Stroke, Acute
Conditions
Keywords
Mechanical Thrombectomy, Recanalization, Reperfusion
Brief summary
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
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.
Interventions
See arm/group descriptions.
DRUGPlacebo
See arm/group descriptions.
Sponsors
Fundació La Marató de TV3
Fundacion Clinic per a la Recerca Biomédica
Hospital Clinic of Barcelona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The solutions of alteplase or placebo are limpid, transparent and colorless. Alteplase (Actilyse 10 mg powder and solvent for solution for injection and infusion) and placebo will be provided in kind by Boëhringer Ingelheim. The secondary conditioning of the investigation treatment will be performed by Alcura Health Spain S.A.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. 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 3. 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) 4. Age ≥18 5. 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. 6. Informed consent obtained from patient or acceptable patient surrogate
Exclusion criteria
1. NIHSS score on admission \>25 2. Contraindication to IV t-PA as per local national guidelines (except time to therapy) 3. Use of carotid artery stents during the endovascular procedure requiring dual antiplatelet therapy during the first 24h 4. Female who is pregnant or lactating or has a positive pregnancy test at time of admission 5. 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) 6. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency 7. Known coagulopathy, INR \> 1.7 or use of novel anticoagulants \< 48h from symptom onset 8. Platelets \< 50,000 9. Renal Failure as defined by a serum creatinine \> 3.0 mg/dl (or 265.2 μmol/l) or glomerular Filtration Rate \[GFR\] \< 30 10. Subject who requires hemodialysis or peritoneal dialysis, or who have a contraindication to an angiogram for whatever reason 11. Any hemorrhage on CT/MRI 12. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI scan is normal 13. Suspicion of aortic dissection 14. Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol 15. History of life threatening allergy (more than rash) to contrast medium 16. SBP \>185 mmHg or DBP \>110 mmHg refractory to treatment 17. Serious, advanced, terminal illness with anticipated life expectancy \< 6 months 18. Pre-existing neurological or psychiatric disease that would confound evaluation 19. Presumed vasculitis or septic embolization 20. Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Good outcome at 90 days | Day 90 after treatment. | The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Shift analysis of the 90-day modified Rankin Scale (mRS). | Day 90 after treatment. | 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). |
| Infarct expansion ratio. | 48 (+/- 24h) hours of stroke | Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke |
| Rate of infarct expansion at 24 hours. | 48 (+/- 24h) hours of stroke | Proportion of patients with/without infarct expansion (dichotomous variable). |
| Final infarct volume. | 48 (+/- 24h) hours of stroke | Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset |
| TERTIARY OUTCOME: Barthel Scale at day 90 | Day 90 after treatment. | Barthel Scale score of 95 to 100, at day 90 |
| TERTIARY OUTCOME: Ischemic worsening within 72 hours os stroke onset | 72 hours of stroke onset | Ischemic worsening (≥ 4 points in the NIHSS score) within 72 hours of stroke onset not attributable to stroke recurrence |
| TERTIARY OUTCOME: Quality of life measured at 90 days | Day 90 after treatment. | Quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D-3L) at 90 days |
| Angiographic improvement on the Arterial Occlusive Lesion (AOL) scale | 10 minutes after treatment | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with improved mTICI 2b score | 10 minutes after treatment | Proportion of patients with improved mTICI 2b score 1. IV Alteplase use on admission (yes versus no) 2. MT started within 7.3h of symptoms onset versus MT started between 7.4h and 24h. 3. Admission serum glucose concentration≤100 mg/dL versus \>100 mg/dL 4. Males vs. Females 5. Baseline angiographic score mTICI2b brain reperfusion versus baseline angiographic score eTICI2c/3 brain reperfusion. |
Countries
Spain
Outcome results
None listed