Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy

Study Overview
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Brief Summary
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Multicenter, randomized, placebo-controlled, double blind, phase 2b trial of acute stroke patients treated with mechanical thrombectomy (MT), in which two therapies are compared: rt-PA or placebo. Allocation at each center will account for 1 stratum: use of alteplase (yes vs. no) before MT. Subjects will be followed up to 90 days post-randomization.

Detailed Description
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The study objective is to evaluate whether rt-PA is safe and efficient as an add-on to mechanical thrombectomy in patients with acute ischemic stroke and complete or near-complete recanalization of a proximal vessel occlusion and successful brain reperfusion on cerebral angiogram (corresponding to mTICI score 2b/3) The study is a multicenter, randomized, placebo-controlled, double blind, phase 2b trial of acute stroke patients treated with MT, in which two therapies are compared: rt-PA or placebo. Allocation at each center will account for 1 stratum: use of alteplase (yes vs. no) before MT. Subjects will be followed up to 90 days post-randomization Patients will be enrolled in the angiosuit by interventionalists or neurologists once a mTICI 2b/3 is confirmed on cerebral angiography. The primary outcome is the proportion of patients with a mRS 0 to 1 at 90 days. A sample size of 100 patients per treatment arm in a 1:1 allocation will have at least 80% statistical power for the primary outcome (mRS with 0-1 score values) assuming a rate of 40% in the control arm and a 21% benefit in the experimental arm (odds ratio (OR) of 2.33) for a 5% two-sided type I error. This sample size will also guarantee the study power for that relative treatment benefit even if the success rate in the control group rises up to ≈56%. No study losses are accounted for since all randomised patients will be included in the analysis.

Official Title
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CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial

Conditions
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Stroke, Acute

Intervention / Treatment
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* Drug: Intraarterial alteplase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients with symptomatic large vessel occlusion (LVO) in the anterior, middle or posterior cerebral artery treated with MT resulting in an mTICI score 2b/3 at end of the procedure.. Patients with an mTICI score 2b/3 on the diagnostic cerebral angiography before the onset of MT are also eligible for the study. Estimated delay to onset of rescue intraarterial rt-PA administration <24 hours from symptom onset, defined as the point in time the patient was last seen well No significant pre-stroke functional disability (modified Rankin scale 0-1), or mRS >1 that according to the investigator is not related to neurological disease (i.e. amputation, blindness) Age ≥18 ASPECTS >6 on non-contrast CT (NCCT) scan or MRI if symptoms lasting <4.5 hours or ASPECTS >6 on CT-Perfusion (CTP) or DWI-MRI if symptoms >4.5 <24 hours. Informed consent obtained from patient or acceptable patient surrogate EXCLUSION CRITERIA: NIHSS score on admission >25 Contraindication to IV t-PA as per local national guidelines (except time to therapy) Use of carotid artery stents during the endovascular procedure requiring dual antiplatelet therapy during the first 24h Female who is pregnant or lactating or has a positive pregnancy test at time of admission Current participation in another investigation drug or device treatment study (except observational study i.e.: RACECAT or clinical trials not testing new medical devices or new drugs i.e.IMAGECAT) Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency Known coagulopathy, INR > 1.7 or use of novel anticoagulants < 48h from symptom onset Platelets < 50,000 Renal Failure as defined by a serum creatinine > 3.0 mg/dl (or 265.2 μmol/l) or glomerular Filtration Rate [GFR] < 30 Subject who requires hemodialysis or peritoneal dialysis, or who have a contraindication to an angiogram for whatever reason Any hemorrhage on CT/MRI Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI scan is normal Suspicion of aortic dissection Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol History of life threatening allergy (more than rash) to contrast medium SBP >185 mmHg or DBP >110 mmHg refractory to treatment Serious, advanced, terminal illness with anticipated life expectancy < 6 months Pre-existing neurological or psychiatric disease that would confound evaluation Presumed vasculitis or septic embolization Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, randomized, placebo-controlled, double blind, phase 2b trial of acute stroke patients treated with MT, in which two therapies are compared: rt-PA or placebo.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraarterial alteplase<br>All the patients will be given a 15 minutes IA infusion of alteplase (Actylise®) at a drug concentration of 1.0 mg/ml. At 15 minutes of IA treatment onset, the infusion will be stopped and the angiographic score assessed. If the angiographic score is improved compared with the baseline score the procedure is terminated, otherwise a new angiographic series will be repeated in 10 minutes before the end of the procedure in front and profile projections. Study drug will be prepared according to the following steps: Dilute 3 vials of 10 mgs (alteplase) in 30 cc of sterile water for injection (SWI), to attain a 30 cc solution at a concentration of 1mg/ml Calculate the volume of cc of infusion and therefore the total dose as per the formula: (Patient's weight in Kgs multiplied by 0.225) | Drug: Intraarterial alteplase<br>* See arm/group descriptions.<br>* Other names: Intraarterial alteplase recombinant tissue plasminogen activator (rTPA);|
| Placebo Comparator: Placebo<br>The placebo will consist of a lyophilized white powder containing 0.2 mol/L arginine phosphate, 0.01% polysorbate 80, and pH 7.4 after reconstitution. Study drug will be prepared according to the following steps: Dilute 3 vials of 10 mgs (placebo) in 30 cc of sterile water for injection (SWI), to attain a 30 cc solution at a concentration of 1mg/ml Calculate the volume of cc of infusion and therefore the total dose as per the formula: (Patient's weight in Kgs multiplied by 0.225) | Drug: Placebo<br>* See arm/group descriptions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Good outcome at 90 days | The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days | Day 90 after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shift analysis of the 90-day modified Rankin Scale (mRS). | The shift analysis of the modified Rankin Scale (mRS), at day 90. The mRS at 90 days will be analyzed using a proportional odds model (POM) that combine into single worst rank the last two categories (5: severe incapacity and 6: death). | Day 90 after treatment. | 
| Infarct expansion ratio. | Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke | 48 (+/- 24h) hours of stroke | 
| Rate of infarct expansion at 24 hours. | Proportion of patients with/without infarct expansion (dichotomous variable). | 48 (+/- 24h) hours of stroke | 
| Final infarct volume. | Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset | 48 (+/- 24h) hours of stroke | 
| Angiographic improvement on the Arterial Occlusive Lesion (AOL) scale | Proportion of patients with angiographic improvement on the Arterial Occlusive Lesion (AOL) scale. AOL describes arterial patency at the site of occlusion based on the degree of luminal opening (none, partial, or complete) with further qualification based simply on the presence (grades 2 or 3) or absence (grades 0 or 1) of any downstream flow. | 10 minutes after treatment | 
| TERTIARY OUTCOME: Barthel Scale at day 90 | Barthel Scale score of 95 to 100, at day 90 | Day 90 after treatment. | 
| TERTIARY OUTCOME: Ischemic worsening within 72 hours os stroke onset | Ischemic worsening (≥ 4 points in the NIHSS score) within 72 hours of stroke onset not attributable to stroke recurrence | 72 hours of stroke onset | 
| TERTIARY OUTCOME: Quality of life measured at 90 days | Quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D-3L) at 90 days | Day 90 after treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mechanical Thrombectomy, Recanalization, Reperfusion