Stroke, AcuteRESISTNCT03481777
Remote Ischemic Conditioning in Patients With Acute Stroke (RESIST)
A study testing Remote Ischemic Conditioning in people with Stroke, Acute and Ischemic Stroke, run by Grethe Andersen at 4 sites in Denmark.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Stroke, Acute, Ischemic Stroke, Hemorrhagic Stroke
- What is being tested?
- Remote Ischemic Conditioning
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,500 participants
- Where
- 4 sitesDenmark
- Study dates
- 15 Mar 2018to 3 Feb 2023
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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
Trial locations and contacts
4 sites in 1 country.
Denmark4 sites
Aalborg University Hospital
Aalborg, DK, 9000
Department of Neurology Aarhus University Hospital
Aarhus, Danmark, DK-8000
Department of Neurology Regional Hospital West Jutland
Holstebro, DK-7500
Odense University Hospital
Odense, DK, 5000
About this study
Official title: Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study
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.
Read the 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.
- Conditions
- Stroke, Acute, Ischemic Stroke, Hemorrhagic Stroke, Intracerebral Hemorrhage, Cerebrovascular Disorders, Central Nervous System Diseases
- Being tested
- Remote Ischemic Conditioning, Sham Remote Ischemic Conditioning
- Keywords
- Remote Ischemic Conditioning, Neuroprotection
- Medical subject headings
- Stroke, Ischemic Stroke, Hemorrhagic Stroke, Cerebral Hemorrhage, Cerebrovascular Disorders, Central Nervous System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Remote Ischemic ConditioningDevice
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 ConditioningDevice
Sham Comparator (Sham-RIC)
| Study group | Role | What they receive |
|---|---|---|
| Remote Ischemic Conditioning | Active comparator | 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.
* Initial remote ischemic conditioning: prehospital phase, all included patients
* Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres
* Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital
Usual care with or without acute reperfusion therapy Receives: Device: Remote Ischemic Conditioning |
| Sham - Remote Ischemic Conditioning | Sham comparator | 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.
* Initial Sham remote ischemic conditioning: prehospital phase, all included patients
* Sham Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres
* Sham Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital
Usual care with or without acute reperfusion therapy. Receives: Device: Sham Remote Ischemic Conditioning |
What is being measured
The primary outcome is the main question the study is designed to answer.
Modified Rankin Scale 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.
the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death)
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.
Measured: 3 months
Secondary outcomes (11)
Difference Neurological Impairment During the First 24 Hours
Neurological deficits are documented using Prehospital Stroke Score (PreSS). Prehospital Stroke Score is assessed in the the ambulance and 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). The PreSS score range from 0-6, with 6 representing the most severe neurological deficits.
Measured: 24 hours
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke
Clinical outcome (modified Rankin Scale) at 3 months in acute stroke patients (target diagnosis) (generalized ordinal logistic regression). TThe assessment will performed by two independent telephone or face-to-face assessors.
the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Measured: 3 months
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy
Clinical outcome (modified Rankin Scale) at 3 months inacute ischemic stroke receiving reperfusion therapy (generalized ordinal logistic regression). The assessment will performed by two independent telephone or face-to-face assessors.
the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Measured: 3 months
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH)
Clinical outcome (modified Rankin Scale) at 3 months in patients with intracerebral hemorrhage (ICH) (generalized ordinal logistic regression).
The assessment will performed by two independent telephone or face-to-face assessors.
the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
Measured: 3 months
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
Measured: 3 months
Major Adverse Cardiac and Cerebral Events (MACCE)
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.
Measured: 3 months
Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS)
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function.
Measured: 24 hours
Early Neurological Improvement in Patients With Intracerebral Hemorrhage (ICH)
Reduction in National Institute of Health Stroke Scale (NIHSS) ≥ 4 (baseline versus 24-Hour NIHSS). NIHSS range from 0 to 42, with higher scores representing worse neurological function.
Measured: 24 hours
Quality of Life Measures at 3 Months in AIS and ICH Patients
Quality of life (WHO-5 Well-Being Index) measures in AIS and ICH patients at 3 months
Measured: 3 months
Bed-day Use in AIS and ICH Patients
Bed-day use, measured at 3 months, in AIS and ICH patients
Measured: 3 months
Three-month and One-year Mortality
All-cause mortality is assessed and subdivided into cardiovascular mortality versus non-cardiovascular mortality
Measured: 3 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Mar 2018
- Study start15 Mar 2018
- Primary completion3 Feb 2023
- Study completion3 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Stroke, AcuteStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective, randomized, patient-assessor blinded, sham-controlled trial
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 1,500 participants (actual)
Sponsor and investigators
- Lead sponsor
- Grethe Andersen
- Sponsor type
- University, hospital or other
- Collaborators
- Danish National Research Foundation, Central Denmark Region
- Responsible party
- Sponsor-investigator, Grethe Andersen, Aarhus University Hospital
- Investigators
- Grethe Andersen, MD, DMSc, Principal investigator, Aarhus University Hospital, Department of Neurology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03481777
- Sponsor's protocol ID
- 2017114177
- Acronym
- RESIST
- Status last verified
- Jan 2025
- First submitted
- 12 Mar 2018
- Last updated
- 27 Jan 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in this article after deidentification
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.
PubMed 26585977Hougaard 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.
PubMed 24203849Blauenfeldt 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.
PubMed 32232175Blauenfeldt 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.
PubMed 37787796Blauenfeldt 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.
PubMed 38165678Blauenfeldt 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.
PubMed 38299363Bilgin-Freiert A, Andersen G, Cehov B, Gude MF, Morgenstjerne Orskov K, Hjort N, Hindsholm MF, Pedersen NL, Valentin JB, Homburg AM, Modrau B, Behrndtz AB, Johnsen SP, Hess DC, Simonsen CZ, Blauenfeldt RA. The effect of Remote Ischemic Condition on Hematoma growth in patients with Intracerebral Hemorrhage: a subgroup analysis from the RESIST trial. J Stroke Cerebrovasc Dis. 2026 Sep 8:108746. doi: 10.1016/j.jstrokecerebrovasdis.2026.108746. Online ahead of print.
PubMed 42710698Ganesh A, Gaist D, Modrau B, Gude MF, Behrndtz AB, Andersen G, Simonsen CZ, Blauenfeldt RA. Pre-hospital treatment duration and efficacy of remote ischaemic conditioning in the RESIST randomised-controlled trial. Eur Stroke J. 2026 Jan 1;11(1):aakaf015. doi: 10.1093/esj/aakaf015.
PubMed 41614496Blauenfeldt RA, Hess DC, Gaist D, Modrau B, Valentin JB, Johnsen SP, Hjort N, Behrndtz AB, Gude MF, Zhao W, Jensen J, Andersen G, Simonsen CZ. The Effect of Remote Ischemic Conditioning in Patients Treated with Endovascular Therapy: A RESIST Trial Post Hoc Study. Transl Stroke Res. 2025 Dec;16(6):2173-2184. doi: 10.1007/s12975-025-01379-5. Epub 2025 Sep 6.
PubMed 40913213Blauenfeldt RA, Waller J, Drasbek KR, Bech JN, Hvas AM, Larsen JB, Andersen MN, Nielsen MC, Kjolhede M, Kjeldsen M, Gude MF, Khan MB, Baban B, Andersen G, Hess DC. Effect of Remote Ischemic Conditioning on the Form and Function of Red Blood Cells in Patients With Acute Ischemic Stroke. Stroke. 2025 Mar;56(3):603-612. doi: 10.1161/STROKEAHA.124.048976. Epub 2025 Jan 30.
PubMed 39882626
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Remote Ischemic Conditioning in Patients With Acute Stroke: a Multicenter Randomized, Patient-assessor Blinded, Sham-controlled Study
- ClinicalTrials.gov ID
- NCT03481777
- Acronym / sponsor ID
- RESIST / 2017114177
- Conditions
- Stroke, Acute, Ischemic Stroke, Hemorrhagic Stroke, Intracerebral Hemorrhage, Cerebrovascular Disorders, Central Nervous System Diseases
- Keywords
- Remote Ischemic Conditioning, Neuroprotection
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,500 participants (actual)
- Lead sponsor
- Grethe AndersenUniversity, hospital or other
- Collaborators
- Danish National Research Foundation, Central Denmark Region
- Study start
- 15 Mar 2018 (actual)
- Primary completion
- 3 Feb 2023 (actual)
- Study completion
- 3 Feb 2023 (actual)
- First posted
- 29 Mar 2018 (actual)
- Results
- Posted 27 Jan 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Prospective, randomized, patient-assessor blinded, sham-controlled trial
| Arm | Type | Receives |
|---|---|---|
| Remote Ischemic Conditioning | Active comparator | Device: Remote Ischemic ConditioningRemote 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. * Initial remote ischemic conditioning: prehospital phase, all included patients * Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres * Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital Usual care with or without acute reperfusion therapy |
| Sham - Remote Ischemic Conditioning | Sham comparator | Device: Sham Remote Ischemic ConditioningSham 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. * Initial Sham remote ischemic conditioning: prehospital phase, all included patients * Sham Remote ischemic conditioning at +6 hours: In-hospital, only patients with AIS and ICH, all centres * Sham Remote Ischemic Postconditioning (twice daily for 7 days): In-hospital/rehabilitation, Only patients with AIS and ICH and only at Aarhus University Hospital Usual care with or without acute reperfusion therapy. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Remote Ischemic ConditioningRIC is commonly achieved by inflation of a blood pressure cuff to induce 5-minute cycles of limb ischemia alternating with 5 minutes of reperfusion. | Device | Remote Ischemic Conditioning |
| Sham Remote Ischemic ConditioningSham Comparator (Sham-RIC) | Device | Sham - Remote Ischemic Conditioning |
Primary outcome
Modified Rankin Scale 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. the mRS range from 0 to 6, with higher scores representing worse outcome (mRS 0, no symptoms; mRS 6, death) 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.
11 secondary outcomes
Difference Neurological Impairment During the First 24 Hours
Time frame: 24 hours
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke
Time frame: 3 months
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Acute Ischemic Stroke Receiving Reperfusion Therapy
Time frame: 3 months
Clinical Outcome (Modified Rankin Scale (mRS) at 3 Months in Patients With Intracerebral Hemorrhage (ICH)
Time frame: 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
Major Adverse Cardiac and Cerebral Events (MACCE)
Time frame: 3 months
Early Neurological Improvement in Acute Ischemic Stroke Patients (AIS)
Time frame: 24 hours
Early Neurological Improvement in Patients With Intracerebral Hemorrhage (ICH)
Time frame: 24 hours
Quality of Life Measures at 3 Months in AIS and ICH Patients
Time frame: 3 months
Bed-day Use in AIS and ICH Patients
Time frame: 3 months
Three-month and One-year Mortality
Time frame: 3 and 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26585977Hess 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.
- Background: PubMed 24203849Hougaard 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.
- Background: PubMed 32232175Blauenfeldt 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.
- Results publication: PubMed 37787796Blauenfeldt 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.
- Results publication: PubMed 38165678Blauenfeldt 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.
- Results publication: PubMed 38299363Blauenfeldt 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.
- Derived from this study: PubMed 42710698Bilgin-Freiert A, Andersen G, Cehov B, Gude MF, Morgenstjerne Orskov K, Hjort N, Hindsholm MF, Pedersen NL, Valentin JB, Homburg AM, Modrau B, Behrndtz AB, Johnsen SP, Hess DC, Simonsen CZ, Blauenfeldt RA. The effect of Remote Ischemic Condition on Hematoma growth in patients with Intracerebral Hemorrhage: a subgroup analysis from the RESIST trial. J Stroke Cerebrovasc Dis. 2026 Sep 8:108746. doi: 10.1016/j.jstrokecerebrovasdis.2026.108746. Online ahead of print.
- Derived from this study: PubMed 41614496Ganesh A, Gaist D, Modrau B, Gude MF, Behrndtz AB, Andersen G, Simonsen CZ, Blauenfeldt RA. Pre-hospital treatment duration and efficacy of remote ischaemic conditioning in the RESIST randomised-controlled trial. Eur Stroke J. 2026 Jan 1;11(1):aakaf015. doi: 10.1093/esj/aakaf015.
- Derived from this study: PubMed 40913213Blauenfeldt RA, Hess DC, Gaist D, Modrau B, Valentin JB, Johnsen SP, Hjort N, Behrndtz AB, Gude MF, Zhao W, Jensen J, Andersen G, Simonsen CZ. The Effect of Remote Ischemic Conditioning in Patients Treated with Endovascular Therapy: A RESIST Trial Post Hoc Study. Transl Stroke Res. 2025 Dec;16(6):2173-2184. doi: 10.1007/s12975-025-01379-5. Epub 2025 Sep 6.
- Derived from this study: PubMed 39882626Blauenfeldt RA, Waller J, Drasbek KR, Bech JN, Hvas AM, Larsen JB, Andersen MN, Nielsen MC, Kjolhede M, Kjeldsen M, Gude MF, Khan MB, Baban B, Andersen G, Hess DC. Effect of Remote Ischemic Conditioning on the Form and Function of Red Blood Cells in Patients With Acute Ischemic Stroke. Stroke. 2025 Mar;56(3):603-612. doi: 10.1161/STROKEAHA.124.048976. Epub 2025 Jan 30.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in this article after deidentification
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Grethe Andersen, MD, DMSc principal investigator
Aarhus University Hospital, Department of Neurology
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Remote Ischemic Conditioning in people with Stroke, Acute and Ischemic Stroke, run by Grethe Andersen at 4 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Modified Rankin Scale at 3 Months in Acute Stroke (AIS and ICH) (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03481777, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2025; AzTrials last refreshed its copy on 26 Oct 2026.