Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy

NCT ID: NCT03876119

Last Updated: 2022-05-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-05
• Study Completion Date: 2021-05-31

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.

Conditions

Stroke, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Intraarterial alteplase

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:

1. 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

2. 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)

Group Type: EXPERIMENTAL

Intraarterial alteplase

Intervention Type: DRUG

See arm/group descriptions.

Placebo

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:

1. 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

2. 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)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

See arm/group descriptions.

Interventions

Intraarterial alteplase

See arm/group descriptions.

Intervention Type: DRUG

Placebo

See arm/group descriptions.

Intervention Type: DRUG

Other Intervention Names

Intraarterial alteplase recombinant tissue plasminogen activator (rTPA)

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fundació La Marató de TV3

OTHER

Sponsor Role: collaborator

Fundacion Clinic per a la Recerca Biomédica

OTHER

Sponsor Role: collaborator

Hospital Clinic of Barcelona

OTHER

Sponsor Role: lead

Responsible Party

Angel Chamorro, M.D., Ph.D.

Director, Comprehensive Stroke Center, Hospital Clinic Barcelona. Professor of Neurology, University of Barcelona.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Angel Chamorro, MD, PhD

Role: STUDY_CHAIR

Comprehensive Stroke Center, Hospital Clinic Barcelona.

Arturo Renú, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Comprehensive Stroke Center, Hospital Clinic Barcelona.

Marián Muchada, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario de Vall d'Hebrón

Elisa Cuadrado, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital del Mar

Anna Ramos, MD

Role: PRINCIPAL_INVESTIGATOR

Germans Trias i Pujol Hospital

Pol Camps, MD

Role: PRINCIPAL_INVESTIGATOR

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Pere Cardona, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitari de Bellvitge

Mikel Terceño, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Girona Dr. Josep Trueta

Locations

Germans Trias i Pujol Hospital

Badalona, , Spain

Hospital Clinic of Barcelona

Barcelona, , Spain

Hospital del Mar

Barcelona, , Spain

Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Universitari de Bellvitge

Barcelona, , Spain

Hospital Universitari Vall d'Hebrón

Barcelona, , Spain

Hospital Josep Trueta (HJT)

Girona, , Spain

Countries

Spain

References

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.

Reference Type: BACKGROUND

PMID: 28912596 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28318984 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25882510 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 31852410 (View on PubMed)

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.

Reference Type: RESULT

PMID: 35143603 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CHOICE

Identifier Type: -

Identifier Source: org_study_id