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Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury

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ClinicalTrials.gov Identifier: NCT03176823
Recruitment Status : Not yet recruiting
First Posted : June 6, 2017
Last Update Posted : June 6, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
Brief Summary:

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.


Condition or disease Intervention/treatment
Traumatic Brain Injury Trauma, Nervous System Reperfusion Injury Ischemia, Brain Device: CellAegis Technologies autoRIC device Other: Best Practice Management of Traumatic Brain Injury

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Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Care Provider, Investigator, Outcomes Assessor)
Masking Description: While it is not technically possible to mask participants to the application of RIC versus sham therapies, all participants in this trial by design will be intubated in an intensive care unit with severe traumatic brain injury; it is improbable that our inability to mask the patients will compromise outcomes or induce bias as patients are unlikely to have consciousness or memory of the therapy.
Primary Purpose: Treatment
Official Title: Remote Ischemic Conditioning as a Treatment for Traumatic Brain Injury: a Prospective Randomized Controlled Trial.
Anticipated Study Start Date : August 1, 2017
Estimated Primary Completion Date : July 31, 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Sham Comparator: Control Arm
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.
Other: Best Practice Management of Traumatic Brain Injury
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.
Experimental: RIC Arm
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.
Device: CellAegis Technologies autoRIC device
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.
Other Name: Remote Ischemic Conditioning
Other: Best Practice Management of Traumatic Brain Injury
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.


Outcome Measures

Primary Outcome Measures :
  1. Neuron Specific Enolase (NSE) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  2. Calcium Binding Protein Beta (S100B) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  3. Glial Fibrillary Acidic Protein (GFAP) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  4. Monocyte Chemoattractant Protein (MCP1) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  5. Epinephrine [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  6. Norepinephrine [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  7. Interleukin 10 (IL10) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  8. Interleukin 1 Beta (IL1B) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  9. Tumor Necrosis Factor Alpha (TNF Alpha) [ Time Frame: 18 months ]
    Serum concentration, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  10. International Normalized Ratio (INR) [ Time Frame: 18 months. ]
    Standard coagulation parameter, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  11. Prothrombin Time (PTT) [ Time Frame: 18 months ]
    Standard coagulation parameter, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.

  12. Rotational Thromboelastometry (ROTEM) [ Time Frame: 18 Months ]
    ROTEM coagulation assessment using the commercial ROTEM device traditionally used for the assessment of trauma-induced coagulopathy, to be collected immediately after RIC treatment, treatment plus six hours, and treatment plus twenty-four hours.


Secondary Outcome Measures :
  1. Cerebral vascular perfusion, acute [ Time Frame: 18 months ]
    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.

  2. Cerebral vascular perfusion, acute [ Time Frame: 21 months ]
    Patients will undergo Arterial Spin Loading Functional Magnetic Resonance Imaging (fMRI) at 3 months post-trauma to quantify blood flow to the recovered and remodeled brain parenchyma.

  3. Intracranial Pressure (ICP) measurement, first 24 hours [ Time Frame: 18 months ]
    The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over the first 24 hours.

  4. Intracranial Pressure (ICP) measurement, 24-96 hours [ Time Frame: 18 months ]
    The number of episodes of ICP >20 mmHg, measured in 15 minute increments, over 24-96 hours.

  5. Escalation along an established care algorithm [ Time Frame: 18 months ]
    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.

  6. Mortality beyond 12 hours post-admission [ Time Frame: 18 months ]
    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.

  7. Incidence of surgical decompression beyond 12 hours post-admission [ Time Frame: 18 months ]
    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.

  8. Hospital length of stay, number of days [ Time Frame: 21 months ]
    Number of continuous calendar days or partial calendar days admitted to an acute-care hospital.

  9. Intensive Care Unit length of stay, number of days [ Time Frame: 21 months ]
    Number of continuous calendar days or partial calendar days admitted to an intensive-care unit.

  10. Total duration of mechanical ventilation, number of days [ Time Frame: 21 months ]
    Number of calendar days or partial calendar days including treatment with invasive ventilation.

  11. Destination of discharge [ Time Frame: 21 months ]
    Home (functionally independent), rehabilitation facility, or chronic care facility

  12. Glasgow Outcomes Scale, Extended (GOSE) [ Time Frame: 24 months ]
    The GOSE scale assessing neurocognitive function will be assessed on hospital discharge, at three months post-discharge, and at 6 months post-discharge.

  13. Disability Rating Scale (DRS) [ Time Frame: 24 months ]
    The DRS scale assessing neurocognitive function will be assessed on hospital discharge, at three months post-discharge, and at 6 months post-discharge.

  14. Patient Health Questionnaire 9th edition (PHQ-9) [ Time Frame: 24 months ]
    The PHQ-9 screen for mental health disorders will be assessed on hospital discharge, at three months post-discharge, and at 6 months post-discharge.

  15. Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders 5th edition (PCL-5) [ Time Frame: 24 months ]
    The PCL-5 screen for Post-Traumatic Stress Disorder will be assessed on hospital discharge, at three months post-discharge, and at 6 months post-discharge.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Severe blunt traumatic brain injury presenting to St Michael's Hospital within 8 hours of trauma
  • Glasgow Coma Scale (GCS) less than or equal to 8
  • Presence on CT Scan of intra-cranial hematoma which adequately explains level of consciousness (epidural, subdural, subarachnoid hematomae)
  • Able to undergo intervention within 8 hours of trauma

Exclusion Criteria:

  • 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
  • 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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03176823


Contacts
Contact: Markus T Ziesmann, MD 204 297-0116 mtziesmann@gmail.com
Contact: Ori Rotstein, MD 416 864-6060 ext 5304 rotsteino@smh.ca

Locations
Canada, Ontario
St Michaels Hospital Not yet recruiting
Toronto, Ontario, Canada, M5B 1W8
Contact: Markus T Ziesmann, MD MSc    204 297-0116    mtziesmann@gmail.com   
Contact: Ori Rotstein, MD    416 864-6060 ext 5304    rotsteino@smh.ca   
Sponsors and Collaborators
St. Michael's Hospital, Toronto
Dr. Markus Ziesmann
Dr. Shawn Rhind
Dr. Sandro Rizoli
Canadian Institute for Military and Veteran Health Research
More Information

Publications:
ACS TQIP Best Practices in the Management of Traumatic Brain Injury. 2015.

Responsible Party: St. Michael's Hospital, Toronto
ClinicalTrials.gov Identifier: NCT03176823     History of Changes
Other Study ID Numbers: RIC in TBI
First Posted: June 6, 2017    Key Record Dates
Last Update Posted: June 6, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Ischemia
Brain Injuries, Traumatic
Reperfusion Injury
Trauma, Nervous System
Brain Ischemia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Cerebrovascular Disorders