Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies

NCT04400981 | Completed DMC

• 1 other identifier: PRIN 2017CY3J3W
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 4

Brief Summary

Phase II, prospective, randomized, multicenter, open-label, pilot clinical trial comparing remote ischemic conditioning (RIC) plus standard medical therapy to standard medical therapy alone, in patients with acute ischemic stroke within 9 hours of stroke onset that are not eligible to recanalization therapies.

Conditions

Ischemic Stroke

Keywords

remote ischemic conditioning; acute ischemic stroke; neuroprotection

Outcome Measures

Primary Outcomes (1)

• Efficacy of Remote ischemic conditioning at 72 hours

  Early neurological improvement at 72 hours, defined as NIHSS percent change (\[Admission NIHSS-72-hour NIHSS\]×100/Admission NIHSS).

  72 hours

Secondary Outcomes (8)

• Efficacy of Remote ischemic conditioning at 24 hours

  24 hours

• Efficacy of Remote ischemic conditioning at 48 hours

  48 hours

• Functional status at 90 days

  90 days

• number of paticipants with symptomatic intracerebral hemorrhage

  36 hours

• Pain related to remote ischemic conditioning

  72 hours

Study Arms (2)

Intervention arm: RIC plus standard medical therapy

EXPERIMENTAL

Remote ischemic conditioning (RIC) will be applied immediately after randomization in the Emergency Department, through a standard blood pressure cuff placed around the non-paretic arm. The protocol includes 4 cycles of intermittent manually induced upper limb ischemia, alternating 5 minutes of inflation (20mmHg above systolic blood pressure) and 5 minutes of deflation. Patients randomized to remote ischemic conditioning will also receive standard medical therapy

Procedure: Remote ischemic conditioning; Other: standard medical therapy

Control arm: Standard medical therapy alone

ACTIVE COMPARATOR

Standard medical therapy will be administered immediately after randomization in the Emergency Department. Standard medical therapy comprises single antiplatelet therapy, either aspirin given in a total dose ranging between 100 to 300 mg per day on days 1-5 and followed by aspirin 100mg/day on days 1-5 followed by aspirin 100mg/day, or Clopidogrel 75mg/day (at the discretion of the patient's attending physician), unless an indication for early anticoagulation (e.g. atrial fibrillation, mechanical heart valve, deep venous thrombosis, pulmonary embolism, antiphospholipid antibody syndrome, hypercoagulable state) or dual antiplatelet therapy (e.g. early carotid stenting) is present. All patients will receive standard deep venous thrombosis (DVT) prevention therapy together with appropriate treatment for blood pressure control, glycemic control and cholesterol reduction.

Other: standard medical therapy

Interventions

Remote ischemic conditioning PROCEDURE

Remote ischemic conditioning will be applied immediately after randomization in the Emergency Department, through a standard blood pressure cuff placed around the non-paretic arm. The protocol includes 4 cycles of intermittent manually induced upper limb ischemia, alternating 5 minutes of inflation (20mmHg above systolic blood pressure) and 5 minutes of deflation.

Intervention arm: RIC plus standard medical therapy

standard medical therapy OTHER

Standard medical therapy comprises single antiplatelet therapy, either aspirin given in a total dose ranging between 100 to 300 mg per day on days 1-5 and followed by aspirin 100mg/day on days 1-5 followed by aspirin 100mg/day, or Clopidogrel 75mg/day (at the discretion of the patient's attending physician), unless an indication for early anticoagulation (e.g. atrial fibrillation, mechanical heart valve, deep venous thrombosis, pulmonary embolism, antiphospholipid antibody syndrome, hypercoagulable state) or dual antiplatelet therapy (e.g. early carotid stenting) is present. All patients will receive standard deep venous thrombosis (DVT) prevention therapy together with appropriate treatment for blood pressure control, glycemic control and cholesterol reduction.

Control arm: Standard medical therapy alone; Intervention arm: RIC plus standard medical therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis and/or diagnosis on neuromaging of anterior circulation acute ischemic stroke (due to either large or small vessel occlusion) within 9 hours of symptom onset. Information regarding time of stroke onset will be obtained by patient, family member or anyone present at the time of stroke onset or by the emergency medical technician in case the patient is brought to the Emergency Department by the Emergency Medical Services
• Age ≥ 18 years
• Neurologic deficit with National Institutes of Health Stroke Scale (NIHSS) ≥5 and \<25
• Informed consent obtained from patient whenever possible, or by family member, or legally responsible person in other cases
• Stroke with Unknown Time of Onset: the patient either recognized stroke symptoms on awakening or could not report the timing of the onset of symptoms due to neurological deficits (e.g., as a result of aphasia, anarthria, confusion). For patients who recognized stroke symptoms on awakening, onset was estimated as the midpoint of sleep (i.e., the time between going to sleep and waking up with symptoms) and patients underwent randomization if they were within 9 hours of the estimated time of onset. For patients who could not report the timing of symptom onset, the time that had elapsed since the patient was last known to be well had to be \<9 hours. Information regarding time of going to sleep or last time the patient was seen well will be obtained by patient, family member or anyone who had the last contact with the patient before stroke onset.
• Modified Rankin Scale≤2 prior to stroke onset

You may not qualify if:

• Patients that are candidates for thrombolysis and/or thrombectomy according to AHA/ASA guidelines
• CT Head or brain MRI detecting intracranial hemorrhage, vascular malformation, intracranial masses or any other pathology that could explain symptoms
• Rapidly improving neurological symptoms at the time of first evaluation, judged by the attending Physician (Ref: Clotilde Balucani et al. Rapidly Improving Stroke Symptoms: A Pilot, Prospective Study. J Stroke Cerebrovasc Dis, 24 (6), 1211-6 Jun 2015 )
• Transient Ischemic Attack (TIA), with resolution of symptoms at the time of first evaluation
• Amputation of the upper non paretic arm
• Presence of any ulcer or a bad skin condition in the upper or lower limbs
• History of arterial occlusive disease, sickle cell disease (due to the risk of vaso-occlusive crisis), or upper limb phlebitis
• Pregnancy
• Ongoing participation in any interventional study
• Unavailability for follow-up
• Advanced or terminal illness, judged by the attending Physician, that could make unlikely patient's availability for follow up at 3 months or life expectancy less than 6 months

Sponsors & Collaborators

• University of Milano Bicocca: lead
• San Gerardo Hospital: collaborator
• Università degli Studi dell'Aquila: collaborator
• University of Roma La Sapienza: collaborator
• IRCCS Fondazione Istituto Neurologico Mondino Pavia: collaborator
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator

Study Sites (4)

Ospedale Civile SS. Filippo e Nicola di Avezzano

Avezzano, L'Aquila, 67051, Italy

Location

Ospedale Sant'Andrea

Rome, Lazio, 00189, Italy

Location

Ospedale San Gerardo

Monza, Lombardy, 20900, Italy

Location

IRCCS Fondazione Istituto Neurologico Mondino

Pavia, Pavia, 27100, Italy

Location

Related Publications (14)

• Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006 Jun;7(6):437-48. doi: 10.1038/nrn1927.

  PMID: 16715053 BACKGROUND

• Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong Z, Gala R, Simon RP. In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: ischemic postconditioning. J Cereb Blood Flow Metab. 2008 Feb;28(2):232-41. doi: 10.1038/sj.jcbfm.9600559. Epub 2007 Sep 19.

  PMID: 17882162 BACKGROUND

• Kanoria S, Jalan R, Davies NA, Seifalian AM, Williams R, Davidson BR. Remote ischaemic preconditioning of the hind limb reduces experimental liver warm ischaemia-reperfusion injury. Br J Surg. 2006 Jun;93(6):762-8. doi: 10.1002/bjs.5331.

  PMID: 16609953 BACKGROUND

• Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol. 2005 Aug 2;46(3):450-6. doi: 10.1016/j.jacc.2005.04.044.

  PMID: 16053957 BACKGROUND

• Koch S, Della-Morte D, Dave KR, Sacco RL, Perez-Pinzon MA. Biomarkers for ischemic preconditioning: finding the responders. J Cereb Blood Flow Metab. 2014 Jun;34(6):933-41. doi: 10.1038/jcbfm.2014.42. Epub 2014 Mar 19.

  PMID: 24643082 BACKGROUND

• Cao B, Zhang C, Wang H, Xia M, Yang X. Renoprotective effect of remote ischemic postconditioning in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Ther Clin Risk Manag. 2018 Feb 22;14:369-375. doi: 10.2147/TCRM.S158768. eCollection 2018.

  PMID: 29503556 BACKGROUND

• Pico F, Rosso C, Meseguer E, Chadenat ML, Cattenoy A, Aegerter P, Deltour S, Yeung J, Hosseini H, Lambert Y, Smadja D, Samson Y, Amarenco P. A multicenter, randomized trial on neuroprotection with remote ischemic per-conditioning during acute ischemic stroke: the REmote iSchemic Conditioning in acUtE BRAin INfarction study protocol. Int J Stroke. 2016 Oct;11(8):938-943. doi: 10.1177/1747493016660098. Epub 2016 Jul 19.

  PMID: 27412192 BACKGROUND

• Hougaard KD, Hjort N, Zeidler D, Sorensen L, Norgaard A, Hansen TM, von Weitzel-Mudersbach P, Simonsen CZ, Damgaard D, Gottrup H, Svendsen K, Rasmussen PV, Ribe LR, Mikkelsen IK, Nagenthiraja K, Cho TH, Redington AN, Botker HE, Ostergaard L, Mouridsen K, Andersen G. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Stroke. 2014 Jan;45(1):159-67. doi: 10.1161/STROKEAHA.113.001346. Epub 2013 Nov 7.

  PMID: 24203849 BACKGROUND

• England TJ, Hedstrom A, O'Sullivan S, Donnelly R, Barrett DA, Sarmad S, Sprigg N, Bath PM. RECAST (Remote Ischemic Conditioning After Stroke Trial): A Pilot Randomized Placebo Controlled Phase II Trial in Acute Ischemic Stroke. Stroke. 2017 May;48(5):1412-1415. doi: 10.1161/STROKEAHA.116.016429. Epub 2017 Mar 6.

  PMID: 28265014 BACKGROUND

• Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG; DAWN Trial Investigators. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. doi: 10.1056/NEJMoa1706442. Epub 2017 Nov 11.

  PMID: 29129157 BACKGROUND

• Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. doi: 10.1056/NEJMoa1713973. Epub 2018 Jan 24.

  PMID: 29364767 BACKGROUND

• Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Gunther M, Guibernau J, Hausler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C; WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622. doi: 10.1056/NEJMoa1804355. Epub 2018 May 16.

  PMID: 29766770 BACKGROUND

• Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

  PMID: 31067369 BACKGROUND

• Diamanti S, Beretta S, Tettamanti M, Sacco S, Sette G, Ornello R, Tiseo C, Caponnetto V, Beccia M, Alivernini D, Costanzo R, Ferrarese C. Multi-Center Randomized Phase II Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies (TRICS-9): Study Design and Protocol. Front Neurol. 2021 Nov 3;12:724050. doi: 10.3389/fneur.2021.724050. eCollection 2021.

  PMID: 34803872 DERIVED

MeSH Terms

Conditions

Ischemic Stroke

Condition Hierarchy (Ancestors)

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Simone Beretta, MD, PhD

  San Gerardo Hospital

  PRINCIPAL INVESTIGATOR

• Susanna Diamanti, MD, PhD

  San Gerardo Hospital

  STUDY DIRECTOR

• Carlo Ferrarese, MD, PhD

  San Gerardo Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Clinicians assessing NIHSS at 24 hours, 48 hours and 72 hours and modified Rankin scale at 3 months will be blinded to treatment allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Stroke Neurologist, MD, PhD

Model Details: Phase II, prospective, multicenter, block randomized, parallel, open-label, clinical trial

Study Record Dates

• First Submitted: May 18, 2020
• First Posted: May 26, 2020
• Study Start: August 1, 2021
• Primary Completion: April 30, 2024
• Study Completion: August 30, 2024
• Last Updated: December 12, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Upon completion of the project, after January 2023
• Access Criteria: This information will be available during the course of the trial.

Locations

IT (4)