Clinical trial NCT03876119: Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy
Official title: CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Stroke, Acute
Keywords: Mechanical Thrombectomy
Recanalization
Reperfusion
Lead sponsor: Hospital Clinic of Barcelona
Sponsor class: OTHER
Collaborators: name: Fundació La Marató de TV3
name: Fundacion Clinic per a la Recerca Biomédica
First posted: 2019-03-15
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Good outcome at 90 days
timeFrame: Day 90 after treatment.
Secondary outcomes:
measure: Shift analysis of the 90-day modified Rankin Scale (mRS).
timeFrame: Day 90 after treatment.
measure: Infarct expansion ratio.
timeFrame: 48 (+/- 24h) hours of stroke
measure: Rate of infarct expansion at 24 hours.
timeFrame: 48 (+/- 24h) hours of stroke
measure: Final infarct volume.
timeFrame: 48 (+/- 24h) hours of stroke
measure: Angiographic improvement on the Arterial Occlusive Lesion (AOL) scale
timeFrame: 10 minutes after treatment
measure: TERTIARY OUTCOME: Barthel Scale at day 90
timeFrame: Day 90 after treatment.
measure: TERTIARY OUTCOME: Ischemic worsening within 72 hours os stroke onset
timeFrame: 72 hours of stroke onset
measure: TERTIARY OUTCOME: Quality of life measured at 90 days
timeFrame: Day 90 after treatment.
Other outcomes:
measure: Proportion of patients with improved mTICI 2b score
timeFrame: 10 minutes after treatment
Locations:
city: Badalona
country: Spain
facility: Germans Trias i Pujol Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Girona
country: Spain
facility: Hospital Josep Trueta (HJT)
Study officials:
affiliation: Comprehensive Stroke Center, Hospital Clinic Barcelona.
name: Angel Chamorro, MD, PhD
role: STUDY_CHAIR
affiliation: Comprehensive Stroke Center, Hospital Clinic Barcelona.
name: Arturo Renú, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario de Vall d'Hebrón
name: Marián Muchada, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital del Mar
name: Elisa Cuadrado, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germans Trias i Pujol Hospital
name: Anna Ramos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Pol Camps, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitari de Bellvitge
name: Pere Cardona, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Josep Trueta, Girona
name: Mikel Terceño, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chamorro A, Blasco J, Lopez A, Amaro S, Roman LS, Llull L, Renu A, Rudilosso S, Laredo C, Obach V, Urra X, Planas AM, Leira EC, Macho J. Complete reperfusion is required for maximal benefits of mechanical thrombectomy in stroke patients. Sci Rep. 2017 Sep 14;7(1):11636. doi: 10.1038/s41598-017-11946-y.
citation: Davalos A, Cobo E, Molina CA, Chamorro A, de Miquel MA, Roman LS, Serena J, Lopez-Cancio E, Ribo M, Millan M, Urra X, Cardona P, Tomasello A, Castano C, Blasco J, Aja L, Rubiera M, Gomis M, Renu A, Lara B, Marti-Fabregas J, Jankowitz B, Cerda N, Jovin TG; REVASCAT Trial Investigators. Safety and efficacy of thrombectomy in acute ischaemic stroke (REVASCAT): 1-year follow-up of a randomised open-label trial. Lancet Neurol. 2017 May;16(5):369-376. doi: 10.1016/S1474-4422(17)30047-9. Epub 2017 Mar 16.
citation: Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Roman L, Serena J, Abilleira S, Ribo M, Millan M, Urra X, Cardona P, Lopez-Cancio E, Tomasello A, Castano C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Perez M, Goyal M, Demchuk AM, von Kummer R, Gallofre M, Davalos A; REVASCAT Trial Investigators. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015 Jun 11;372(24):2296-306. doi: 10.1056/NEJMoa1503780. Epub 2015 Apr 17.
citation: Renu A, Blasco J, Millan M, Marti-Fabregas J, Cardona P, Oleaga L, Macho J, Molina C, Roquer J, Amaro S, Davalos A, Zarco F, Laredo C, Tomasello A, Guimaraens L, Barranco R, Castano C, Vivas E, Ramos A, Lopez-Rueda A, Urra X, Muchada M, Cuadrado-Godia E, Camps-Renom P, Roman LS, Rios J, Leira EC, Jovin T, Torres F, Chamorro A; CHOICE Investigators. The Chemical Optimization of Cerebral Embolectomy trial: Study protocol. Int J Stroke. 2021 Jan;16(1):110-116. doi: 10.1177/1747493019895656. Epub 2019 Dec 18.
citation: Renu A, Millan M, San Roman L, Blasco J, Marti-Fabregas J, Terceno M, Amaro S, Serena J, Urra X, Laredo C, Barranco R, Camps-Renom P, Zarco F, Oleaga L, Cardona P, Castano C, Macho J, Cuadrado-Godia E, Vivas E, Lopez-Rueda A, Guimaraens L, Ramos-Pachon A, Roquer J, Muchada M, Tomasello A, Davalos A, Torres F, Chamorro A; CHOICE Investigators. Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial. JAMA. 2022 Mar 1;327(9):826-835. doi: 10.1001/jama.2022.1645.