- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03481777
Remote Ischemic Conditioning in Patients With Acute Stroke (RESIST) (RESIST)
Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Rolf A Blauenfeldt, MD
- Phone Number: 0045 61368874
- Email: rolfblau@rm.dk
Study Contact Backup
- Name: Niels Hjort, MD, PhD
- Phone Number: 0045 78454200
- Email: nielhjor@rm.dk
Study Locations
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-
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Holstebro, Denmark, DK-7500
- Department of Neurology Regional Hospital West Jutland
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-
DK
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Aalborg, DK, Denmark, 9000
- Aalborg University Hospital
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Odense, DK, Denmark, 5000
- Odense University Hospital
-
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Danmark
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Aarhus, Danmark, Denmark, DK-8000
- Department of Neurology Aarhus University Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Remote Ischemic Conditioning
Remote ischemic conditioning (RIC) is applied in the hyperacute prehospital phase using an automated RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes with a deflated cuff. The cuff pressure will be 200 mmHg; but if initial systolic blood pressure is above 175 mmHg, the cuff is automatically inflated to 35 mmHg above the systolic blood pressure.
Usual care with or without acute reperfusion therapy |
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 Comparator: Sham - Remote Ischemic Conditioning
Sham remote ischemic conditioning (Sham-RIC) is applied in the hyperacute prehospital phase using an automated Sham-RIC device. Treatment characteristics: Five cycles (50 minutes), each consisting of five minutes of cuff inflation followed by five minutes with a deflated cuff. The cuff pressure will be always be 20 mmHg.
Usual care with or without acute reperfusion therapy. |
Sham Comparator (Sham-RIC)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Clinical outcome (mRS) at 3 months in acute stroke (AIS and ICH)
Time Frame: 3 months
|
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.
|
3 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Difference neurological impairment during the first 24 hours in all randomized patients
Time Frame: 24 hours
|
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
|
Clinical outcome (modified Rankin Scale (mRS) at 3 months in acute ischemic stroke
Time Frame: 3 months
|
The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.
|
3 months
|
Clinical outcome (modified Rankin Scale (mRS) at 3 months in acute ischemic stroke receiving reperfusion therapy
Time Frame: 3 months
|
The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.
|
3 months
|
Clinical outcome (modified Rankin Scale (mRS) at 3 months in patients with intracerebral hemorrhage (ICH)
Time Frame: 3 months
|
The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.
|
3 months
|
Difference in proportion of patients with complete remission of symptoms within 24 hours (TIA; both with and without DWI)
Time Frame: 3 months
|
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
|
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
Time Frame: 12 months
|
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
|
Early neurological improvement in acute ischemic stroke patients (AIS)
Time Frame: 24 hours
|
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS)
|
24 hours
|
Early neurological improvement in patients with intracerebral hemorrhage (ICH)
Time Frame: 24 hours
|
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS)
|
24 hours
|
Quality of life measures at 3 months in AIS and ICH patients
Time Frame: 3 months
|
Quality of life (WHO-5) measures in AIS and ICH patients
|
3 months
|
Bed-day use in AIS and ICH patients
Time Frame: 3 months
|
Bed-day use, measured at 3 months, in AIS and ICH patients
|
3 months
|
Three-month and one-year mortality
Time Frame: 3 and 12 months
|
All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality
|
3 and 12 months
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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)
Time Frame: 3 months
|
The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.
|
3 months
|
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)
Time Frame: 3 months
|
The assessment will performed by two independent telephone or face-to-face assessors Ordinal logistic regression analysis will be performed.
|
3 months
|
Endovascular treatment(EVT) -eligibility (MRI assessed) in RIC treated AIS patients with large vessel (substudy at Aarhus University Hospital)
Time Frame: 6 hours
|
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
|
6 hours
|
Infarct growth in AIS patients (substudy at Aarhus University Hospital)
Time Frame: 24 hour
|
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
|
Difference in acute (24-hour) hematoma expansion in patients with ICH (substudy at Aarhus University Hospital)
Time Frame: 24 hour
|
24-hour hematoma growth (Difference in hematoma volume between acute and 24-hour CT/MRI) (Substudy at Aarhus University Hospital)
|
24 hour
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Difference in 7 days hematoma volume in patients with ICH (substudy at Aarhus University Hospital)
Time Frame: 7 days
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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
|
Ektacytometry and Analytical Flow Cytometry for eryNOS3 phosphorylation
Time Frame: 12 months
|
Ektacytometry for Erythrocytic Deformability and Analytical Flow Cytometry (FC) for eryNOS3 phosphorylation (pNOS3Ser1177) and s-nitrosylation (-SNO) in RBC
|
12 months
|
MicroRNA and extracellular vesicle profile of RIC-induced neuroprotection (substudy at Aarhus University Hospital)
Time Frame: 12 months
|
MicroRNA and extracellular vesicle characterization of a possible RIC treatment profile
|
12 months
|
Prehospital microRNA and extracellular vesicles (substudy at Aarhus University Hospital)
Time Frame: 12 months
|
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
|
Prehospital Glial Fibrillary Acidic Protein (substudy at Aarhus University Hospital)
Time Frame: 12 months
|
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
|
Coagulation profile of putative stroke patients in prehospital obtained blood samples (substudy at Aarhus University Hospital)
Time Frame: 12 months
|
Functional and immunologic plasma assays will be employed to analyze proteins and pathways in coagulation and fibrinolysis.
|
12 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Grethe Andersen, MD, DMSc, Aarhus University Hospital, Department of Neurology
Publications and helpful links
General Publications
- 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.
- 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.
- Blauenfeldt RA, Hjort N, Gude MF, Behrndtz AB, Fisher M, Valentin JB, Kirkegaard H, Johnsen SP, Hess DC, Andersen G. A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design. Eur Stroke J. 2020 Mar;5(1):94-101. doi: 10.1177/2396987319884408. Epub 2019 Oct 25.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2017114177
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ANALYTIC_CODE
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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