Atrial Cardiopathy Criteria:
(# boxes wide) x (# boxes tall) x (4000) = p=wave terminal force >5000
NT-proBNP > 250 for enrollment
Left atrial size index based on TTE (left atrial diameter/BSA) ≥ 3 cm/m2
- 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.
- 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). PFO 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.
The goal of this study is to improve walking ability after stroke. Trial arms, 1) fast walking training with a step activity monitoring program (FAST+SAM) , 2) fast walking training alone (FAST) 3) a step activity monitoring and feedback program alone (SAM).
– age 21-85
– >6 months post stroke
– able to walk without assistance from another person (assistive devices are allowed)
– self-selected walking speed > 0.3 m/s and < 1.0 m/s
– resting heart rate between 40 and 100 beats per minute
– resting blood pressure between 90/60 and 170/90
– evidence of cerebellar stroke
– other potentially disabling neurologic conditions in addition to stroke
– lower limb botulinum toxin injection < 4 months prior
– current participation in physical therapy
– inability to walk outside of home prior to stroke
– coronary artery bypass graft, stent placement, or myocardial infarction within past 3 months
– musculoskeletal pain that limits activity
– inability to communicate with investigators
– score >1 on question 1b and >0 on question 1c on NIH Stroke Scale
All inclusion criteria are based on the subjects’ medical records, except for #1 and #3 (screening assessment). Subjects are eligible to be included in the trial only if all of the following criteria apply:
- Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
- Male or female, age ≥ 45 years at the time of signing informed consent
- Body mass index (BMI) ≥ 27 kg/m2
- Have established CV disease as evidenced by at least one of the following:
- prior myocardial infarction
- prior stroke (ischemic or hemorrhagic stroke)
- symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) < 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease
All exclusion criteria are based on the subjects’ medical records, except for #4 (HbA1c, central laboratory) and the urine pregnancy test (#17). Subjects are excluded from the trial if any of the following criteria apply:
- Any of the following: myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischemic attack within the past 60 days prior to the day of screening
- Planned coronary, carotid or peripheral artery revascularization known on the day of screening
- Presently classified as being in New York Heart Association (NYHA) Class IV heart failure
- HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening
- History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)
- Treatment with glucose-lowering agent(s) within 90 days before screening
- Treatment with any GLP-1 RA within 90 days before screening
- History or presence of chronic pancreatitis
- Presence of acute pancreatitis within the past 180 days prior to the day of screening
- Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
- End stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis
- Presence or history of malignant neoplasms within the past 5 years prior to the day of screening Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
- Severe psychiatric disorder which in the investigator’s opinion could compromise compliance with the protocol
- Known or suspected hypersensitivity to trial product(s) or related products
- Previous participation in this trial. Participation is defined as randomisation
- Receipt of any investigational medicinal product within 30 days before screening
- Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method
- Any disorder, unwillingness or inability, which in the investigator’s opinion, might jeopardise the subject’s safety or compliance with the protocol
General Inclusion Criteria:
- Written informed consent or witnessed informed consent in the event that the subject is unable to sign
- informed consent due to paresis of the affected arm.
- Ischemic stroke that includes the supratentorial region (including infratentorial stroke with supratentorial involvement) occurring within 6 to 12 months of the time that surgical intervention will be performed (Qualifying Stroke Event).
- Aged between 35 and 75 (inclusive)
- Qualifying Stroke Event must be confirmed by CT or MRI.
- Must have current Moderate or Moderately Severe disability as measured by modified Rankin Score = 3 or 4 due to the Qualifying Stroke Event.
- Must have some residual upper limb movement as defined by the GRASP manual e.g. ability to actively shoulder shrug against gravity and wrist extension (palpable by the investigator; or visible lift of the fingers with hand resting on a table)
- Must have sufficient cognitive and language abilities to comprehend verbal commands and to carry out the study assessments.
- No medical conditions that would preclude neurosurgery with appropriate preparation and management.
- Sufficient putamen, globus pallidus, or caudate nucleus volume on the affected side to enable delivery of the CTX0E03 DP.
- Able to attend study related Visits and complete any diary, telephone or questionnaire assessments.
- Females of childbearing potential (FOCBP) (or within 2 years of last menstrual cycle) must have a confirmed negative pregnancy test at time of treatment and agree to use two reliable methods of contraception (e.g. oral contraceptive and condom, intra-uterine device (IUD) and condom, diaphragm with spermicide and condom) for six months following surgery.
- Sexually active males with partners who are FOCBP must be willing to use a reliable method of contraception (e.g. barrier and spermicide or as described above) for six months following surgery.
General Exclusion Criteria:
- Permanent disability corresponding to a Modified Rankin Score of >1 prior to the Qualifying Stroke Event.
- Stroke due to hemorrhage, (whether caused by atherosclerotic disease or due to atypical cause), or stroke known or suspected of being caused-by, or related-to, connective tissue disorder, congenital disorder of the cerebral vessels or a disorder of thrombosis (See Appendix 1). Subjects with atrial fibrillation as a suspected cause of stroke are NOT excluded.
- Neurosurgical pathway obstructed by vascular malformation or cavity.
- History of neurological or other disease resulting in significant functional impairment (e.g. Parkinson’s disease, motor neuron disease, moderate dementia, arthritis, contractures or fixed anatomical abnormality).
- Any contraindications to CT scan or MRI e.g. presence of a magnetic-sensitive cardiac pacemaker, metal fragments in eye, contrast allergy etc.
- Inability to stop or transition off valproic acid or other demethylating agents or HDAC inhibitors for 1 week before and 4 weeks after treatment with CTX0E03 DP.
- Use of selective serotonin reuptake inhibitors (SSRI), unless the subject is on a stable dose that has been started at least 2-months before screening (V1).
- Use of antispasticity medications (excluding oral antispasticity medications if they have been taken regularly for at least four months prior to treatment with CTX0E03 DP).
- Inability to discontinue anticoagulation therapy for a required interval (see Section 7.2).
- Subjects with a severe comorbid disorder that has reasonable likelihood of limiting survival to less than 24 months.
- History of malignant disease within the last 5 years, (excluding benign tumours such as non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, benign polyps).
- Any history of primary or secondary brain malignant disease.
- Subjects who have previously participated in a cell-based therapy study at any time or in any other study involving an investigational product or rehabilitation study within the last 30 days.
- Any clinically significant laboratory values, including positive Class I HLA antibodies specific for CTX0E03, during screening (refer to Section 188.8.131.52 for more details on HLA antibodies).
- Inability to adhere to the study post-surgery upper limb standard Physical Therapy regimen e.g. excessive spasticity or pain.
- Planned initiation of any other new physical therapy regimen within 6-months post-treatment.
- Any other conditions that, in the opinion of the investigators, would preclude safe and/or effective participation.
General Inclusion Criteria
- Patients ≥35 years old.
- Carotid stenosis defined as:
a. Stenosis ≥70% by catheter angiography (NASCET Criteria); or
b. by DUS with ≥70% stenosis defined by a peak systolic velocity of at least 230 cm/s plus at least one of the following:
i. an end diastolic velocity ≥100 cm/s, or
ii. internal carotid/common carotid artery peak systolic velocity ratio ≥ 4.0, or
iii. CTA with ≥ 70% stenosis, or
iv. MRA with ≥ 70% stenosis.
- No medical history of stroke or TIA ipsilateral to the stenosis within 180 days of randomization. Life-long asymptomatic patients will be defined as having no medical history of stroke or transient ischemic attack and negative responses to all of the symptom items on the Questionnaire for Verifying Stroke-free Status (QVSS).18
- Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent.
- Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization.
- Patients must agree to comply with all protocol-specified follow-up appointments.
- Patients must sign a consent form that has been approved by the local governing Institutional Review Board (IRB)/Medical Ethics Committee (MEC) of the respective clinical site.
- Randomization to treatment group will apply to only one carotid artery for patients with bilateral carotid stenosis. Management of the non-randomized stenosis may be done in accordance with local PI recommendation. Treatment of the non-study internal carotid artery must take place at least 30 days prior to randomization, or greater than 44 days after randomization and 30 days after the study procedure is completed (whichever is longer).
- Carotid stenosis must be treatable with CEA, CAS, or either procedure.
General Exclusion Criteria
- Intolerance or allergic reaction to a study medication without a suitable management alternative.
- GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
- Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes.
- Severe dementia.
- Intracranial hemorrhage within the past 12 months.
- Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
- Patient objects to future blood transfusions.
- Platelet count <100,000/μl or history of heparin-induced thrombocytopenia.
- Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.
- Chronic atrial fibrillation.
- Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
- Other high-risk cardiac sources of emboli, including left ventricular aneurysm, severe cardiomyopathy, aortic or mitral mechanical heart valve, severe calcific aortic stenosis (valve area < 1.0 cm2), endocarditis, moderate to severe mitral stenosis, left atrial thrombus, or any intracardiac mass, or known unrepaired PFO with prior paradoxical embolism.
- Unstable angina defined as rest angina with ECG changes that is not amenable to revascularization (patients should undergo planned coronary revascularization at least 30 days before randomization).
- Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.
- Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.
- Known malignancy other than basal cell non-melanoma skin cancer. There are two exceptions to this rule: patients with prior cancer treatment and no recurrence for >5 years are eligible for enrollment and cancer patients with life expectancy of greater than 5 years are eligible for enrollment.
- Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.
- Serum creatinine ≥2.5 mg/dl or estimated GFR ≤40 cc/min (at screening).
- Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
- Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
- Actively participating in another drug or aortic arch or cerebrovascular device trial for which participation in CREST-2 would be compromised with regard to follow-up assessment of outcomes or continuation in CREST-2.
- Inability to understand and cooperate with study procedures or provide informed consent.
- Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
- Previous ipsilateral CEA or CAS.
- Ipsilateral internal or common carotid artery occlusion.
- Intra-carotid floating thrombus.
- Ipsilateral intracranial aneurysm > 5 mm.
- WHO Class III obesity (BMI >40 kg/m2).
- Contra-lateral common or internal carotid artery occlusion.
- Coronary artery disease with two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot, be revascularized.
- Any of the following anatomical: radical neck dissection; surgically inaccessible lesions (e.g. above cervical spine level 2 (C2)); adverse neck anatomy that limits surgical exposure (e.g. spinal immobility – inability to flex neck beyond neutral or kyphotic deformity, or short obese neck); presence of tracheostomy stoma; laryngeal nerve palsy contralateral to target vessel; or previous extracranial-intracranial or subclavian bypass procedure ipsilateral to the target vessel.
- Occlusive or critical ilio-femoral disease including severe tortuosity or stenosis that necessitates additional endovascular procedures to facilitate access to the aortic arch or that prevents safe and expeditious femoral access to the aortic arch. “String sign” of the ipsilateral common or internal carotid artery.
- Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries.
Specific Carotid Endarterectomy Exclusion Criteria:
Patients who are being considered for revascularization by CEA must not have any of the following criteria:
– Serious adverse reaction to anesthesia not able to be overcome by pre-medication.
– Distal/intracranial stenosis greater than index lesion.
Specific Carotid Artery Stenting Exclusion Criteria:
Patients who are being considered for revascularization by CAS must not have any of the following criteria:
- Allergy to intravascular contrast dye not amenable to pre-medication.
- Type III, aortic arch anatomy.
- Angulation or tortuosity (≥ 90 degree) of the innominate and common carotid artery that precludes safe, expeditious sheath placement or that will transmit a severe loop to the internal carotid after sheath placement.
- Severe angulation or tortuosity of the internal carotid artery (including calyceal origin from the carotid bifurcation) that precludes safe deployment of embolic protection device or stent. Severe tortuosity is defined as 2 or more ≥ 90 degree angles within 4 cm of the target stenosis.
- Proximal/ostial CCA, innominate stenosis or distal/intracranial stenosis greater than index lesion.
Excessive circumferential calcification of the stenotic lesion defined as >3mm thickness of calcification seen in orthogonal views on fluoroscopy.(Note: Anatomic considerations such as tortuosity, arch anatomy, and calcification must be evaluated even more carefully in elderly subjects (≥ 70 years).)
- Target ICA vessel reference diameter <4.0 mm or >9.0 mm. Target ICA measurements may be made from angiography of the contralateral artery. The reference diameter must be appropriate for the devices to be used.
- Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).
- Non-contiguous lesions and long lesions (>3 cm).
- Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.
TCDs in older patients who received 7T MRI to look for R to L shunt & impaired cerebral vasoreactivity
Internet-based CBT after stroke, 18 years or older, stroke within 6 months, regular access to the internet, symptoms of mild to moderately depressed mood, defined as a score of 5-19 on the PHQ-9 questionnaire
Moderate or severe MCA stenosis, measuring CVR in the setting of MCA stenosis, one time MRI Study (MRI will be done as outpatient)
VISUAL RECOVERY TRIAL:
Contact: Madhura Tamhankar
– Hemianopia or Quadrantanopia of at least 4 months due to occipital lobe ischemia.
– Age 18-75.
– Must have at least 20/40 vision in each eye and must be computer savvy. Involves training on a visual training software 1 hour/day for 6-7 days of the week
– Cognitive disability, motor disability ( weakness or tremors of arm or hand), inability to maintain fixation cortical blindness and ocular disease
There will be two visits in the beginning and 2 visits in the end of 6 months. The primary end point is to demonstrate improvement in visual fields at the end of six months.
Patients will be pain $30 per visit so $120 total. They get to keep the software. The patients who are in the placebo group will then get the real training in the end if the study shows effectiveness.