Intraarterial Alteplase Versus Placebo After Mechanical Thrombectomy

Stroke, Acute Clinical Trial

— CHOICE  

Official title:

CHemical OptImization of Cerebral Embolectomy in Patients With Acute Stroke Treated With Mechanical Thrombectomy (CHOICE) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03876119
• Other study ID #: CHOICE
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: December 5, 2018
• Est. completion date: May 31, 2021

Study information

• Verified date: May 2022
• Source: Hospital Clinic of Barcelona
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: May 31, 2021
• Est. primary completion date: May 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Stroke
• Stroke, Acute

Intervention

Drug:
• Intraarterial alteplase
See arm/group descriptions.
• Placebo
See arm/group descriptions.

Locations

Country	Name	City	State
Spain	Germans Trias i Pujol Hospital	Badalona
Spain	Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital Josep Trueta (HJT)	Girona

Sponsors (3)

Lead Sponsor	Collaborator
Hospital Clinic of Barcelona	Fundació La Marató de TV3, Fundacion Clinic per a la Recerca Biomédica

Country where clinical trial is conducted

Spain, 

References & Publications (5)

Chamorro Á, Blasco J, López A, Amaro S, Román LS, Llull L, Renú 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. — View Citation

Dávalos A, Cobo E, Molina CA, Chamorro A, de Miquel MA, Román LS, Serena J, López-Cancio E, Ribó M, Millán M, Urra X, Cardona P, Tomasello A, Castaño C, Blasco J, Aja L, Rubiera M, Gomis M, Renú A, Lara B, Martí-Fàbregas J, Jankowitz B, Cerdà 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. — View Citation

Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Román L, Serena J, Abilleira S, Ribó M, Millán M, Urra X, Cardona P, López-Cancio E, Tomasello A, Castaño C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Pérez M, Goyal M, Demchuk AM, von Kummer R, Gallofré M, Dávalos 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. — View Citation

Renú A, Blasco J, Millán M, Martí-Fàbregas J, Cardona P, Oleaga L, Macho J, Molina C, Roquer J, Amaro S, Dávalos A, Zarco F, Laredo C, Tomasello A, Guimaraens L, Barranco R, Castaño C, Vivas E, Ramos A, López-Rueda A, Urra X, Muchada M, Cuadrado-Godía E, Camps-Renom P, Román LS, Ríos J, Leira EC, Jovin T, Torres F, Chamorro Á; 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. — View Citation

Renú A, Millán M, San Román L, Blasco J, Martí-Fàbregas J, Terceño M, Amaro S, Serena J, Urra X, Laredo C, Barranco R, Camps-Renom P, Zarco F, Oleaga L, Cardona P, Castaño C, Macho J, Cuadrado-Godía E, Vivas E, López-Rueda A, Guimaraens L, Ramos-Pachón A, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proportion of patients with improved mTICI 2b score	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.	10 minutes after treatment
Primary	Good outcome at 90 days	The primary outcome will be the proportion of patients with a mRS 0 to 1 at 90 days	Day 90 after treatment.
Secondary	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).	Day 90 after treatment.
Secondary	Infarct expansion ratio.	Infarct Expansion Ratio on DWI-MRI (continuous variable), at 48h (+/- 24h) of stroke	48 (+/- 24h) hours of stroke
Secondary	Rate of infarct expansion at 24 hours.	Proportion of patients with/without infarct expansion (dichotomous variable).	48 (+/- 24h) hours of stroke
Secondary	Final infarct volume.	Infarction Volume on Diffusion Weighted Imaging (Magnetic Resonance Imaging) at 48h (+/- 24h) of stroke onset	48 (+/- 24h) hours of stroke
Secondary	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.	10 minutes after treatment
Secondary	TERTIARY OUTCOME: Barthel Scale at day 90	Barthel Scale score of 95 to 100, at day 90	Day 90 after treatment.
Secondary	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	72 hours of stroke onset
Secondary	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	Day 90 after treatment.