Outpatient Trials

Arcadia
Arcadia-CSI
Aspire
Enrich
Crest-2
Crest-H
Trains
Reduce
Discovery
Catch
Discover
Thornhill
Visual Recovery

ARCADIA: Devin

Atrial Cardiopathy Criteria:
 (# boxes wide) x (# boxes tall) x (4000) = p=wave terminal force >5000
OR
NT-proBNP > 250 for enrollment
OR
Left atrial size index based on TTE (left atrial diameter/BSA) ≥ 3 cm/m2

Enrollment VideoDownload
  • Inclusion Criteria: 
    1. Age ≥45 years.
    2. Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.
    3. Modified Rankin Scale (MRS) score ≤4.
    4. Ability to be randomized no later than 180 days after stroke onset.
    5. ESUS, defined as all of the following:
    6. 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.
  • Exclusion Criteria:
    1. History of AF, AF on 12-lead ECG, or any AF of any duration during heart-rhythm monitoring prior to randomization.
    2. Clear indication for treatment-dose anticoagulant therapy, such as venous thromboembolism or a mechanical heart valve.
    3. Left ventricular ejection fraction <30%.
    4. Definite indication for antiplatelet agent (e.g., aspirin or clopidogrel after implantation of a coronary artery stent).
    5. History of spontaneous intracranial hemorrhage.
    6. Chronic kidney disease with serum creatinine ≥2.5 mg/dL.
    7. Active hepatitis or hepatic insufficiency with Child-Pugh score B or C (see MOP for definition).
    8. Clinically significant bleeding diathesis.
    9. Anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 109/L) that is chronic in the judgment of the investigator.
    10. GI bleeding within the past year considered clinically significant by the investigator.
    11. Pregnancy risk: − Female patient who is known to be pregnant.
    12. Female patient who is sexually active and premenopausal without a negative pregnancy test performed after stroke onset.
    13. Female patient who is sexually active and premenopausal, and who does not commit to adequate birth control.
    14. Male patient who is sexually active with a premenopausal female partner, and who does not commit to adequate birth control.
    15. Known allergy or intolerance to aspirin or apixaban.
    16. Concomitant participation in another clinical trial involving a drug or acute stroke intervention.
    17. Considered by the investigator to have a condition that precludes follow-up or safe participation in the trial.
    18. Inability to obtain written, informed consent from patient or surrogate for trial participation.

How to handle patients with swallowing impairment
If a subject is unable to safely swallow whole tablets, the study tablets may be crushed and suspended in 60 mL of water, D5W, apple juice or mixed with applesauce and administered orally. The crushed tablets should be administered immediately but are stable for up to 4 hours. The crushed study drug may also be administered via nasogastric tube when mixed with 60mL of water or D5W.

ARCADIA-CSI: Devin

  • INCLUSION CRITERIA:
    1. Randomized in ARCADIA & on study drug
    2. Able to undergo magnetic resonance imaging (MRI)
    3. Able to provide self-consent for ARCADIA-CSI in English (cognitive status and language ability sufficient to provide informed consent)
    4. A score of 0 or 1 on language component of the NIHSS at the time of ARCADIA-CSI enrollment
  • EXCLUSION CRITERIA:
    1. Diagnosis of dementia
    2. Known active illicit drug use
    3. Psychiatric admission of ECT for major depression within last two years
    4. Education less than 8 years
    5. History of traumatic brain injury with loss of consciousness of more than 30 minutes

ASPIRE: MaryLiz

  • INCLUSION CRITERIA:
    1. Age at least 18 years
    2. Intracerebral hemorrhage (ICH) (including primary intraventricular hemorrhage) confirmed by brain CT or MRI
    3. Can be randomized within 14-180 days after ICH onset
    4. Non-valvular AF (defined as atrial fibrillation or atrial flutter), documented by electrocardiography or a physician-confirmed history of AF
    5. CHA2DS2-VASc score20 ≥ 2
    6. Provision of signed and dated informed consent form by patient or legally authorized representative
    7. For females of reproductive potential: use of highly effective contraception
  • EXCLUSION CRITERIA:
    1. Index event is hemorrhagic transformation of brain infarction or hemorrhage into a tumor
    2. History of an earlier ICH within 12 months preceding index event
    3. Active infective endocarditis
    4. Clear indication for anticoagulant drugs (e.g., requires anticoagulation for DVT or PE) or antiplatelet drugs (e.g., requires aspirin or clopidogrel for recent MI)
    5. Previous or planned left atrial appendage closure
    6. Clinically significant bleeding diathesis
    7. Serum creatinine ≥2.5 mg/dL
    8. Active hepatitis or hepatic insufficiency with Child-Pugh score B or C
    9. Anemia (hemoglobin <8 g/dL) or thrombocytopenia (<100 x 109/L) that is chronic in the judgment of the investigator
    10. Pregnant or breastfeeding
    11. Known allergy to aspirin or apixaban
    12. Concomitant participation in a competing therapeutic trial
    13. Considered by the investigator to have a condition that precludes safe or active participation in the trial
    14. Persistent, uncontrolled systolic blood pressure (≥180 mm Hg)
    15. ICH caused by an arteriovenous malformation (AVM) that has not yet been secured
  • Patient may be enrolled if exclusion resolves within 180 days of index ICH (e.g., blood pressure is controlled, AVM secured).

ENRICH: Nichole

  • INCLUSION CRITERIA:
    1. Written informed consent provided
    2. Age ≥45 years, at the time of signing the informed consent
    3. Previous intracranial hemorrhage (symptomatic, spontaneous and non-traumatic intraparenchymal, intraventricular, and/or cSAH, and symptomatic spontaneous or non-penetrating traumatic subdural hemorrhages) on or off antithrombotic therapy (Table 2)
    4. Documented atrial fibrillation (paroxysmal, persistent, permanent)
    5. CHA2DS2-VASc score ≥2
  • EXCLUSION CRITERIA:
    1. Recent intracranial hemorrhage (within 14 days)
    2. Secondary macrovascular, neoplastic or infectious causes of intracranial hemorrhage (except for antithrombotic treatment or non-penetrating traumatic subdural hemorrhages)
    3. Traumatic or aneurysmal cSAH
    4. Need for ongoing oral anticoagulant therapy for indication other than AF (e.g. mechanical heart valve, venous thromboembolic disease)
    5. Need for ongoing antiplatelet therapy for indication where edoxaban would not be a suitable substitute
    6. Plans for left atrial appendage occlusion
    7. Estimated creatinine clearance (CrCl) < 15 mL/min or >95 mL/min
    8. Platelet count less than 100,000mm3 at enrollment or other bleeding diathesis
    9. Persistent, uncontrolled hypertension (systolic BP averaging >150 mmHg)
    10. Chronic use of NSAID
    11. Clinically significant active bleeding, including gastrointestinal bleeding
    12. Lesions or conditions at increased risk of clinically significant bleeding, e.g. active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis
    13. Antiphospholipid antibody syndrome
    14. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
    15. Known hypersensitivity to edoxaban
    16. Estimated inability to adhere to study procedures
    17. Pregnancy or breastfeeding*
    18. Estimated life expectancy < 6 months at the time of enrollment
    19. Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)

CREST-2: Nichole

  • General Inclusion Criteria:
    1. Patients ≥35 years old.
    2. 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.
    3. 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
    4. Patients must have a modified Rankin Scale score of 0 or 1 at the time of informed consent.
    5. Women must not be of childbearing potential or, if of childbearing potential, have a negative pregnancy test prior to randomization.
    6. Patients must agree to comply with all protocol-specified follow-up appointments.
    7. 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.
    8. 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).
    9. Carotid stenosis must be treatable with CEA, CAS, or either procedure.
  • General Exclusion Criteria
    1. Intolerance or allergic reaction to a study medication without a suitable management alternative.
    2. GI hemorrhage within 1 month prior to enrollment that would preclude antiplatelet therapy.
    3. Prior major ipsilateral stroke in the past with substantial residual disability (mRS ≥ 2) that is likely to confound study outcomes.
    4. Severe dementia.
    5. Intracranial hemorrhage within the past 12 months.
    6. Current neurologic illness characterized by fleeting or fixed neurologic deficits that cannot be distinguished from TIA or stroke.
    7. Patient objects to future blood transfusions.
    8. Platelet count <100,000/μl or history of heparin-induced thrombocytopenia.
    9. Anticoagulation with Phenprocoumon (Marcumar®), warfarin, or a direct thrombin inhibitor, or anti-Xa agents.
    10. Chronic atrial fibrillation.
    11. Any episode of atrial fibrillation within the past 6 months or history of paroxysmal atrial fibrillation that is deemed to require chronic anticoagulation.
    12. 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.
    13. 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).
    14. Left Ventricular Ejection fraction <30% or admission for heart failure in prior 6 months.
    15. Respiratory insufficiency with life expectancy < 4 years or FEV1 <30% of predicted value.
    16. 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.
    17. Any major surgery, major trauma, revascularization procedure, or acute coronary syndrome within the past 1 month.
    18. Serum creatinine ≥2.5 mg/dl or estimated GFR ≤40 cc/min (at screening).
    19. Major (non-carotid) surgery/procedures planned within 3 months after enrollment.
    20. Currently listed or being evaluated for major organ transplantation (i.e. heart, lung, liver, kidney).
    21. 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.
    22. Inability to understand and cooperate with study procedures or provide informed consent.
    23. Non-atherosclerotic carotid stenosis (dissection, fibromuscular dysplasia, or stenosis following radiation therapy).
    24. Previous ipsilateral CEA or CAS.
    25. Ipsilateral internal or common carotid artery occlusion.
    26. Intra-carotid floating thrombus.
    27. Ipsilateral intracranial aneurysm > 5 mm.
    28. WHO Class III obesity (BMI >40 kg/m2).
    29. Contra-lateral common or internal carotid artery occlusion.
    30. Coronary artery disease with two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot, be revascularized.
  • Specific Carotid Endarterectomy Exclusion Criteria:
    • Patients who are being considered for revascularization by CEA must not have any of the following criteria:
      1. Serious adverse reaction to anesthesia not able to be overcome by pre-medication.
      2. Distal/intracranial stenosis greater than index lesion.
      3. 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.
  • Specific Carotid Artery Stenting Exclusion Criteria:
    • Patients who are being considered for revascularization by CAS must not have any of the following criteria:
      1. Allergy to intravascular contrast dye not amenable to pre-medication.
      2. Type III, aortic arch anatomy.
      3. 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.
      4. 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.
      5. 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).)
      6. 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.
      7. Inability to deploy or utilize an FDA-approved Embolic Protection Device (EPD).
      8. Non-contiguous lesions and long lesions (>3 cm).
      9. Qualitative characteristics of stenosis and stenosis-length of the carotid bifurcation (common carotid) and/or ipsilateral external carotid artery, that preclude safe sheath placement.
      10. 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.
      11. Angiographic, CT, MR or ultrasound evidence of severe atherosclerosis of the aortic arch or origin of the innominate or common carotid arteries that would preclude safe passage of the sheath and other endovascular devices to the target artery as needed for carotid stenting.

TRAINS:

  • INCLUSION CRITERIA:
    1. Stroke that occurred within 3 months of study enrollment
    2. Presence of cognitive impairment attributable to stroke as evidenced by MoCA ≤ 25 or CLQT severity composite score > 1.4 and < 3.5
    3. Between the ages of 18 and 90
    4. Able to follow simple commands as evidenced by NIHSS subtest 1C =0
  • EXCLUSION CRITERIA:
    1. History of chronic, serious, or unstable neurologic illness(es) other than stroke Current unstable medical illness(es)
    2. History of reoccurring seizures or epilepsy
    3. Current abuse of alcohol or drugs (prescription or otherwise)
    4. Active and severe psychiatric disorder
    5. Subjects with metallic objects in the face or head other than dental apparatus such as braces, fillings, and implants. – Pregnancy. If the subject cannot rule out pregnancy then a pregnancy test will be conducted prior to inclusion into the study.

REDUCE: MaryLiz

  • INCLUSION CRITERIA:
    1. Age ≥ 18 years
    2. Symptomatic ICH confirmed by head CT or brain MRI during hospitalization
    3. Written, informed consent by patient or surrogate
    4. Ability to comply with all study procedures and available for the duration of the study
  • EXCLUSION CRITERIA:
    1. Secondary ICH due to trauma, vascular malformation, or tumor
    2. Life expectancy < 1 year
    3. eGFR <45
    4. Serum potassium greater than or equal to the upper limit of normal of the lab on the two most recent consecutive potassium levels prior to enrollment
    5. Known hypersensitivity to spironolactone
    6. Upper arm greater than 17 inches in circumference
    7. Pregnancy, planned pregnancy, or breastfeeding
    8. Currently on a mineralocorticoid-receptor antagonist and/or recommended to start a mineralocorticoid-receptor antagonist as a part of their routine clinical care at the time of study screening.  
    9. Systolic BP >200 mmHg or diastolic BP >110 mmHg at the time of randomization
    10. Systolic BP <120 mmHg at the time of randomization
    11. Any condition which, in the judgement of the investigator, increases the risk to the patient
    12. History of Addison’s disease

DISCOVERY: Ann

  • Inclusion Criteria:
    1. Age ≥18 years
    2. Admitted to the hospital with a diagnosis of AIS, ICH, or aSAH
    3. Radiographic confirmatory evidence of: (1) AIS (based on a focal area of restricted diffusion on MRI), (2) non-traumatic ICH (based on evidence of acute parenchymal hemorrhage CT or brain MRI) or (3) non-traumatic acute aSAH (based on evidence of subarachnoid hemorrhage on CT or MRI and evidence of aneurysm on CT angiography, MR angiography, or conventional catheter-based angiography)
    4. Able to complete baseline visit in person or by phone within 6 weeks of stroke onset
    5. Able to provide informed consent by self or proxy
    6. Fluent in English or Spanish prior to stroke onset
  • Exclusion Criteria:
    1. Documented history of pre-stroke dementia or fails dementia pre-screen
    2. Concurrently enrolled into a study that is not approved under the DISCOVERY Co-Enrollment Policy
    3. Unable to complete study protocol (advanced directives such as comfort measures only, or inability to complete the study due to severe medical/behavioral co-morbidities), as determined by physician investigator during screening process
    4. Contraindication to MRI: presence of electrically, magnetically, or mechanically activated implants (such as cardiac pacemakers, cochlear implants, implanted pumps); or metallic clips in the brain

CATCH: Sarah

  • INCLUSION CRITERIA:
    1. 18 years of age or older
    2. Newly prescribed CGRP monoclonal antibody therapy for migraine prevention
    3. Subject must sign the informed consent form
  • EXCLUSION CRITERIA:
    1. History of anti-CGRP medication use (including small molecule antagonists)
    2. History of stroke
    3. History of brain mass (other than meningioma)
    4. Skull defect or skull surgery that will interfere with TCD monitoring
    5. Unable or unwilling to remain in bed for 30 minutes to tolerate TCD monitoring
    6. Unable or unwilling to return for 3-month study visit
    7. Any other illness/condition that the investigator feels would pose a hazard to the subject from participation in the study

DISCOVER: Steph

TCDs in older patients who received 7T MRI to look for R to L shunt & impaired cerebral vasoreactivity

THORNHILL STUDY: Steph

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
madhura.tamhankar@uphs.upenn.edu

  • Inclusion Criteria:
    1. Hemianopia or Quadrantanopia of at least 4 months due to occipital lobe ischemia.
    2. Age 18-75.
    3. 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
  • Exclusion Criteria:
    1. 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 at 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.