Acute ischemic stroke

Escape-MeVO (Endovascular treatment to improve outcomes for medium vessel occlusions)

Trial summary

530 participants with medium vessel occlusion (M2, M3, A2, A3, P2, P3) will be randomized 1:1 for best medical treatment with or without endovascular thrombectomy. A Medtronic Solitaire device must be used for the first endovascular attempt.

Inclusion criteria

• Acute ischemic stroke clinically eligible for immediate EVT
• Age ≥18 years at the date of randomization
• Time from onset (or last-seen-well) to randomization <12 hours
• Disabling stroke defined as follows:
  • Baseline National Institutes of Health Stroke Scale (NIHSS) score 6+ at the time of randomization, or
  • NIHSS 3-5 with disabling deficit (eg. hemianopia, aphasia, loss of hand function) as determined by the attending physician in context of the patient’s life situation
• Confirmed symptomatic and endovascularly treatable MeVO based on neurovascular non-invasive imaging (mCTA or MRA), at one or more of the following locations: M2 or M3 segment, A2 or A3 segment, P2 or P3 segment
• Clinical deficit commensurate with MeVO occlusion location
• Signed informed consent or two-physician consent

Exclusion criteria

• ASPECTS 7 or lower
• Exclusion imaging criteria depend on the imaging modalities available:
  • NCCT + mCTA: Well demarcated hypodensity in the majority of the brain parenchyma supplied by the occluded vessel or absence of collaterals in the affected territory on the delayed phases of the mCTA
  • NCCT + (m)CTA + CTP**: Lack of core:penumbra mismatch (if the CTP is uninterpretable, e.g., due to motion artifacts, apply exclusion criteria from above. If single-phase CTA is performed, score collaterals accordingly. If NCCT + mCTA + CTP are all performed, the core: penumbra mismatch criteria are sufficient for exclusion)
  • MRI: Diffusion restriction in the majority of the brain parenchyma supplied by the occluded vessel
  • If MR perfusion is performed: lack of core:penumbra mismatch
• Any evidence of intracranial hemorrhage on qualifying imaging
• Patients living in a nursing home or requiring daily nursing care or assistance with activities of daily living
• Patient has a major co-morbid illness, such as severe dementia, advanced cancer, advanced heart failure etc. such that they are unlikely to be able to complete follow-up or they are unlikely to achieve the primary outcome due to the underlying illness (rather than the stroke or its treatment)
• Pregnancy: female with positive urine or serum beta human chorionic gonadotropin (β-hCG) test
• Participation in another clinical therapeutic intervention trial

EASI-TOC (Endovascular acute stroke intervention – tandem occlusion)

Trial summary

Patients will be randomized (1:1) to undergo acute ICA stenting during the thrombectomy procedure (either before or after intracranial thrombectomy, at the discretion of the treating physician) or to intracranial thrombectomy alone without ICA stenting.

Inclusion criteria

• Occlusion of the carotid terminus, M1 or M2 segments of the middle cerebral artery (MCA)
• A neurological deficit judged to be disabling by the patient and/or treating physician (? NIHSS threshold)
• Any acute imaging judged by the treating physician to demonstrate salvageable brain tissue possibly amenable to EVT (? ASPECTS threshold)
• Arterial puncture within 24 hours of onset or last known normal
• Ipsilateral high-grade (>70%) cervical internal carotid artery (ICA) stenosis or occlusion of presumed atherosclerotic etiology

Exclusion criteria

• Pre-existing neurological impairment (modified Rankin score ≥3)
• Isolated cervical carotid occlusion without intracranial occlusion
• ICA stenosis or occlusion attributable to arterial dissection

TEMPO-2 (tenecteplase vs. standard of card for minor stroke with intracranial occlusion within 12 hours of onset)

Trial Summary

Randomized controlled trial of tenecteplase vs. placebo for minor non-disabling stroke / TIA

Inclusion criteria

• Acute ischemic stroke in an adult patient (>18 years old)
• Onset or last seen well time to treatment time <12 hours
• TIA or minor stroke defined as a baseline NIHSS 0-5 at the time of randomization. Patients don’t have to have persistent demonstrable neurological deficit on physical neurological examination.
• Any acute intracranial occlusion or near occlusion (TICI 0 or 1) (MCA, ACA, PCA, VB territories) defined by non-invasive acute imaging (CTA or MRA) that is neurologically relevant to the presenting symptoms and signs. An acute occlusion is defined as TICI 0 or TICI 1 flow. Practically this can include a small amount of forward flow in the presence of a near occlusion AND Delayed washout of contrast with pial vessels on multiphase CTA in a region of brain concordant with clinical symptoms and signs OR; any area of focal perfusion abnormality identified using CT or MR perfusion – e.g. transit delay (TTP, MTT or TMax), in a region of brain concordant with clinical symptoms and signs.
• Pre-stroke independent functions status: mRS <2
• Informed consent from the patient or surrogate
• Patients can be treated within 90 minutes of the first slice of CT or MRI.

Exclusion criteria

• Hyperdensity on NCCT consistent with intracranial hemorrhage
• Large acute stroke ASPECTS <7 visible on baseline CT scan.
• Core of established infarction. No large area (estimated >10cc) of grey matter hypodensity at a similar density to white matter or in the judgement of the enrolling neurologist is consistent with a subacute ischemic stroke.
• Baseline functional status MRS 3-5
• Patient has a severe or fatal or disabling illness that will prevent improvement or follow up or such that the treatment would not likely benefit the patient.
• Pregnancy.
• Planned thrombolysis with IV tPA or endovascular acute treatment.
• In-hospital stroke unless these patients are at their baseline prior to the stroke.
• Commonly accepted exclusions for medical thrombolytic treatment. These are commonly relative contraindications (i.e. the final decision is at the discretion of the treating physician):
  • INR >1.7 or known full anticoagulation with the use of any standard or novel anticoagulant therapy with full anticoagulant dosing. (DVT prophylaxis dosing shall not prohibit enrollment).
  • For LMWH or novel anticoagulants >48 hours off drug will be considered sufficient to allow trial enrollment.
  • Dual antiplatelet therapy does not prohibit enrollment.
  • For patients who are known not to be taking anticoagulant therapy it is not necessary to wait for coagulation lab results (e.g. PT, PTT) prior to treatment).
  • Patients who have been acutely treated with GP2b3a inhibitors.
  • Arterial puncture at a non-compressible site in the previous seven days.
  • Clinical stroke or serious head or spinal trauma in the preceding 3 months that would normally preclude use if a thrombolytic agent.
  • History of intracranial hemorrhage, SAH or other brain hemorrhage that would normally preclude use of a thrombolytic agent.
  • Major surgery within the last 3 months that the treating physician considers a contraindication to thrombolytic therapy.
  • Severe hypo-or hyperglycemia thought to be the principal cause of the neurological symptoms.
  • Hypertension refractory to anti-hypertensive medication such that target BP <185/110 cannot be achieved before treatment.
  • Known platelet count below 100,000/mm3 (Treatment should not be delayed to wait for platelet count unless thrombocytopenia is known or suspected.
  • Gastrointestinal or genitourinary bleeding within the past 3 months that would normally preclude use of a thrombolytic agent

Acute intracerebral hemorrhage

ANNEXA-I (Andexanet alfa versus standard supportive care for oral FXa-related ICH)

Trial summary

Randomized clinical trial of andexanet alfa for intracranial hemorrhage in patients receiving therapeutically-dosed oral Factor-Xa inhibitor (apixaban, edoxaban, rivaroxaban)

Inclusion criteria

• Age 18 – 89 years old
• An acute intracerebral bleeding episode, defined as an estimated blood volume > 0 to ≤ 60 mL acutely observed radiographically within the cerebrum. Patients may have extracerebral (e.g., subdural, subarachnoid) or extracranial (e.g., gastrointestinal, intraspinal) bleeding additionally, but the intracerebral hemorrhage must be considered the most clinically significant bleed at the time of enrollment.
• Performance of a head CT or MRI scan demonstrating the intracerebral bleeding within 2 hours prior to randomization (the baseline scan may be repeated to meet this criterion).
• Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater], or edoxaban [last dose 30 mg or greater]):
  1. ≤ 15 hours prior to randomization.
  2. > 15 hours prior to randomization or unknown time of last dose, if documented anti-fXa activity is > 100 ng/mL (or over the equivalent IU/mL threshold on a LMWH assay; see Laboratory Manual) within 2 hours prior to consent.
• Time from bleeding symptom onset < 6 hours prior to the baseline imaging scan. Time of trauma (if applicable) or time last seen normal may be used as surrogates for time of symptom onset. (If the baseline scan is repeated to meet Inclusion Criterion #3, the time from bleeding symptom onset must be < 6 hours prior to the 2nd baseline imaging scan.)
• Willingness to use medically acceptable methods of contraception through 30 days following study drug dose (for female and male subjects who are fertile).
• Have a negative pregnancy test documented prior to enrollment (for women of childbearing potential).

Exclusion criteria

• Planned surgery, including Burr holes for hematoma drainage, within 12 hours after randomization. Minimally invasive surgery/procedures not directly related to the treatment of intracranial bleeding and that are not expected to significantly affect hematoma volume are allowed (e.g. Burr holes for intracranial pressure monitoring, endoscopy, bronchoscopy, central lines).
• GCS <7 at the time of consent. If a patient is intubated and/or sedated at the time of consent, they may be enrolled if it can be documented that they were intubated/sedated for non-neurologic reasons within 2 hours prior to consent.
• Any bleeding into the epidural space.
• Anticipation that the baseline and follow up brain scans will not be able to use the same imaging modalities (i.e., patients with a baseline CT scan should have a CT scan in follow up; similarly for MRI).
• Expected survival of <1 month (unrelated to the intracranial bleed).
• Recent history (within 2 weeks) of a diagnosed TE or clinically relevant symptoms of the following: venous thromboembolism (e.g. DVT, PE, CVT), MI, DIC, CVA, TIA, acute coronary syndrome, or arterial systemic embolism within 2 weeks prior to screening
• Acute decompensated heart failure or cardiogenic shock at the time of randomization
• Severe sepsis or septic shock at the time of randomization
• Pregnant or lactating

Post-admission trials

CoVasc-ICH (Colchicine for the prevention of vascular events after an acute intracerebral hemorrhage)

Trial summary

100 patients with acute intracerebral hemorrhage and atherosclerosis will be randomized 1:1 to colchicine 0.5 mg daily or matching oral placebo. The primary outcome for the study is recruitment rate (feasibility).

Inclusion criteria

• Adult patients presenting with spontaneous intraparenchymal hemorrhage within 48 hours of symptom onset and qualifying for at least one of the following categories:
  • history of symptomatic coronary, peripheral and/or carotid artery disease (severe atherosclerotic vascular disease), or
  • ii. visualized extracranial cervical/intracranial atherosclerotic disease causing any degree of stenosis/occlusion or presence of aortic arch plaque with maximum thickness ≥1 mm (moderate atherosclerotic vascular disease), or
  • iii. two or more risk factors including: age 60 years or older, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease (eGFR: 15-50mL/min), history of ischemic stroke or current smoking (mild atherosclerotic vascular disease).

Exclusion criteria

• Secondary causes of ICH (such as trauma, macrovascular anomalies, neoplasms or bleeding diathesis)
• Inflammatory bowel disease or chronic diarrhea
• Cirrhosis or severe hepatic dysfunction
• Renal insufficiency (eGFR<15mL/min)
• Concurrent or planned treatment with strong CYP3A4 inhibitors (atazanavir, clarithromycin, darunavir/ritonavir, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, tipranavir/ritonavir) or P-gp inhibitors (cyclosporine, ranolazine)
• Pregnancy or breast-feeding
• Known allergy or sensitivity to colchicine
• A strong indication for colchicine where assignment to placebo is deemed unacceptable
• Estimated life expectancy less than 6 months at the time of enrollment, and
• Inability to adhere to study procedures

CREST-2 (carotid endarterectomy and aggressive medical therapy versus aggressive medical therapy alone for asymptomatic carotid stenosis )

Status

Recruiting

Trial summary

Medical management vs. revascularization for asymptomatic carotid stenosis

Inclusion criteria

• Patients ≥35 years old.
• Carotid stenosis defined as:
  • Stenosis ≥70% by catheter angiography (NASCET Criteria)
  • Carotid US with ≥70% stenosis defined by a peak systolic velocity of at least 230 cm/s plus at least one of the following:
    • an end diastolic velocity ≥100 cm/s, or
    • internal carotid/common carotid arterypeak systolic velocity ratio ≥4.0, or
    • CTA with ≥ 70% stenosis
    • MRA with ≥ 70% stenosis.
• No medical history of stroke or TIA ipsilateral to the stenosis within 180 days of randomization.
• Patients must have an mRS 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 procedures.

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.
• History of major symptomatic intracranial hemorrhage within 12 months that was not related to anticoagulation.
• Prior Intracranial hemorrhage that the investigator believes represents a contraindication to the perioperative or periprocedural antithrombotic and antiplatelet treatments necessary to complete endarterectomy or stenting per protocol.  
• 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 AF within the past 6 months or history of paroxysmal AF 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).
• LVEF<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.
• Either the serum creatinine ≥ 2.5 mg/dl or estimated GFR < 30 cc/min.
• 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.
• Extreme morbid obesity that would compromise patient safety during the procedure or would compromise patient safety during the periprocedural period.
• Coronary artery disease with two or more proximal or major diseased coronary arteries with ≥ 70% stenosis that have not, or cannot, be revascularized.
• Specific to carotid endarterectomy
• Serious adverse reaction to anesthesia not able to be overcome by pre-medication.
• Distal/intracranial stenosis greater than index lesion.
• 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 extracranialintracranial or subclavian bypass procedure ipsilateral to the target vessel.  

CONVINCE (colchicine vs. no colchicine for secondary prevention)

Status

Recruiting

Trial summary

Colchicine vs. placebo for secondary stroke prevention

Inclusion criteria

• Age >40 years
• Patient has had either:
  • An ischemic stroke without major disability (mRS 3 or less),
  • A high-risk TIA, defined as: i. Transient focal neurological symptoms of presumed vascular cause with, in addition, one or more of the following criteria:
    • ABCD2 score of >4, with motor or speech symptoms (dysarthria or dysphasia)
    • DWI hyperintensity on acute MRI
    • Stenosis (lumen narrowing of >50% on ultrasound, MRA, CTA, or invasive angiography) of the internal carotid, vertebral, MCA, ACA or basilar artery in the arterial territory consistent with symptoms
  • ​​​​​​​A brain CT or MRI has excluded primary intracranial hemorrhage
  • The stroke/TIA has occurred >72 hours before randomization AND no more than 28 days prior to randomization
  • Qualifying stroke/TIA probably caused by large artery stenosis, small artery occlusion (lacunar stroke), or cryptogenic embolism, with cardiac embolism or other defined stroke mechanism deemed unlikely in the opinion of the treating physician.
  • eGFR > 50 ml/min
  • In the opinion of the treating physician, patient is medically stable, capable of participating in a randomized trial, and willing to attend follow up.

Exclusion criteria

• Stroke/TIA, probably caused by identified atrial fibrillation (permanent or paroxysmal), in the opinion of the treating physician.
• Stroke/TIA probably caused by other identified cardiac source (intra-cardiac thrombus, endocarditis, metallic heart valve, low ejection fraction <30%).
• Stroke/TIA caused by dissection, endocarditis, paradoxical embolism, drug use, venous thrombosis, carotid or cardiac surgery, hypercoagulability states, migraine, or inherited cerebrovascular disorders
• History of myopathy or myalgias with raised creatine kinase on statin therapy.
• Blood dyscrasia (Hgb <10 g/dL, platelet count <150 x109/L, WBC <4×109/L)
• Impaired hepatic function (transaminases greater than twice the upper limit of normal)
• Concurrent treatment with colchicine contraindicated drugs: CYP3A4 inhibitors (clarithromycin, erythromycin, telithromycin, other macrolide antibiotics, ketoconazole, itraconazole, voriconazole, ritonavir, atazanavir, indinavir, other HIV protease inhibitors, verapamil, diltiazem, quinidine, digoxin, disulfiram) or P-gp inhibitors (cyclosporine) at randomization.
• Symptomatic peripheral neuropathy and preexisting progressive neuromuscular disease.
• Inflammatory bowel disease (Crohn’s or ulcerative colitis) or chronic diarrhea.
• Dementia, sufficient to impair independence in basic activities of daily living.
• Active malignancy, known hepatitis B or C or HIV infection
• Impaired swallow preventing oral administration of Colchicine
• History of poor medication compliance.
• Unlikely to comply with study procedures due to severe or fatal comorbid illness or other factor (e.g. inability to travel for follow up visits), in opinion of randomizing physician.
• Pregnancy, breastfeeding, or pre-menopausal woman
• Patient concurrently participating in another clinical trial with an investigational drug or device, or use of investigational drug within 30 or 5 half-lives before the screening visit (whichever is longer).
• Known allergy or sensitivity to colchicine
• Requirement for colchicine therapy for treatment of acute gout, gout prevention, or other rheumatological disorder
• Requirement for chronic daily immunosuppressants oral steroids, or NSAIDS

• Receipt of any of the following drugs or blood products within 7 days prior to consent:
  1. VKA (e.g. warfarin)
  2. Dabigatran
  3. Prothrombin Complex Concentrate products (e.g. Kcentra) or rfVIIa (e.g., NovoSeven) or anti-inhibitor coagulant complex (e.g. FEIBA)
• Past use of andexanet or planned use of commercial andexanet
• Treatment with an investigational drug <30 days prior to consent 
• Any tumor-related bleeding.
• Known hypersensitivity to any component of andexanet.
• NIHSS >35 at the time of consent.