Traumatic Brain InjuryNCT03176823

Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury

A study testing CellAegis Technologies autoRIC device and Best Practice Management of Traumatic Brain Injury in people with Traumatic Brain Injury and Trauma, Nervous System, run by Unity Health Toronto at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Traumatic Brain Injury, Trauma, Nervous System, Reperfusion Injury
What is being tested?: CellAegis Technologies autoRIC device and Best Practice Management of Traumatic Brain Injury
Type of treatment: Medical device
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 44 participants
Where: 1 siteCanada
Study dates: 3 May 2019to 3 Mar 2024
Phase: Interventional
Are there results?: None posted in the registry

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

Severe blunt traumatic brain injury presenting to St Michael's Hospital within 48 hours of trauma
Glasgow Coma Scale (GCS) less than or equal to 12
Presence on CT Scan of intra-cranial hematoma which adequately explains level of consciousness (epidural, subdural, subarachnoid hematomae)
Able to undergo intervention within 48 hours of trauma

Who cannot join

Age <18 years
Lack of informed consent or withdrawal of consent, provided by legal substitute decision maker
Unknown timing of trauma
Unable to safely undergo ischemic conditioning of the upper extremity due to major trauma, previous surgery, known vascular disease or previous radiation treatment
Acute significant injury (those injuries which in isolation would require admission to hospital) outside the head and neck region
Pre-hospital therapeutic anticoagulation or anti-platelet agent use

Show all 9Show fewer

Surgical intervention within 12 hours of presentation to hospital, excluding pressure monitor insertion
Patient death within 24 hours of admission
Pre-intervention insertion of intra-cranial pressure monitor, as surgical trauma may influence biomarker measurements

Trial locations and contacts

1 site in 1 country.

Canada1 site

St Michaels Hospital
Toronto, Ontario, M5B 1W8

Other trials in Canada

About this study

Official title: Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury: a Prospective Randomized Controlled Trial.

The prevention of secondary brain injury is a primary goal in treating patients with severe traumatic brain injury (TBI). Secondary brain injury results from tissue ischemia induced by increased vascular resistance in the at-risk brain tissue due to compression by traumatic hematomas, and development of cytotoxic and vasogenic tissue edema. While traumatic hematomas may be managed surgically, cytotoxic and vasogenic edema with resulting perfusion impairment perpetuates brain ischemia and injury. Animal models suggest that remote ischemic conditioning (RIC) can reverse these effects and improve perfusion. Based on these findings it is hypothesized that RIC will exert beneficial effects on TBI in man, thereby representing a new therapeutic strategy for severe TBI.

Patients presenting to our institution suffering from severe TBI will be considered for enrollment. Eligible patients will have sustained a blunt, severe TBI (defined by Glasgow Coma Scale <8) with associated intra-cranial hematoma(s) not requiring immediate surgical decompression, with admission to an intensive care unit and insertion of an intra-cranial pressure monitor. Patients will be randomized to RIC versus sham-RIC intervention cohorts. RIC interventions will be performed using an automated device on the upper extremity delivering 20 cumulative minutes of limb ischemia in a single treatment session. The planned enrollment is a cohort of 40 patients.

Outcomes of this study will include multiple domains. Our primary outcome will include serial assessments of validated serum biomarkers of neuronal injury and systemic inflammation. Secondary outcomes will include descriptions of the clinical course of each patient, radiologic assessment of brain perfusion, and neurocognitive and psychological assessment post-discharge.

If clinical outcomes are improved using RIC, this study would support RIC as a novel treatment for TBI. Its advantages include safety and simplicity and, requiring no specialized equipment, its ability to be used in any environment including pre-hospital settings or in austere theatres. The investigators anticipate that TBI patients treated with RIC will have improved clinical, biochemical, and neuropsychological outcomes compared to standard treatment protocols.

Read the detailed description

Traumatic brain injury is a leading cause of morbidity and mortality in victims of blunt trauma, leading to a tremendous economic cost, chronic neuropsychological sequelae and productive years of life lost. Treatment of inoperable primary brain injury consists largely of supportive care to support natural healing and prevention or reduction of secondary insults (1).

Many of the phenomena of secondary injury are related to ischemic sequelae of injury progression. Brain parenchymal edema increases both regional and global intra-cranial pressures, decreasing perfusion pressure, resulting in impaired perfusion, an oxygen debt, and ischemic injury (2). Local compression from traumatic hematomas may act in concert with edema to further impair perfusion. One strategy that has been successfully employed in the treatment of other ischemic insults is an intervention known as "remote ischemic conditioning" (RIC). RIC is felt to induce systemic responses which promote physiologic adaptations to moderate ischemia and minimize the impact of subsequent ischemic insults. Because these effects are systemic, extremity ischemic conditioning may impact brain injury. In the setting of TBI, where all patients carry a risk of ischemic secondary injury, early intervention with RIC may minimize the harm of secondary ischemic insults and improve outcomes.

The systemic effects of RIC have been demonstrated in a variety of organ systems and mechanisms of ischemia. Application of RIC has demonstrable benefits in preventing ischemia-induced organ dysfunction in insults to the heart (3-6), kidneys (7,8), and ocular organ systems (9). Our recent work has demonstrated its benefit in preventing organ injury following hemorrhagic shock (10). The technique has also demonstrated promise in reducing brain injury secondary to stroke or neurosurgical trauma (11-13).

Ischemic conditioning of brain injuries has proven benefits in animal models. Limb preconditioning reduces toxic oxygen free radicals, reduces neuronal apoptosis, reduces intra-cranial inflammation, improves integrity of the blood-brain barrier, and reduces brain parenchymal edema (14,15). RIC also improves microvascular perfusion to ischemic tissues which, in the brain, may reduce secondary injury by promoting perfusion to the at-risk injured brain (16). Even when performed after the intra-cranial trauma in a "post-conditioning" model, limb ischemic conditioning is associated with decreased apoptosis, decreased edema, and decreased brain infarction volumes (17,18). A single recent trial of RIC in human TBI patients showed a decrease in serum biomarkers of central nervous system (CNS) injury in the conditioned cohort (19).

Given the promising findings of the remote ischemic conditioning technique in reducing biomarkers of intra-cranial inflammation, an assessment of the clinical effectiveness of post-traumatic remote ischemic conditioning in modifying the outcomes of patients with isolated severe traumatic brain injuries is warranted.

Outcomes of this proposed prospective, randomized controlled trial will fall into the following validated categories:

Biomarkers of neuronal injury and systemic inflammation (20-28)
Radiologic evidence of improved acute- and delayed-phase perfusion (29-33)
Clinical course in hospital from admission to discharge
Neurocognitive and neuropsychological outcomes, 6 month follow-up (34-46)

The known physiologic effects of RIC are theoretically beneficial to patients suffering severe TBI who are at risk of clinical deterioration due to secondary injury. By mitigating the effects of inflammation and edema and improving microvascular perfusion, at-risk brain tissue may be salvaged and thus patient outcomes improved. This theory is supported by the existing evidence and a well-planned selection of outcome measures including biochemical, clinical, and radiographic outcomes may demonstrate the benefits of RIC in this patient population.

Conditions: Traumatic Brain Injury, Trauma, Nervous System, Reperfusion Injury, Ischemia, Brain
Being tested: CellAegis Technologies autoRIC device, Best Practice Management of Traumatic Brain Injury
Keywords: Brain injury, Remote ischemic conditioning (RIC), Trauma, Biomarkers
Medical subject headings: Brain Injuries, Traumatic, Trauma, Nervous System, Reperfusion Injury, Brain Ischemia, Brain Injuries, Wounds and Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CellAegis Technologies autoRIC deviceDevice
Also called Remote Ischemic Conditioning
The autoRIC device from CellAegis technologies will be applied as per the manufacturer's instructions on an upper extremity. The device will automatically inflate and deflate a blood pressure cuff to supra-systolic blood pressures, maintaining an occlusive pressure for a period of five minutes, followed by five minutes of re-perfusion with cuff deflation, completing a ten minute cycle. This cycle will repeat four times for a cumulative total of twenty minutes of occlusive conditioning over forty minutes of intervention time.
Best Practice Management of Traumatic Brain InjuryOther
Standard treatment of TBI in a dedicated trauma-neuro intensive care unit will include a tiered management strategy corresponding to many published treatment algorithms, including the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) guidelines for the management of intra-cranial hypertension. Standard practice without limitations will be applied to both cohorts of patients in this study.

Study groups in NCT03176823
Study group	Role	What they receive
Control Arm	Sham comparator	Control-arm patients will be treated with standard "Best Practice" management of traumatic brain injury, with the addition of sham-RIC. The sham intervention will use a purpose-built device which will visually and audibly mimic a functional RIC device, with the key distinction being non-inflation of the arm cuff with resultant non-occlusion and no induced ischemia. To mask patient enrollment, all patients in both study arms will have the arm and RIC device draped in an opaque sheet so that the extremity distal to the RIC device are not visible to medical staff during the period of intervention. Receives: Other: Best Practice Management of Traumatic Brain Injury
RIC Arm	Experimental	The RIC treatment will be applied with a purpose-built commercial RIC device which will aid in standardizing dose and delivery. Therapeutic RIC will be provided by the CellAegis Technologies autoRIC device on an upper extremity. As with the control cohort, this cohort will undergo complete extremity draping. Receives: Device: CellAegis Technologies autoRIC device; Other: Best Practice Management of Traumatic Brain Injury

What is being measured

The primary outcome is the main question the study is designed to answer.

Neuron Specific Enolase (NSE) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
S100A12 - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Calcium Binding Protein Beta (S100B) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Glial Fibrillary Acidic Protein (GFAP) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Monocyte Chemoattractant Protein (MCP1) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Epinephrine - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Norepinephrine - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Interleukin 10 (IL10) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Interleukin 1 Beta (IL1B) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Tumor Necrosis Factor Alpha (TNF Alpha) - biomarker
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
International Normalized Ratio (INR) - standard lab test.
Standard coagulation parameter, to be measured at all time points specified below.
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Prothrombin Time (PTT) - standard lab test.
Standard coagulation parameter, to be measured at all time points specified below
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Rotational Thromboelastometry (ROTEM), standard lab test.
ROTEM coagulation assessment using the commercial ROTEM device traditionally used for the assessment of trauma-induced coagulopathy, to be measured at all time points specified below
Measured: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours

Secondary outcomes (14)

Cerebral vascular perfusion, acute
Patients will undergo Arterial Spin Loading Functional Magnetic Resonance Imaging (fMRI) at 72 hours post-RIC to quantify blood flow to the acutely ischemic brain parenchyma.
Measured: 24 hours
Intracranial Pressure (ICP) measurement, first 24 hours
The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over the first 24 hours.
Measured: 24 hours
Intracranial Pressure (ICP) measurement, 24-96 hours
The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over 24-96 hours.
Measured: 24 hours, 96 hours
Escalation along an established care algorithm
Patient care interventions will be plotted against the Tier 1, Tier 2, and Tier 3 categories of interventions described by the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) guidelines for the management of traumatic intracranial hypertension.
Measured: 12 months
Mortality beyond 12 hours post-admission
Patient deaths occurring in the first 12 hours will result in patient-exclusion as it is unlikely that these patients would have had different outcomes regardless of treatment strategies.
Measured: 12 months
Incidence of surgical decompression beyond 12 hours post-admission
Patient progression to need for definitive surgery occurring in the first 12 hours will result in patient-exclusion as it is unlikely that these patients would have had different outcomes regardless of treatment strategies.
Measured: 12 months
Hospital length of stay, number of days
Number of continuous calendar days or partial calendar days admitted to an acute-care hospital.
Measured: 12 months
Intensive Care Unit length of stay, number of days
Number of continuous calendar days or partial calendar days admitted to an intensive-care unit.
Measured: 2 months
Total duration of mechanical ventilation, number of days
Number of calendar days or partial calendar days including treatment with invasive ventilation.
Measured: 2 months
Destination of discharge
Home (functionally independent), rehabilitation facility, or chronic care facility
Measured: 12 months
Glasgow Outcomes Scale, Extended (GOSE) - neurocognitive test
The GOSE scale assessing neurocognitive function will be assessed on hospital, discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Measured: discharge, 3 months, 6 months, and 12 months
Disability Rating Scale (DRS) - neurocognitive function rating
The DRS scale assessing neurocognitive function will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Measured: discharge, 3 months, 6 months, and 12 months
Patient Health Questionnaire 9th edition (PHQ-9) - neurological - self assessment
The PHQ-9 screen for mental health disorders will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Measured: discharge, 3, 6, and 12 months
Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders 5th edition (PCL-5) - neurological - self assessment
The PCL-5 screen for Post-Traumatic Stress Disorder will be assessed on hospital discharge, at three months post-discharge, and at 6 and 12 months post-discharge.
Measured: discharge, 3 months, 6 months, and 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

3 May 20193 Mar 2024

First posted6 Jun 2017
Study start3 May 2019
Primary completion1 Nov 2023
Study completion3 Mar 2024

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (44)Papers the sponsor has linked to this study.
Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
More trials run by Unity Health TorontoThe sponsor's other registered studies.
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: This trial is a prospective double-blind parallel cohort study of patients undergoing either standard of care plus placebo (sham-RIC) or standard treatment plus a single session of upper extremity remote ischemic conditioning.
Masking: Triple blind
Who is masked: Care provider, Investigator, Outcomes assessor
Enrolment: 44 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03176823
Sponsor's protocol ID: RIC in TBI
Status last verified: Mar 2024
First submitted: 15 May 2017
Last updated: 15 Mar 2024
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

ACS TQIP Best Practices in the Management of Traumatic Brain Injury. 2015.
Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991 Nov;75(5):685-93. doi: 10.3171/jns.1991.75.5.0685.
PubMed 1919689
Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727-34. doi: 10.1016/S0140-6736(09)62001-8.
PubMed 20189026
Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE; CONDI Investigators. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014 Jan;35(3):168-75. doi: 10.1093/eurheartj/eht369. Epub 2013 Sep 12.
PubMed 24031025
Pei H, Wu Y, Wei Y, Yang Y, Teng S, Zhang H. Remote ischemic preconditioning reduces perioperative cardiac and renal events in patients undergoing elective coronary intervention: a meta-analysis of 11 randomized trials. PLoS One. 2014 Dec 31;9(12):e115500. doi: 10.1371/journal.pone.0115500. eCollection 2014.
PubMed 25551671
Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, Hoole SP. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv. 2013 Jun;6(3):246-51. doi: 10.1161/CIRCINTERVENTIONS.112.000184. Epub 2013 May 21.
PubMed 23696599
Er F, Nia AM, Dopp H, Hellmich M, Dahlem KM, Caglayan E, Kubacki T, Benzing T, Erdmann E, Burst V, Gassanov N. Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial). Circulation. 2012 Jul 17;126(3):296-303. doi: 10.1161/CIRCULATIONAHA.112.096370. Epub 2012 Jun 26.
PubMed 22735306
Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189.
PubMed 26024502
Liu X, Sha O, Cho EY. Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury. J Mol Neurosci. 2013 Nov;51(3):639-46. doi: 10.1007/s12031-013-0036-2. Epub 2013 Jun 5.
PubMed 23733254
Leung CH, Caldarone CA, Wang F, Venkateswaran S, Ailenberg M, Vadasz B, Wen XY, Rotstein OD. Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor. Ann Surg. 2015 Jun;261(6):1215-25. doi: 10.1097/SLA.0000000000000877.
PubMed 25185480
DAHL NA, BALFOUR WM. PROLONGED ANOXIC SURVIVAL DUE TO ANOXIA PRE-EXPOSURE: BRAIN ATP, LACTATE, AND PYRUVATE. Am J Physiol. 1964 Aug;207:452-6. doi: 10.1152/ajplegacy.1964.207.2.452. No abstract available.
PubMed 14205366
Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res. 1990 Sep 24;528(1):21-4. doi: 10.1016/0006-8993(90)90189-i.
PubMed 2245337
Chen J, Graham SH, Zhu RL, Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab. 1996 Jul;16(4):566-77. doi: 10.1097/00004647-199607000-00006.
PubMed 8964795
Wei D, Ren C, Chen X, Zhao H. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One. 2012;7(2):e30892. doi: 10.1371/journal.pone.0030892. Epub 2012 Feb 8.
PubMed 22347410
Wang Y, Ge P, Yang L, Wu C, Zha H, Luo T, Zhu Y. Protection of ischemic post conditioning against transient focal ischemia-induced brain damage is associated with inhibition of neuroinflammation via modulation of TLR2 and TLR4 pathways. J Neuroinflammation. 2014 Jan 24;11:15. doi: 10.1186/1742-2094-11-15.
PubMed 24460643

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Active, not recruiting
TMS-fNIRS Personalized Dosing
Post Traumatic Stress Disorder, Traumatic Brain Injury
Recruiting
Middle Meningeal Artery Embolisation in Chronic Subdural Hematoma
Chronic Subdural Hematoma
Recruiting
Virtual Reality in Rehabilitation of Executive Functions in Children With Mild or Moderate Traumatic Brain Injury
Traumatic Brain Injury
Not yet recruitingPhase 2/3
Valproic AcId for Traumatic BRAin INjury Trial
Moderate Traumatic Brain Injury (TBI), Severe Traumatic Brain Injury
Active, not recruiting
Pilot TMS in Mild TBI
Persistent Post Concussive Headache, Mild Traumatic Brain Injury

All Traumatic Brain Injury trials

Study at a glance

From the registry record, last updated by the sponsor on 15 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury: a Prospective Randomized Controlled Trial.
ClinicalTrials.gov ID: NCT03176823
Acronym / sponsor ID: RIC in TBI
Conditions: Traumatic Brain Injury, Trauma, Nervous System, Reperfusion Injury, Ischemia, Brain
Keywords: Brain injury, Remote ischemic conditioning (RIC), Trauma, Biomarkers
Study type: Interventional
Recruitment status: Completed
Enrolment: 44 participants (actual)
Lead sponsor: Unity Health TorontoUniversity, hospital or other
Collaborators: Defence Research and Development Canada
Study start: 3 May 2019 (actual)
Primary completion: 1 Nov 2023 (actual)
Study completion: 3 Mar 2024 (actual)
First posted: 6 Jun 2017 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Outcomes of this proposed prospective, randomized controlled trial will fall into the following validated categories:

Biomarkers of neuronal injury and systemic inflammation (20-28)
Radiologic evidence of improved acute- and delayed-phase perfusion (29-33)
Clinical course in hospital from admission to discharge
Neurocognitive and neuropsychological outcomes, 6 month follow-up (34-46)

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (care provider, investigator, outcomes assessor)
Number of arms: 2
Model description: This trial is a prospective double-blind parallel cohort study of patients undergoing either standard of care plus placebo (sham-RIC) or standard treatment plus a single session of upper extremity remote ischemic conditioning.

Arm	Type	Receives
Control Arm	Sham comparator	Other: Best Practice Management of Traumatic Brain InjuryControl-arm patients will be treated with standard "Best Practice" management of traumatic brain injury, with the addition of sham-RIC. The sham intervention will use a purpose-built device which will visually and audibly mimic a functional RIC device, with the key distinction being non-inflation of the arm cuff with resultant non-occlusion and no induced ischemia. To mask patient enrollment, all patients in both study arms will have the arm and RIC device draped in an opaque sheet so that the extremity distal to the RIC device are not visible to medical staff during the period of intervention.
RIC Arm	Experimental	Device: CellAegis Technologies autoRIC device, Other: Best Practice Management of Traumatic Brain InjuryThe RIC treatment will be applied with a purpose-built commercial RIC device which will aid in standardizing dose and delivery. Therapeutic RIC will be provided by the CellAegis Technologies autoRIC device on an upper extremity. As with the control cohort, this cohort will undergo complete extremity draping.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (4 listed)

Severe blunt traumatic brain injury presenting to St Michael's Hospital within 48 hours of trauma
Glasgow Coma Scale (GCS) less than or equal to 12
Presence on CT Scan of intra-cranial hematoma which adequately explains level of consciousness (epidural, subdural, subarachnoid hematomae)
Able to undergo intervention within 48 hours of trauma

Key exclusion criteria (9 listed)

Age <18 years
Lack of informed consent or withdrawal of consent, provided by legal substitute decision maker
Unknown timing of trauma
Unable to safely undergo ischemic conditioning of the upper extremity due to major trauma, previous surgery, known vascular disease or previous radiation treatment
Acute significant injury (those injuries which in isolation would require admission to hospital) outside the head and neck region

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
CellAegis Technologies autoRIC deviceAlso: Remote Ischemic ConditioningThe autoRIC device from CellAegis technologies will be applied as per the manufacturer's instructions on an upper extremity. The device will automatically inflate and deflate a blood pressure cuff to supra-systolic blood pressures, maintaining an occlusive pressure for a period of five minutes, followed by five minutes of re-perfusion with cuff deflation, completing a ten minute cycle. This cycle will repeat four times for a cumulative total of twenty minutes of occlusive conditioning over forty minutes of intervention time.	Device	RIC Arm
Best Practice Management of Traumatic Brain InjuryStandard treatment of TBI in a dedicated trauma-neuro intensive care unit will include a tiered management strategy corresponding to many published treatment algorithms, including the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) guidelines for the management of intra-cranial hypertension. Standard practice without limitations will be applied to both cohorts of patients in this study.	Other	Control Arm, RIC Arm

Primary outcome

Neuron Specific Enolase (NSE) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
S100A12 - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Calcium Binding Protein Beta (S100B) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Glial Fibrillary Acidic Protein (GFAP) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Monocyte Chemoattractant Protein (MCP1) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Epinephrine - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Norepinephrine - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Interleukin 10 (IL10) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Interleukin 1 Beta (IL1B) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
Tumor Necrosis Factor Alpha (TNF Alpha) - biomarker
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Plasma concentration measured by measured by enzyme-linked immunosorbent ELISA and multiplex platform at all time points specified below.
International Normalized Ratio (INR) - standard lab test.
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Standard coagulation parameter, to be measured at all time points specified below.
Prothrombin Time (PTT) - standard lab test.
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
Standard coagulation parameter, to be measured at all time points specified below
Rotational Thromboelastometry (ROTEM), standard lab test.
Time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours
ROTEM coagulation assessment using the commercial ROTEM device traditionally used for the assessment of trauma-induced coagulopathy, to be measured at all time points specified below

14 secondary outcomes

Cerebral vascular perfusion, acute
Time frame: 24 hours
Intracranial Pressure (ICP) measurement, first 24 hours
Time frame: 24 hours
Intracranial Pressure (ICP) measurement, 24-96 hours
Time frame: 24 hours, 96 hours
Escalation along an established care algorithm
Time frame: 12 months
Mortality beyond 12 hours post-admission
Time frame: 12 months
Incidence of surgical decompression beyond 12 hours post-admission
Time frame: 12 months
Hospital length of stay, number of days
Time frame: 12 months
Intensive Care Unit length of stay, number of days
Time frame: 2 months
Total duration of mechanical ventilation, number of days
Time frame: 2 months
Destination of discharge
Time frame: 12 months
Glasgow Outcomes Scale, Extended (GOSE) - neurocognitive test
Time frame: discharge, 3 months, 6 months, and 12 months
Disability Rating Scale (DRS) - neurocognitive function rating
Time frame: discharge, 3 months, 6 months, and 12 months
Patient Health Questionnaire 9th edition (PHQ-9) - neurological - self assessment
Time frame: discharge, 3, 6, and 12 months
Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders 5th edition (PCL-5) - neurological - self assessment
Time frame: discharge, 3 months, 6 months, and 12 months

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2024.
BackgroundACS TQIP Best Practices in the Management of Traumatic Brain Injury. 2015.
Background: PubMed 1919689Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg. 1991 Nov;75(5):685-93. doi: 10.3171/jns.1991.75.5.0685.
Background: PubMed 20189026Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727-34. doi: 10.1016/S0140-6736(09)62001-8.
Background: PubMed 24031025Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE; CONDI Investigators. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J. 2014 Jan;35(3):168-75. doi: 10.1093/eurheartj/eht369. Epub 2013 Sep 12.
Background: PubMed 25551671Pei H, Wu Y, Wei Y, Yang Y, Teng S, Zhang H. Remote ischemic preconditioning reduces perioperative cardiac and renal events in patients undergoing elective coronary intervention: a meta-analysis of 11 randomized trials. PLoS One. 2014 Dec 31;9(12):e115500. doi: 10.1371/journal.pone.0115500. eCollection 2014.
Background: PubMed 23696599Davies WR, Brown AJ, Watson W, McCormick LM, West NE, Dutka DP, Hoole SP. Remote ischemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv. 2013 Jun;6(3):246-51. doi: 10.1161/CIRCINTERVENTIONS.112.000184. Epub 2013 May 21.
Background: PubMed 22735306Er F, Nia AM, Dopp H, Hellmich M, Dahlem KM, Caglayan E, Kubacki T, Benzing T, Erdmann E, Burst V, Gassanov N. Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial). Circulation. 2012 Jul 17;126(3):296-303. doi: 10.1161/CIRCULATIONAHA.112.096370. Epub 2012 Jun 26.
Background: PubMed 26024502Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, Goebel U, Schwer CI, Rosenberger P, Haeberle H, Gorlich D, Kellum JA, Meersch M; RenalRIPC Investigators. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015 Jun 2;313(21):2133-41. doi: 10.1001/jama.2015.4189.
Background: PubMed 23733254Liu X, Sha O, Cho EY. Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury. J Mol Neurosci. 2013 Nov;51(3):639-46. doi: 10.1007/s12031-013-0036-2. Epub 2013 Jun 5.
Background: PubMed 25185480Leung CH, Caldarone CA, Wang F, Venkateswaran S, Ailenberg M, Vadasz B, Wen XY, Rotstein OD. Remote Ischemic Conditioning Prevents Lung and Liver Injury After Hemorrhagic Shock/Resuscitation: Potential Role of a Humoral Plasma Factor. Ann Surg. 2015 Jun;261(6):1215-25. doi: 10.1097/SLA.0000000000000877.
Background: PubMed 14205366DAHL NA, BALFOUR WM. PROLONGED ANOXIC SURVIVAL DUE TO ANOXIA PRE-EXPOSURE: BRAIN ATP, LACTATE, AND PYRUVATE. Am J Physiol. 1964 Aug;207:452-6. doi: 10.1152/ajplegacy.1964.207.2.452. No abstract available.
Background: PubMed 2245337Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res. 1990 Sep 24;528(1):21-4. doi: 10.1016/0006-8993(90)90189-i.
Individual participant dataSharing planned: No

Related trials for Traumatic Brain Injury

Active, not recruiting
TMS-fNIRS Personalized Dosing
Post Traumatic Stress Disorder, Traumatic Brain Injury
Recruiting
Middle Meningeal Artery Embolisation in Chronic Subdural Hematoma
Chronic Subdural Hematoma
Recruiting
Virtual Reality in Rehabilitation of Executive Functions in Children With Mild or Moderate Traumatic Brain Injury
Traumatic Brain Injury
Not yet recruitingPhase 2/3
Valproic AcId for Traumatic BRAin INjury Trial
Moderate Traumatic Brain Injury (TBI), Severe Traumatic Brain Injury
Active, not recruiting
Pilot TMS in Mild TBI
Persistent Post Concussive Headache, Mild Traumatic Brain Injury

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.

Ori D Rotstein, MD principal investigator

Unity Health Toronto - St. Michael's hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

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 9 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 15 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. 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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Neuron Specific Enolase (NSE) - biomarker (time frame: Admission (0 hours), 6 hours, 24 hours, 48 hours, and 72 hours). The study lists 13 primary outcomes in all. 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 NCT03176823, which also lists 44 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 15 Mar 2024.