Remote Ischemic Conditioning in Patients With Acute Stroke (RESIST)

Ischemic Stroke Clinical Trial

— RESIST  

Official title:

Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03481777
• Other study ID #: 2017114177
• Status: Completed
• Phase: N/A
• Start date: March 15, 2018
• Est. completion date: February 3, 2023

Study information

• Verified date: April 2023
• Source: Aarhus University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Our primary aim is to investigate whether remote ischemic conditioning (RIC) as an adjunctive treatment can improve long-term recovery in acute stroke patients as an adjunct to standard treatment.

Description:

Stroke is the second-leading cause of death worldwide and a leading cause of serious, long-term disability. The most common type is acute ischemic stroke (AIS) which occurs in 85% of cases. Acute cerebral thromboembolism leads to an area of permanent damage (infarct core) in the most severely hypoperfused area and a surrounding area of impaired, yet salvageable tissue known as the "ischemic penumbra".

Intravenous alteplase (IV tPA) and endovascular treatment (EVT) are approved acute reperfusion treatments of AIS to be started within the first 4½-6 hours (in some up to 24 hours) and as soon as possible after symptom onset to prevent the evolution of the infarct core. However, reperfusion itself may paradoxically result in tissue damage (reperfusion injury) and may contribute to infarct growth. Infarct progression can continue for days following a stroke, and failure of the collateral flow is a critical factor determining infarct growth.

On the other hand, in intracerebral hemorrhage (ICH) the culprit is an eruption of blood into the brain parenchyma causing tissue destruction with a massive effect on adjacent brain tissues. Hematoma expansion as well as inflammatory pathways that are activated lead to further tissue damage, edema, and penumbral hypoperfusion. The prognosis after ICH is poor with a one-month mortality of 40%.

Novel therapeutics and neuroprotective strategies that can be started ultra-early after symptom onset are urgently needed to reduce disability in both AIS and ICH.

Ischemic conditioning is one of the most potent activators of endogenous protection against ischemia-reperfusion injury. Remote Ischemic Conditioning (RIC) can be applied as repeated short-lasting ischemia in a distant tissue that results in protection against subsequent long-lasting ischemic injury in the target organ. This protection can be applied prior to or during a prolonged ischemic event as remote ischemic pre-conditioning (RIPreC) and per-conditioning (RIPerC), respectively, or immediate after reperfusion as remote ischemic post-conditioning (RIPostC). RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion.

Preclinical studies show that RIC induces a promising infarct reduction in an experimental stroke model. Results from a recent proof-of-concept study at our institution indicate that RIPerC applied during ambulance transportation as an adjunctive to in-hospital IV tPA increases brain tissue survival after one month. Furthermore, RIPerC patients had less severe neurological symptoms at admission and tended to have decreased perfusion deficits.

To-date, no serious adverse events have been documented in RIC.

RIC is a non-pharmacologic and non-invasive treatment without noticeable discomfort that has first-aid potential worldwide. However, whether combined remote ischemic per- and postconditioning can improve long-term recovery in AIS and ICH has never been investigated in a randomized controlled trial.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1500
• Est. completion date: February 3, 2023
• Est. primary completion date: February 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female patients (= 18 years)

• Prehospital putative stroke (Prehospital Stroke Score, PreSS >= 1)

• Onset of stroke symptoms < 4 hours before RIC/Sham-RIC

• Independent in daily living before symptom onset (mRS = 2)

Exclusion Criteria:

• Intracranial aneurisms, intracranial arteriovenous malformation, cerebral neoplasm or abscess

• Pregnancy

• Severe peripheral arterial disease in the upper extremities

• Concomitant acute life-threatening medical or surgical condition

• Arteriovenous fistula in the arm selected for RIC

Related Conditions & MeSH terms

• Central Nervous System Diseases
• Cerebral Hemorrhage
• Cerebrovascular Disorders
• Hemorrhage
• Hemorrhagic Stroke
• Intracerebral Hemorrhage
• Ischemia
• Ischemic Stroke
• Nervous System Diseases
• Stroke
• Stroke, Acute

Intervention

Device:
• Remote Ischemic Conditioning
RIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion.
• Sham Remote Ischemic Conditioning
Sham Comparator (Sham-RIC)

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg	DK
Denmark	Department of Neurology Aarhus University Hospital	Aarhus	Danmark
Denmark	Department of Neurology Regional Hospital West Jutland	Holstebro
Denmark	Odense University Hospital	Odense	DK

Sponsors (3)

Lead Sponsor	Collaborator
Grethe Andersen	Center of Functionally Integrative Neuroscience (CFIN) Aarhus University, Central Denmark Region

Country where clinical trial is conducted

Denmark, 

References & Publications (2)

Hess DC, Blauenfeldt RA, Andersen G, Hougaard KD, Hoda MN, Ding Y, Ji X. Remote ischaemic conditioning-a new paradigm of self-protection in the brain. Nat Rev Neurol. 2015 Dec;11(12):698-710. doi: 10.1038/nrneurol.2015.223. Epub 2015 Nov 20. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Clinical outcome (modified Rankin Scale (mRS) at 3 months in ischemic stroke patients and the extended remote ischemic postconditioning protocol (substudy at Aarhus University Hospital)	The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.	3 months
Other	Clinical outcome (modified Rankin Scale (mRS) at 3 months in intracerebral hemorrhage patients and the extended remote ischemic postconditioning protocol (substudy at Aarhus University Hospital)	The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.	3 months
Other	Endovascular treatment(EVT) -eligibility (MRI assessed) in RIC treated AIS patients with large vessel (substudy at Aarhus University Hospital)	Proportion of RIC treated AIS patients with large vessel occlusion (LVO) eligible to EVT treatment compared to standard treatment, adjusted for prehospital stroke severity (PreSS) and symptom duration; Severe Stroke (NIHSS = 10); Groin puncture feasible within 6 hours from stroke onset; MRI-time-of-flight (TOF) documented internal carotid artery (ICA), Intracranial ICA (ICA-T) and first and second stem of the middle cerebral artery (M1 and M2, respectively); No contraindications to MRI (pacemaker, vomiting, respiratory insufficiency, obesity); MRI-Diffusion weighted imaging (DWI) lesion volume = 70 mL	6 hours
Other	Infarct growth in AIS patients (substudy at Aarhus University Hospital)	24-hour infarct growth on DWI-MRI (Difference in lesion volume between acute and 24-hour DWI-MRI) (Substudy at Aarhus University Hospital)	24 hour
Other	Difference in acute (24-hour) hematoma expansion in patients with ICH (substudy at Aarhus University Hospital)	24-hour hematoma growth (Difference in hematoma volume between acute and 24-hour CT/MRI) (Substudy at Aarhus University Hospital)	24 hour
Other	Difference in 7 days hematoma volume in patients with ICH (substudy at Aarhus University Hospital)	7-day hematoma reduction (Difference in hematoma volume between acute and 7-day (day 5 to 9) CT ) (Substudy at Aarhus University Hospital)	7 days
Other	Ektacytometry and Analytical Flow Cytometry for eryNOS3 phosphorylation	Ektacytometry for Erythrocytic Deformability and Analytical Flow Cytometry (FC) for eryNOS3 phosphorylation (pNOS3Ser1177) and s-nitrosylation (-SNO) in RBC	12 months
Other	MicroRNA and extracellular vesicle profile of RIC-induced neuroprotection (substudy at Aarhus University Hospital)	MicroRNA and extracellular vesicle characterization of a possible RIC treatment profile	12 months
Other	Prehospital microRNA and extracellular vesicles (substudy at Aarhus University Hospital)	Diagnostic abilities of a prehospital microRNA and extracellular vesicles blood samples profile combined with prehospital stroke severity on the differentiation of hemorrhagic from ischemic stroke and to grade ischemic stroke severity	12 months
Other	Prehospital Glial Fibrillary Acidic Protein (substudy at Aarhus University Hospital)	Predictive abilities of Glial Fibrillary Acidic Protein (GFAP) in prehospital obtained blood samples combined with prehospital stroke severity to differentiate hemorrhagic from ischemic stroke and to grade ischemic stroke severity	12 months
Other	Coagulation profile of putative stroke patients in prehospital obtained blood samples (substudy at Aarhus University Hospital)	Functional and immunologic plasma assays will be employed to analyze proteins and pathways in coagulation and fibrinolysis.	12 months
Primary	Clinical outcome (mRS) at 3 months in acute stroke (AIS and ICH)	Clinical outcome (modified Rankin Scale) at 3 months in acute stroke patients (target diagnosis) (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors.; If disagreement occurs the patient will be contacted by a third assessor (face-to-face or telephone) who is blinded to the intervention who will assess the level of dependency.; If disagreement occurs between two telephone assessments - a third, and final, telephone or face-to-face assessment will be made.; If disagreement occurs between one face-to-face assessment and one telephone assessment; the face-to-face will be considered the final assessment; If disagreement occurs between two face-to-face assessments - a third, and final, telephone or face-to-face assessment will be made.	3 months
Secondary	Difference neurological impairment during the first 24 hours in all randomized patients	Neurological deficits are documented using PreSS (Prehospital Stroke score both prehospital and in-hospital). Prehospital Stroke Score is assessed at 24-hour or at discharge (if discharge occurs before 24 hours). The PreSS score consists of the Cincinnati Prehospital Stroke Scale (CPSS) with an additional opportunity to report other neurological symptoms (e.g. ataxia, sensory disturbances and visual field loss), and PASS (Prehospital Acute Stroke Severity Scale) Ordinal logistic regression	24 hours
Secondary	Clinical outcome (modified Rankin Scale (mRS) at 3 months in acute ischemic stroke	The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.	3 months
Secondary	Clinical outcome (modified Rankin Scale (mRS) at 3 months in acute ischemic stroke receiving reperfusion therapy	The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.	3 months
Secondary	Clinical outcome (modified Rankin Scale (mRS) at 3 months in patients with intracerebral hemorrhage (ICH)	The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.	3 months
Secondary	Difference in proportion of patients with complete remission of symptoms within 24 hours (TIA; both with and without DWI)	Difference in proportion of patients with complete remission of symptoms within 24 hours (TIA; both with and without DWI) Diagnosis of TIA is documented in the electronic case report form	3 months
Secondary	Major Adverse Cardiac and Cerebral Events (MACCE) and recurrent ischemic events based on registry data at 3 and 12 months in ICH, AIS patients, TIA and non-vascular diagnosis	MACCE is defined as: Cardiovascular events (cardiovascular death, myocardial infarction, acute ischemic or hemorrhagic stroke); Cardiovascular death: Death from known cardiovascular cause or sudden death from unknown cause (no identified cause of death in medical history and/or autopsy); Acute myocardial infarction: Admission with a discharge diagnosis of ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP); Stroke: Admission with a discharge diagnosis of acute ischemic or hemorrhagic stroke. Evaluation is performed using the Danish National Patient Register (LPR) and the DSR at two time points (6 and 15 months after the inclusion of the last patient).; Diagnosis of AIS/TIA, ICH and MI (STEMI, NSTEMI, and UAP) are made according to national clinical practice guidelines.	12 months
Secondary	Early neurological improvement in acute ischemic stroke patients (AIS)	Reduction in National Institute of Health Stroke Scale (NIHSS) = 4 (baseline versus 24-Hour NIHSS)	24 hours
Secondary	Early neurological improvement in patients with intracerebral hemorrhage (ICH)	Reduction in National Institute of Health Stroke Scale (NIHSS) = 4 (baseline versus 24-Hour NIHSS)	24 hours
Secondary	Quality of life measures at 3 months in AIS and ICH patients	Quality of life (WHO-5) measures in AIS and ICH patients	3 months
Secondary	Bed-day use in AIS and ICH patients	Bed-day use, measured at 3 months, in AIS and ICH patients	3 months
Secondary	Three-month and one-year mortality	All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality	3 and 12 months