Clinical trial NCT03481777: Remote Ischemic Conditioning in Patients With Acute Stroke (RESIST)
Official title: Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stroke, Acute
Ischemic Stroke
Hemorrhagic Stroke
Intracerebral Hemorrhage
Cerebrovascular Disorders
Central Nervous System Diseases
Keywords: Remote Ischemic Conditioning
Neuroprotection
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
Collaborators: name: Danish National Research Foundation
name: Central Denmark Region
First posted: 2018-03-29
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, patient-assessor blinded, sham-controlled trial
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH)
timeFrame: 3 months
Secondary outcomes:
measure: Difference Neurological Impairment During the First 24 Hours
timeFrame: 24 hours
measure: Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke
timeFrame: 3 months
measure: Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy
timeFrame: 3 months
measure: Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH)
timeFrame: 3 months
measure: Difference in Proportion of Patients With Complete Remission of Symptoms Within 24 Hours (TIA; Both With and Without DWI)
timeFrame: 3 months
measure: Major Adverse Cardiac and Cerebral Events (MACCE)
timeFrame: 3 months
measure: Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS)
timeFrame: 24 hours
measure: Early Neurological Improvement in Patients With Intracerebral Hemorrhage (ICH)
timeFrame: 24 hours
measure: Quality of Life Measures at 3 Months in AIS and ICH Patients
timeFrame: 3 months
measure: Bed-day Use in AIS and ICH Patients
timeFrame: 3 months
measure: Three-month and One-year Mortality
timeFrame: 3 and 12 months
Other outcomes:
measure: 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]
timeFrame: 3 months
measure: 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)
timeFrame: 3 months
measure: Endovascular Treatment(EVT) -Eligibility (MRI Assessed) in RIC Treated AIS Patients With Large Vessel (Substudy at Aarhus University Hospital)
timeFrame: 6 hours
measure: Infarct Growth in AIS Patients (Substudy at Aarhus University Hospital)
timeFrame: 24 hour
measure: Difference in Acute (24-hour) Hematoma Expansion in Patients With ICH (Substudy at Aarhus University Hospital)
timeFrame: 24 hour
measure: Difference in 7 Days Hematoma Volume in Patients With ICH (Substudy at Aarhus University Hospital)
timeFrame: 7 days
measure: Ektacytometry and Analytical Flow Cytometry for eryNOS3 Phosphorylation
timeFrame: 12 months
measure: MicroRNA and Extracellular Vesicle Profile of RIC-induced Neuroprotection
timeFrame: 12 months
measure: Prehospital microRNA and Extracellular Vesicles (Substudy at Aarhus University Hospital)
timeFrame: 12 months
measure: Prehospital Glial Fibrillary Acidic Protein (Substudy at Aarhus University Hospital)
timeFrame: 12 months
measure: Coagulation Profile of Putative Stroke Patients in Prehospital Obtained Blood Samples
timeFrame: 12 months
Locations:
city: Aarhus
country: Denmark
facility: Department of Neurology Aarhus University Hospital
state: Danmark
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
state: DK
city: Odense
country: Denmark
facility: Odense University Hospital
state: DK
city: Holstebro
country: Denmark
facility: Department of Neurology Regional Hospital West Jutland
Study officials:
affiliation: Aarhus University Hospital, Department of Neurology
name: Grethe Andersen, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
citation: 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.
citation: Blauenfeldt RA, Hjort N, Valentin JB, Homburg AM, Modrau B, Sandal BF, Gude MF, Hougaard KD, Damgaard D, Poulsen M, Diedrichsen T, Schmitz ML, von Weitzel-Mudersbach P, Christensen AA, Figlewski K, Grove EL, Hreietharsdottir MK, Lassesen HM, Wittrock D, Mikkelsen S, Vaeggemose U, Juelsgaard P, Kirkegaard H, Rostgaard-Knudsen M, Degn N, Vestergaard SB, Damsbo AG, Iversen AB, Mortensen JK, Petersson J, Christensen T, Behrndtz AB, Botker HE, Gaist D, Fisher M, Hess DC, Johnsen SP, Simonsen CZ, Andersen G. Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial. JAMA. 2023 Oct 3;330(13):1236-1246. doi: 10.1001/jama.2023.16893.
citation: Blauenfeldt RA, Simonsen CZ, Valentin JB, Johnsen SP, Hjort N, Andersen G. Outcomes Following Adherence to a Randomized Stroke Trial Protocol. JAMA Netw Open. 2024 Jan 2;7(1):e2349730. doi: 10.1001/jamanetworkopen.2023.49730.
citation: Blauenfeldt RA, Mortensen JK, Hjort N, Valentin JB, Homburg AM, Modrau B, Sandal BF, Gude MF, Berhndtz AB, Johnsen SP, Hess DC, Simonsen CZ, Andersen G. Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial. Stroke. 2024 Apr;55(4):874-879. doi: 10.1161/STROKEAHA.123.046144. Epub 2024 Feb 1.