding
- Any condition that, in the opinion of the Investigator, contraindicates anticoagulant therapy or would have an unacceptable risk of bleeding such as a large infarct volume (per Investigator discretion) or uncontrolled hypertension.
- Hemorrhage, tumor, arteritis, large vessel dissection, arteriovenous malformation (AVM) or other pathology that could account for index symptoms must be excluded by CT or MRI interpreted locally.
- Symptomatic carotid stenosis for which endarterectomy or stenting is planned within 90 days
- Use of thrombolytic therapy or mechanical thrombectomy for treatment of index event
- Any condition for which chronic anticoagulation is recommended
- Requirement for continued use of dual anti-platelet therapy (DAPT) for more than 21 days or non-aspirin antiplatelet therapy or anticoagulant for another medical condition (e.g. prophylaxis for venous thromboembolism).
- Note: Treatment with clopidogrel, aspirin, dipyridamole or another P2Y12 inhibitor prior to enrollment is allowed. Treatment with aspirin at a different dose before enrollment is also allowed. All participants must transition to the protocol-defined treatments and doses at randomization. No clopidogrel loading dose is needed for participants who received a clopidogrel loading dose prior to randomization. Participants who report taking chronic clopidogrel also require a 300-mg clopidogrel loading dose unless the Investigator can verify that the patient has taken the daily dose for at least the preceding 3 days. Participants who have received dipyridamole or another P2Y12 inhibitor must receive the clopidogrel loading dose after discontinuing the non-clopidogrel P2Y12 inhibitor or dipyridamole/dipyridamole-containing treatment.
- History of hemorrhage into the brain, subarachnoid hemorrhage, subdural hematoma or spinal cord hemorrhage except cerebral microbleeds (CMB) and petechiae on imaging.
- Note: CMBs are defined as rounded foci of <10 mm in size that appear hypointense and distinct from vascular flow voids, leptomeningeal hemasiderosis, or non-hemorrhagic subcortical mineralization on T2* weighted MRI.55
- History of clinically meaningful hepatic disease and/or clinically significant abnormal liver function.
- Intracranial tumor (except meningioma, which is permitted) or aneurysm >5 mm
- History of end stage renal disease (ESRD) with eGFR <15 mL/min/m2, or requiring dialysis
- Any investigational drug or placebo exposure within 4 weeks of study drug administration
- Any prior exposure to BMS-986177
- Planned use of anticoagulants including warfarin or other vitamin K antagonists, oral thrombin and Factor Xa inhibitors, bivalirudin, hirudin, argatroban, unfractionated and low molecular weight heparins, with the exception of heparin or low molecular weight heparin (LMWH) used to maintain patency of indwelling catheters.
- Note: Participants who received 1 or 2 doses of UFH or LMWH for DVT prophylaxis prior to enrollment can be randomized. The use of anticoagulants for post-stroke DVT prophylaxis is prohibited. For post-stroke DVT prophylaxis, non-pharmacological prophylaxis (i.e. intermittent pneumatic compression) is recommended.
- Planned concomitant use of omeprazole or esomeprazole after randomization for the duration of clopidogrel treatment (H2 blockers and pantoprazole are allowed).
- Anticipated concomitant chronic (>14 days) use of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID (including COX-2 inhibitors) use prior to randomization is allowed.
- Use of strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers in the 7 days prior to randomization or the need for ongoing treatment with concomitant oral or intravenous therapy with strong CYP3A4/P-gp inhibitors or strong CYP3A4/P-gp inducers DURING the study.
- Inability to comply with restrictions and prohibited treatments as listed in Section 7.7.1.
Physical and Laboratory Test Findings
- Any of the following laboratory results outside of the ranges specified below prior to study treatment administration, confirmed by repeat:
- Hemoglobin <9 g/dL
- Platelet count <100,000 mm3
- aPTT >1.4x upper limit of normal (ULN)
- INR >7
- AST or ALT >3x ULN
- Any of the following on 12-lead ECG prior to study drug administration.
- Atrial fibrillation or atrial flutter
- Complete heart block or Mobitz 2 second degree heart block
- Known positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1 and HIV-2 antibody.
Allergies and Adverse Drug Reaction
- History of allergy to BMS-986177, clopidogrel, aspirin, or aspirin-containing compounds.
- History of any significant drug allergy (such as anaphylaxis).
- History of drug-induced hematologic or hepatic abnormalities.
Other Exclusion Criteria
- Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and Bristol-Myers Squibb approval is required.
- Participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
- Participants in whom MRI procedures cannot be performed. Section 22.214.171.124 provides a list of some common conditions that may preclude the participants from having MRI. However, this should not be used as a substitute for local clinical standards of care. The ultimate decision to perform MRI in an individual participant rests with the site radiologist, the Investigator and the standard set by the local practice.
- Males or females aged ≥ 18 and ≤ 85 years.
- WOCBP must have a negative urine HCG pregnancy test at Screening and be practicing a medically acceptable method of contraception. If serum bHCG is the standard of care, then this value can be used to determine eligibility.
- A clinical diagnosis of mild to moderate cortical or subcortical AIS.
- Able to swallow the softgel capsules as defined by the investigator.
- Completes screening procedures such that study treatment is first administered within 24 hours of stroke onset. The stroke onset time will be defined as the last known normal.
- If tPA is given as part of standard of care, the first dose of NBP must be administered no sooner than 4 hours after the end of the tPA infusion.
- A standard NIHSS score of 4 to 17, inclusive. If patients receive tPA and/or endovascular treatment (EVT), the NIHSS score must be obtained after the infusion and/or procedure is completed. If sedation is used for EVT, then the NIHSS score must be obtained after sedation no longer confounds the assessment. All subjects must meet a NIHSS consciousness score of 0-1 in order to meet eligibility.
- Functionally independent, as defined by mRS score of 0 to 1 before their present illness
- Capable of understanding the purpose and risk of the study and has signed, in writing, the ICF. If the subject is not capable of this at the time of enrollment, a legally authorized representative (LAR) will provide written informed consent in accordance with all regulations.
- Ability to comply with study requirements.
- Female subjects who are pregnant, lactating/breast-feeding, or plan to become pregnant within the next 3 months.
- Suspected diagnosis of stroke isolated to brainstem or brain areas other than cortical or subcortical AIS that may have caused the present symptoms, based on the opinion of the Investigator.
- Rapidly improving or resolving symptoms, suggesting a possible transient ischemic attack (TIA) rather than a qualifying stroke.
- Signs of acute intracranial hemorrhage or symptomatic hemorrhagic transformation of AIS defined by a 4-point worsening in NIHSS from presentation, or other cause of acute stroke symptoms (other than early ischemic findings) on cranial imaging at Screening.
- History of intracranial hemorrhage.
- Seizure at onset of stroke.
- A previous clinical diagnosis of stroke within 6 months of current AIS. A previously undiagnosed stroke evidenced on screening CT or MRI may be enrolled provided it does not affect neurological and functional assessments based on the opinion of the Investigator.
- Uncontrolled severe hypertension defined as a systolic blood pressure (SBP) ≥ 220 mm Hg or diastolic blood pressure (DBP) ≥ 110 mm Hg.
- Treatment with intensive antihypertensive therapy within 4 hours of randomization.
- SBP < 100 mm Hg, temperature > 38.0º C, or heart rate < 40 beats/minute or > 120 beats/minute at Screening or prior to randomization.
- A glucose level of < 50 mg/dL at Screening.
- An international normalized ratio (INR) ≥ 1.5 if not being treated with anticoagulant therapy, or an INR ≥ 3.5 if being treated with an acceptable anticoagulant therapy.
- A serum ALT or AST level > 1.5 × ULN, or bilirubin > 1.5 ULN (except in setting of known Gilbert’s disease) at Screening.
- Clinically significant renal dysfunction (including serum creatinine level > 2.0 mg/dL or 177 μmol/L) at Screening.
- A hemoglobin level < 10 g/dL at Screening.
- Current or within the last 6 months prior to Screening, New York Heart Association Class III/IV heart failure, severe uncorrected valve disease, known or suspected infective/vegetative endocarditis, ventricular tachycardia, or torsade de pointes.
- Corrected QTcF (Friderica) > 450 ms for male subjects or > 470 ms for female subjects (average of 3 ECG tracings) prior to randomization.
- Current diagnosis of cancer or is being treated or has received any treatments for cancer within the last 5 years except basal cell carcinoma or curatively resected squamous cell carcinoma.
- Known life expectancy < 6 months (for any reason).
- Known allergy or hypersensitivity to celery or soybeans.
- Received treatment with any other investigational drug within 30 days before Baseline, was previously treated with NBP, is currently taking celery seed extract, or is currently participating in another clinical study.
- Known or suspected history of alcohol or drug dependence within the past 6 months, or is known to have abused alcohol (eg, been intoxicated) within the last 24 hours.
- Known history of hepatitis B, hepatitis C, HIV, or TB.
- Any other reasons that, in the opinion of the investigator, make the subject unsuitable for enrollment.
- Ability to provide informed consent by patient or legally authorized representative.
- A clinical diagnosis of acute ischemic stroke in the MCA territory (PCA and/or ACA territory involvement in addition to primary MCA territory stroke is acceptable).
- Aged 18 to 85 years old, inclusive, at the time of informed consent.
- Screening NIHSS ≥10.
- Prior to the current stroke, no significant disability in the opinion of the Investigator (able to independently perform all duties and activities of daily living without assistance from a caregiver, spouse, or another person).
- A large hemispheric infarction defined, in order of preference, as either:
- a magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) lesion volume of 80 to 300 cm3, or
- a computed tomography perfusion (CTP) core lesion volume of 80 to 300 cm3, or
- an Alberta Stroke Program Early computed tomography (CT) Score (ASPECTS) on non-contrast computed tomography (NCCT) of 1 to 5 with involvement of at least 2 defined cortical regions, if lesion volume from MRI DWI or CTP is not available.
- For subjects who receive thrombectomy prior to randomization, inclusion into the study must be based on an infarct volume of 80 to 300 cm3 measured by post-thrombectomy MRI-DWI.
- Study drug treatment infusion should be initiated as soon as possible but no later than 10 hours after time of symptom onset, if known, or the time last known normal (if time to symptom onset is unknown).
- In the judgment of the Investigator, the subject is likely to have supportive care withdrawn in the first day.
- Commitment to decompressive craniectomy (DC) prior to enrollment.
- Evidence (clinical or imaging) of concurrent infarction in the contralateral hemisphere deemed by the Investigator to be sufficiently serious so as to affect functional outcome. This would include, for example, a contralateral ACA infarct that leads to bilateral leg paralysis.
- Clinical signs of herniation, e.g., 1 or 2 dilated, fixed pupils; unconsciousness related to edema (i.e., ≥2 on item 1a on the NIHSS); and/or loss of other brain stem reflexes, attributable to edema or herniation according to the Investigator’s judgment.
- Brain hemorrhage (other than small petechial/punctate hemorrhages) on NCCT/MRI.
- NCCT/MRI evidence of anteroseptal/pineal shift >2 mm prior to enrollment.
- Use of intra-arterial thrombolytic agents, alone or in combination with thrombectomy.
- Patients who are currently being considered for thrombectomy and/or IV thrombolysis may not be randomized into the study until these procedures have been completed OR the decision not to perform them has been made. These treatments should not be delayed for study screening procedures. When thrombectomy is performed prior to randomization, study eligibility must be assessed using inclusion criterion #7.
- Subjects with, in the opinion of the Investigator, life expectancy < 3 months not related to current LHI, or those unlikely to be compliant with follow up.
- Subjects in whom a peripheral IV line cannot be placed.
- Subjects with mental disability (prior to qualifying LHI) or wards of the state.
- Subjects whose stroke symptoms are rapidly improving and are not expected in the opinion of the Investigator to have NIHSS≥10 at the time of randomization.
- Known allergy to BIIB093 or to another sulfonylurea drug or any of the components of the formulated BIIB093 or matching placebo.
- Subjects who are known to have taken oral glibenclamide within the past 10 hours.
- Known history of clinically significant severe form of renal or hepatic disorder, in the Investigator’s opinion (e.g., dialysis or cirrhosis, respectively).
- Known history of chronic obstructive pulmonary disease that, in the judgment of the Investigator, is severe (e.g., requiring home oxygen).
- Known history of clinically significant hypoglycemia, in the Investigator’s opinion based on known medical history or local screening laboratory assessments (i.e. screening blood glucose <70 mg/dL [~3.9 mmol/L]).
- Subjects who have or have ever had diabetic ketoacidosis or diabetic coma/precoma.
- Acute ST elevation myocardial infarction (MI), and/or acute decompensated heart failure, and/or QTc >520 msec, and/or admission for an acute coronary syndrome, MI, cardiac arrest, or non-voluntary coronary intervention (percutaneous coronary intervention or coronary artery surgery) within the past 3 months.
- New York Heart Association heart failure III/IV (class III: marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m); class IV: severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients).
- Known cardiac ventricular tachycardia.
- Subjects with known glucose-6-phosphate dehydrogenase enzyme deficiency.
- Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) that required hospitalization or was clinically significant in the opinion of the Investigator within 3 days prior to Screening.
- Females who are pregnant or women of childbearing potential with a positive pregnancy test at time of admission.
- Nursing women who are unable to stop breastfeeding during study treatment infusion and for 7 days following the end of study treatment infusion.
- Known current participation or known history of participation in any other investigational study that involved treatment with an investigational drug within 14 days prior to enrollment.
- Inability to comply with study requirements.
- Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the subject unsuitable for enrollment.
- Ischemic stroke due to small vessel disease, large vessel cervical or intracranial atherosclerosis within the past 10 days
- 60 years of age or older, or age 50 to 59 years plus a documented medical history of at least one of the following additional risk factors for stroke:
- Congestive heartfailure
- Hypertension (Systolic Blood Pressure >140)
- Diabetes Mellitus
- Prior Stroke (>90 days ago, other than study qualifying indexevent)
- Vascular disease (e.g. coronary artery disease, heart attack, peripheral artery disease and complex aortic plaque)
- Cryptogenic stroke
- Cardioembolic stroke
- Untreated hyperthyroidism
- Recent myocardial infarction <1 month of stroke
- Recent cardiac surgery (e.g. coronary artery bypass surgery (CABG)) <1 month of stroke
- Mechanical heart valve
- Valvular disease requiring immediate surgical intervention
- History of atrial fibrillation or atrial flutter
- Permanent indication for oral anticoagulation
- Patient/legally authorized representative has signed the Informed Consent Form
- Age > 18 years
- AIS symptom onset within 4.5 to 24 hours
- Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they present within the 4.5- to 24-hour time limits).
- All study-related treatment needs to occur within 24 hours.
- Signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke involving occlusion of the ICA, M1, or M2 vessels
- Functionally independent (mRS 0-2) prior to stroke onset
- Baseline NIHSS >5 and that remains >5 immediately prior to randomization
- Neuroimaging: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial, with or without tandem MCA lesions) by MRA or CTA AND target mismatch profile on CT perfusion or MRI (ischemic core volume <70 mL, mismatch ratio is >1.8 and mismatch volume is >15 mL)
- The mismatch volume is determined by FDA-approved imaging software in real time based on the difference between the ischemic core lesion volume and the Tmax>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment.
- Alternative neuroimaging:
- If CTA (or MRA) is technically inadequate: Tmax6s perfusion deficit consistent with an ICA or M1, M2 occlusion AND target mismatch profile (ischemic core volume <70 mL, mismatch ratio >1.8 and mismatch volume >15 mL as determined by RAPID software)
- If magnetic resonance perfusion (MRP) is technically inadequate: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND diffusion-weighted imaging (DWI) lesion volume <25 mL for an M1 or ICA occlusion and <15 mL for an M2 occlusion
- If CTP is technically inadequate: patient can be screened with MRI and randomized if neuroimaging criteria are met.
- Ability to comply with the study protocol, in the investigator’s judgment
- Current participation in another investigational drug or device study
- Active internal bleeding
- Known hypersensitivity or allergy to any ingredients of tenecteplase
- Known bleeding diathesis
- Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency;
- recent oral anticoagulant therapy with INR >1.7
- Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban)
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS
- Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg)
- Baseline platelet count <100,000/mcL (results must be available prior to treatment)
- Baseline blood glucose >400 mg/dL (22.20 mmol/L)
- Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization
- Clot retrieval attempted using a neurothrombectomy device prior to randomization
- Intracranial or intraspinal surgery or trauma within 2 months
- Treatment with a thrombolytic within the last 3 months prior to randomization
- Other serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months
- Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations
- History of cerebrovascular accident in the last 90 days
- Presumed septic embolus; suspicion of bacterial endocarditis
- Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was to be performed
- Unable to undergo a contrast brain perfusion scan with either MRI or CT
- Extensive early ischemic change (hypodensity) on non-contrast CT estimated to be
- >1/3 MCA territory, or significant hypodensity outside the Tmax>6s perfusion lesion that invalidates mismatch criteria (if patient is enrolled based on CT perfusion criteria)
- Significant mass effect
- Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion)
- Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation
Acute Intracerebral Hemorrhage
ICH patients eligible for inclusion in this study must fulfill all of the following criteria:
- Aged 18 to 80 years (inclusive)
- Spontaneous, supratentorial intracerebral hemorrhage in deep brain structures (putamen, thalamus, caudate, and associated deep white matter tracts) with a volume ≥ 10 mL but ≤ 30 mL (calculated by the ABC/2 method) determined by routine clinical MRI or CT.
- < 24 hrs from last known normal
- Glasgow Coma Scale (GCS) best motor score no less than 6.
- Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline (for biologics), whichever is longer.
- History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes (e.g., fingolimod).
- Current use of concomitant medications with potent CYP2C9/3A4 inhibitory or induction potential.
- Necessity for mechanical ventilation at screening.
- Infratentorial (midbrain, pons, medulla, or cerebellum) or superficial cortical (lobar) ICH.
- Candidates for surgical hematoma evacuation or other urgent surgical intervention (i.e., surgical relief of increased intracranial pressure) on initial presentation. If during the treatment period surgical hematoma evacuation or surgical intervention to lower intracranial pressure becomes indicated, the investigational treatment should be stopped.
- Patients with intraventricular hematoma extension, with or without hydrocephalus, on initial presentation.
- Secondary ICH due to:
- brain tumor
- arteriovenous malformation
- thrombocytopenia, defined as platelet count of <150,000/µl
- known history of coagulopathy
- acute sepsis
- traumatic brain injury (TBI)
- disseminated intravascular coagulation (DIC)
- Prior disability due to other disease compromising mRS evaluation defined as an estimated mRS score (by history) of ≥ 3 before ICH.
- Preexisting unstable epilepsy.
- Patients with active systemic bacterial, viral or fungal infections.
- Concomitant drug-related exclusion criteria:
- Intravenous immunoglobulin, immunosuppressive and/or chemotherapeutic medications.
- Moderate immunosuppressives (e.g. azathioprine, methotrexate) and/or fingolimod within 2 months prior to randomization.
- Stronger immunosuppressives (e.g. cyclophosphamide, immunosuppressive mAb) within (minimally) 6 months prior to randomization, or longer with long-lasting immunosuppressive medications as determined by the investigator.
- Cardiovascular exclusion criteria:
- Cardiac conduction or rhythm disorders including sinus arrest or sino-atrial block, heart rate <50 bpm, sick-sinus syndrome, Mobitz Type II second degree AV block or higher grade AV block, or preexisting atrial fibrillation (either by history or observed at screening).
- PR interval >220 msec. Long QT syndrome or QTcF prolongation >450 msec in males or >470 msec in females on screening electrocardiogram (ECG).
- Patients receiving treatment with QT-prolonging drugs having a long half-life (e.g., amiodarone).
- Any of the following abnormal laboratory values prior to randomization:
- White blood cell (WBC) count < 2,000/μl (< 2.0 x 109/L)
- Lymphocyte count < 800/μl (< 0.8 x 109/L)
- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- Patients with any other medically unstable condition or serious laboratory abnormality as determined by the investigator.
Investigator Initiated Trials
- Age ≥ 18 years
- Acute ischemic stroke with radiographic evidence of occlusion of the internal carotid artery and/or middle cerebral artery on either side of the brain
- Patient will undergoing mechanical thrombectomy for acute stroke
- Willingness and ability to sign informed consent by patient or legally acceptable surrogate decision-maker
- Bilateral arterial occlusion
- Hemicraniectomy or other skull defect that would interfere with monitoring.
- History of brain mass (other than meningioma)
- Women of child-bearing age must have a negative pregnancy test (urine or serum) prior to enrollment (which is performed as part of standard care)
- Any other illness or condition that the investigator feels would pose a hazard to the subject from participation in the study
- Age > 18
- Ability and willingness to sign informed consent
- History of any neurological disease
- History of stroke or transient ischemic attack
- Known cerebrovascular abnormality
- History of congestive heart failure
- History of chronic pulmonary disease such as asthma or COPD
- Presence of pneumonia or active pulmonary infection
- Current use of any NO donor medication (sodium nitroprusside or nitroglycerin)
- Age < 18 years
- Skull defect that would interfere with CBF monitoring
- Pregnancy (urine or blood tests will not be performed)
- Structural brain lesion
- Prior neurosurgical procedure
- History of psychiatric disease
- Any medical condition that the clinical investigator feels would pose a hazard to the subject if he/she participated in the study
- Cognitive impairment
- Age ≥18 years of age
- Acute ischemic stroke within the past 6 months
- Regular access to the internet, sufficient to allow a minimum of interactions with the internet daily, either through a personal smartphone or web-based internet browser.
- Subject is willing and able to participate in internet-based cognitive behavioral therapy
- Can participate in the program in English
- Willingness and ability to sign informed consent by the patient
- Symptoms of mild to moderately depressed mood, defined as a score of 5-19 on the Patient Health Questionnaire-9 at the time of study enrollment.
- Severely depressed patients, defined by a score of 20+ on the Patient Health Questionnare-9 are excluded
- Patients with an active bipolar disorder diagnosis are excluded
- Patients with personality disorder diagnoses are excluded
- Patients with active suicidality or past suicide attempts are excluded
- History of schizophrenia or schizoaffective disorder
- Active participation in face-to-face psychotherapy prior to stroke
- Patients with a history of dementia are excluded
- Patients with aphasia, defined as a score of 1 or greater on NIH Stroke Scale Item 9 are excluded.
- Patients without regular internet access through a computer, tablet or smartphone are excluded.
- Subjects requiring long-term inpatient nursing care are excluded. For patients enrolled as inpatients, individuals being discharged to both home and acute rehab are eligible. Individuals being discharged to a skilled nursing facility or hospice are excluded.
- Expected life expectancy less than 6 months or other inability to comply with study follow-up.
- Pregnant women and prisoners are excluded
- Age > 18
- For cases, admission to the Stroke Inpatient Service with a diagnosis of acute ischemic stroke. NIHSS≥1, including at least 1 point for limb weakness. At least half of the stroke patients must have at least 2 points on the NIHSS for limb weakness.
- For controls, admission to the hospital with a TIA, normal MRI, and normal neurologic exam, admission to the Epilepsy Monitoring Unit for differential diagnosis of transient neurologic spells with a normal MRI and normal neurologic exam, or recent cardiac surgery.
- Any medical or psychological conditions that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study.
- A limb amputation above the wrist in the upper extremities and the ankle in the lower extremities.
- For controls:
- History of prior stroke
- Evidence of prior brain injury on MRI when this data is available, excluding mild small vessel ischemic disease
- Evidence of any focal neurologic findings on exam including asymmetric limb weakness or neglect