Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy (CHOICE)

• ClinicalTrials.gov Identifier: NCT03876119
• Recruitment Status: Completed
• First Posted: March 15, 2019
• Last Update Posted: May 20, 2022
• Sponsor: Hospital Clinic of Barcelona
• Collaborators: Fundació La Marató de TV3; Fundacion Clinic per a la Recerca Biomédica
• Information provided by (Responsible Party): Angel Chamorro, M.D., Ph.D., Hospital Clinic of Barcelona

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Stroke, Acute	Drug: Intraarterial alteplase; Drug: Placebo	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.
• Masking: Quadruple (Participant, Care Provider, 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.
• Primary Purpose: Treatment
• Official Title: CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial
• Actual Study Start Date: December 5, 2018
• Actual Primary Completion Date: May 31, 2021
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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: 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; See arm/group descriptions.; Other Name: Intraarterial alteplase recombinant tissue plasminogen activator (rTPA)
Placebo Comparator: 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: 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; See arm/group descriptions.

Outcome Measures

Primary Outcome Measures :

1. Good outcome at 90 days [ Time Frame: Day 90 after treatment. ]
   The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days

Secondary Outcome Measures :

1. Shift analysis of the 90-day modified Rankin Scale (mRS). [ Time Frame: 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).
2. Infarct expansion ratio. [ Time Frame: 48 (+/- 24h) hours of stroke ]
   Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke
3. Rate of infarct expansion at 24 hours. [ Time Frame: 48 (+/- 24h) hours of stroke ]
   Proportion of patients with/without infarct expansion (dichotomous variable).
4. Final infarct volume. [ Time Frame: 48 (+/- 24h) hours of stroke ]
   Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset
5. Angiographic improvement on the Arterial Occlusive Lesion (AOL) scale [ Time Frame: 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.
6. TERTIARY OUTCOME: Barthel Scale at day 90 [ Time Frame: Day 90 after treatment. ]
   Barthel Scale score of 95 to 100, at day 90
7. TERTIARY OUTCOME: Ischemic worsening within 72 hours os stroke onset [ Time Frame: 72 hours of stroke onset ]
   Ischemic worsening (≥ 4 points in the NIHSS score) within 72 hours of stroke onset not attributable to stroke recurrence
8. TERTIARY OUTCOME: Quality of life measured at 90 days [ Time Frame: Day 90 after treatment. ]
   Quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D-3L) at 90 days

Other Outcome Measures:

1. Proportion of patients with improved mTICI 2b score [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

Spain

Germans Trias i Pujol Hospital

Badalona, Spain

Hospital Clinic of Barcelona

Barcelona, Spain, 08036

Hospital del Mar

Barcelona, Spain, 08036

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, 17007

Sponsors and Collaborators

Hospital Clinic of Barcelona

Fundació La Marató de TV3

Fundacion Clinic per a la Recerca Biomédica

Investigators

• Study Chair: Angel Chamorro, MD, PhD; Comprehensive Stroke Center, Hospital Clinic Barcelona.
• Principal Investigator: Arturo Renú, MD, PhD; Comprehensive Stroke Center, Hospital Clinic Barcelona.
• Principal Investigator: Marián Muchada, MD, PhD; Hospital Universitario de Vall d'Hebrón
• Principal Investigator: Elisa Cuadrado, MD, PhD; Hospital del Mar
• Principal Investigator: Anna Ramos, MD; Germans Trias i Pujol Hospital
• Principal Investigator: Pol Camps, MD; Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Principal Investigator: Pere Cardona, MD, PhD; Hospital Universitari de Bellvitge
• Principal Investigator: Mikel Terceño, MD; Hospital Josep Trueta, Girona

  Study Documents (Full-Text)

Documents provided by Angel Chamorro, M.D., Ph.D., Hospital Clinic of Barcelona:

Study Protocol and Statistical Analysis Plan  [PDF] November 28, 2019

More Information

Publications of Results:

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.

Other Publications:

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.

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.

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.

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.

• Responsible Party: Angel Chamorro, M.D., Ph.D., Director, Comprehensive Stroke Center, Hospital Clinic Barcelona. Professor of Neurology, University of Barcelona., Hospital Clinic of Barcelona
• ClinicalTrials.gov Identifier: NCT03876119
• Other Study ID Numbers: CHOICE
• First Posted: March 15, 2019
• Last Update Posted: May 20, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Deidentified individual participant data on outcome measures will be published along with the main results of the trial.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: The data will become available after publication of main study results.
• Access Criteria: The IPD will be available from the Sponsor of the trial on reasonable request.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Angel Chamorro, M.D., Ph.D., Hospital Clinic of Barcelona:

Mechanical Thrombectomy; Recanalization; Reperfusion

Additional relevant MeSH terms:

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Tissue Plasminogen Activator; Plasminogen; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action