REMOTE Ischemic Perconditioning Among Acute Ischemic Stroke Patients ( REMOTE-CAT)

Study Overview
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Brief Summary
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Stroke is one of the leading causes of death worldwide and the main cause of incapacity. Currently, the only therapies for acute ischemic stroke (AIS) patients are the administration of recombinant tissue plasminogen activator (rt-PA) and/or endovascular treatment. Unfortunately, many patients cannot benefit from these therapies due to contraindications or evolution time. Neuroprotective therapies could not only increase the benefits of available reperfusion therapies but also provide an option for patients who are not candidates for these treatments. Remote ischemic conditioning, consisting on brief episodes of transient limb ischemia, represents a new paradigm in neuroprotection. It can be categorized in pre-, per- or postconditioning, depending on the moment of application. According to studies in coronary ischemia, remote ischemic perconditioning (RIPerC) during the ischemic event is safe, cost-effective, feasible and associated with a reduction in myocardial injury. The investigators aim to conduct a multicentre study (5 university hospitals) of pre-hospital RIPerC in AIS patients (within 8 hours of stroke onset), which would include 572 stroke code activated patients (286 would undergo RIPerC and 286 would be sham). Our hypothesis is that RIPerC would be safe and would induce endogenous neuroprotective phenomena associated with good outcomes in AIS patients whether treated with revascularization therapies or not. Moreover, the development of systemic ischemic tolerance should provide metabolomic and lipidomic signatures that would present an opportunity to find specific molecular markers (biomarkers). The main objectives will be to assess: 1) RIPerC clinical benefits in AIS, 2) whether RIPerC is safe not only in AIS but also in all cases of stroke code activation, 3) whether RIPerC is associated with a reduction in cerebral infarct size and 4) metabolomic and lipidomic signatures of the RIPerC effect.

Detailed Description
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Stroke is one of the leading causes of death worldwide and the main cause of incapacity. Currently, the only therapies for acute ischemic stroke (AIS) patients are the administration of rt-PA and/or endovascular treatment. Unfortunately, many patients cannot benefit from these therapies due to contraindications or evolution time. Neuroprotective therapies could not only increase the benefits of available reperfusion therapies but also provide an option for patients who are not candidates for these treatments. However, most neuroprotection trials have so far failed to demonstrate their efficacy in acute phase stroke patients, despite good results in animal studies. Remote ischemic perconditioning (RIPerC) represents a new paradigm in neuroprotection. It upregulates endogenous defense systems to achieve ischemic tolerance in brain ischemia. It consists of brief episodes of transient limb ischemia. According to studies in coronary ischemia, RIPerC during the ischemic event is safe, feasible and related to reduction in myocardial injury. However, there is only limited data about the clinical utility of RIC in AIS patients. Only one small single-centre, randomized, open label clinical trial has been conducted to test RIPerC in AIS patients as an adjunctive therapy intravenous alteplase in the prehospital setting. The investigators want to conduct a multicenter study (involving 5 university hospitals) of prehospital RIPerC in AIS patients (within 8 hours of stroke onset) in which 572 stroke code activated patients will be included (286 subjects will undergo RIPerC and 286 subjects will be sham). RIPerC will consist of five cycles of electronic tourniquet inflation during five minutes and deflation during five minutes. The main endpoint will be a good clinical outcome measured by the modified Rankin score. The investigators will also establish a secondary neuroimaging endpoint defined by the infarct size observed in a Magnetic resonance imaging performed at three days. In addition, the investigators will conduct a substudy of biomarkers in 100 patients. Our hypothesis is that RIPerC will be safe and will induce endogenous neuroprotective phenomenon responsible for good outcome in AIS patients whether treated with revascularization therapies or not. Moreover, the development of systemic ischemic tolerance will provide a metabolomic and lipidomic signature that will offer the opportunity to find specific molecular markers (biomarkers). Project Objectives: To assess RIPerC clinical benefit in AIS measured by the modified Rankin Scale (mRS) score <3. To evaluate whether RIPerC is safe not only in AIS but also in all cases of stroke code activation. To assess whether RIPerC is associated with a reduction of cerebral infarct size. To identify the metabolomic and lipidomic signatures of the RIPerC effect.

Official Title
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REMOTE Ischemic Perconditioning Among Acute Ischemic Stroke Patients in CATalonia: REMOTE-CAT PROJECT

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Other: Remote ischemic perconditioning
* Other: Sham remote perconditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years old Suspected clinical stroke with 8 hours since onset of neurological symptoms Stroke code (SC) activation Independent in daily life before the onset of acute symptoms. (mrs</=2) Rapid arterial occlusion evaluation (RACE) scale score>0 and RACE motor item>0 Written informed consent (patient or representative) Exclusion Criteria: Unknown onset of symptoms Coma (GCS< 8) Malignancy or significant co-morbidity thought to limit life expectancy to <6 months Pregnancy Taking part in another interventional study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Usual care plus RIPerC<br>Usual care for stroke code patients, with or without revascularization therapies, with Remote ischemic perconditioning (RIPerC) using an electronic tourniquet. | Other: Remote ischemic perconditioning<br>* Five 5-minute inflations/deflations of an automatic device placed on the upper non-paretic arm initiated in the ambulance on the way to hospital in the case of stroke code activation and RACE score >0 and RACE motor item>0<br>|
| Sham Comparator: Usual care plus Sham RIPerC<br>Usual care for stroke code patients, with or without revascularization therapies, with Sham remote ischemic conditioning (RIPerC) | Other: Sham remote perconditioning<br>* Sham five 5-minute inflations/deflations of an automatic device placed on the upper non-paretic arm initiated in the ambulance on the way to hospital in the case of stroke code activation and RACE score >0 and RACE motor item>0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dependency | Modified Rankin Scale (MRS) <3. The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels: 0 (no symptom) to 5 (severe disability) and 6 (death). | Day 90±7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early neurological improvement rate | NIHSS decrease >=4 with respect to baseline | Day 1, day 5±1 | 
| Treatment Related Serious Adverse Event Rates | Number of participants with a serious adverse event related to treatment | Day 1, day 5±1, day 90±7 | 
| Size of the infarct volume | The infarct volume will be defined as the hyperintense area on the initial isotropic DWI acquired with a b value of 1000 sec/mm2 | Day 5±1 | 
| Symptomatic intracranial hemorrhage | Symptomatic intracerebral hemorrhage (SICH) defined by the Safe Implementation of Thrombolysis in Stroke Monitoring Study protocol | 24-36 hours | 
| Omic's response | Metabolomic and lipidomic analyses to define a panel of serum biomarkers accurately related to Remote ischemic conditioning phenomenon. | Day 1, day 3, day 5±1 | 
| Early dependency | Modified Rankin Scale <3. The mRS is an ordinal, graded interval scale that assigns patients among 7 global disability levels: 0 (no symptom) to 5 (severe disability) and 6 (death). | Day 5±1, |