Back to resultsIntraarterial Alteplase Versus Placebo After Mechanical Thrombectomy (CHOICE)
Primary Purpose
Stroke, Acute
Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Intraarterial alteplase
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Stroke, Acute focused on measuring Mechanical Thrombectomy, Recanalization, Reperfusion
Eligibility Criteria
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)
Sites / Locations
- Germans Trias i Pujol Hospital
- Hospital Clinic of Barcelona
- Hospital del Mar
- Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
- Hospital Universitari de Bellvitge
- Hospital Universitari Vall d'Hebrón
- Hospital Josep Trueta (HJT)
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Intraarterial alteplase
Placebo
Arm Description
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)
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)
Outcomes
Primary Outcome Measures
Good outcome at 90 days
The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days
Secondary Outcome Measures
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).
Infarct expansion ratio.
Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke
Rate of infarct expansion at 24 hours.
Proportion of patients with/without infarct expansion (dichotomous variable).
Final infarct volume.
Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset
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.
TERTIARY OUTCOME: Barthel Scale at day 90
Barthel Scale score of 95 to 100, at day 90
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
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
Full Information
NCT ID
NCT03876119
First Posted
March 12, 2019
Last Updated
May 16, 2022
Sponsor
Hospital Clinic of Barcelona
Collaborators
Fundació La Marató de TV3, Fundacion Clinic per a la Recerca Biomédica
1. Study Identification
Unique Protocol Identification Number
NCT03876119
Brief Title
Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy
Acronym
CHOICE
Official Title
CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
December 5, 2018 (Actual)
Primary Completion Date
May 31, 2021 (Actual)
Study Completion Date
May 31, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hospital Clinic of Barcelona
Collaborators
Fundació La Marató de TV3, Fundacion Clinic per a la Recerca Biomédica
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke, Acute
Keywords
Mechanical Thrombectomy, Recanalization, Reperfusion
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
121 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Intraarterial alteplase
Arm Type
Experimental
Arm Description
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)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Intraarterial alteplase
Other Intervention Name(s)
Intraarterial alteplase recombinant tissue plasminogen activator (rTPA)
Intervention Description
See arm/group descriptions.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
See arm/group descriptions.
Primary Outcome Measure Information:
Title
Good outcome at 90 days
Description
The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days
Time Frame
Day 90 after treatment.
Secondary Outcome Measure Information:
Title
Shift analysis of the 90-day modified Rankin Scale (mRS).
Description
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).
Time Frame
Day 90 after treatment.
Title
Infarct expansion ratio.
Description
Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke
Time Frame
48 (+/- 24h) hours of stroke
Title
Rate of infarct expansion at 24 hours.
Description
Proportion of patients with/without infarct expansion (dichotomous variable).
Time Frame
48 (+/- 24h) hours of stroke
Title
Final infarct volume.
Description
Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset
Time Frame
48 (+/- 24h) hours of stroke
Title
Angiographic improvement on the Arterial Occlusive Lesion (AOL) scale
Description
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.
Time Frame
10 minutes after treatment
Title
TERTIARY OUTCOME: Barthel Scale at day 90
Description
Barthel Scale score of 95 to 100, at day 90
Time Frame
Day 90 after treatment.
Title
TERTIARY OUTCOME: Ischemic worsening within 72 hours os stroke onset
Description
Ischemic worsening (≥ 4 points in the NIHSS score) within 72 hours of stroke onset not attributable to stroke recurrence
Time Frame
72 hours of stroke onset
Title
TERTIARY OUTCOME: Quality of life measured at 90 days
Description
Quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D-3L) at 90 days
Time Frame
Day 90 after treatment.
Other Pre-specified Outcome Measures:
Title
Proportion of patients with improved mTICI 2b score
Description
Proportion of patients with improved mTICI 2b score
IV Alteplase use on admission (yes versus no)
MT started within 7.3h of symptoms onset versus MT started between 7.4h and 24h.
Admission serum glucose concentration≤100 mg/dL versus >100 mg/dL
Males vs. Females
Baseline angiographic score mTICI2b brain reperfusion versus baseline angiographic score eTICI2c/3 brain reperfusion.
Time Frame
10 minutes after treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Angel Chamorro, MD, PhD
Organizational Affiliation
Comprehensive Stroke Center, Hospital Clinic Barcelona.
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Arturo Renú, MD, PhD
Organizational Affiliation
Comprehensive Stroke Center, Hospital Clinic Barcelona.
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marián Muchada, MD, PhD
Organizational Affiliation
Hospital Universitario de Vall d'Hebrón
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Elisa Cuadrado, MD, PhD
Organizational Affiliation
Hospital del Mar
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Anna Ramos, MD
Organizational Affiliation
Germans Trias i Pujol Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pol Camps, MD
Organizational Affiliation
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pere Cardona, MD, PhD
Organizational Affiliation
Hospital Universitari de Bellvitge
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mikel Terceño, MD
Organizational Affiliation
Hospital Josep Trueta, Girona
Official's Role
Principal Investigator
Facility Information:
Facility Name
Germans Trias i Pujol Hospital
City
Badalona
Country
Spain
Facility Name
Hospital Clinic of Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital del Mar
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
City
Barcelona
Country
Spain
Facility Name
Hospital Universitari de Bellvitge
City
Barcelona
Country
Spain
Facility Name
Hospital Universitari Vall d'Hebrón
City
Barcelona
Country
Spain
Facility Name
Hospital Josep Trueta (HJT)
City
Girona
ZIP/Postal Code
17007
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Deidentified individual participant data on outcome measures will be published along with the main results of the trial.
IPD Sharing Time Frame
The data will become available after publication of main study results.
IPD Sharing Access Criteria
The IPD will be available from the Sponsor of the trial on reasonable request.
Citations:
PubMed Identifier
28912596
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.
Results Reference
background
PubMed Identifier
28318984
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.
Results Reference
background
PubMed Identifier
25882510
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.
Results Reference
background
PubMed Identifier
31852410
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.
Results Reference
background
PubMed Identifier
35143603
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.
Results Reference
result
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Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy
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