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Impact of Fever Prevention in Brain-Injured Patients (INTREPID): Study Protocol for a Randomized Controlled Trial

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Abstract

Background

Multiple studies demonstrate that fever/elevated temperature is associated with poor outcomes in patients with vascular brain injury; however, there are no conclusive studies that demonstrate that fever prevention/controlled normothermia is associated with better outcomes. The primary objective of the INTREPID (Impact of Fever Prevention in Brain-Injured Patients) trial is to test the hypothesis that fever prevention is superior to standard temperature management in patients with acute vascular brain injury.

Methods

INTREPID is a prospective randomized open blinded endpoint study of fever prevention versus usual care in patients with ischemic or hemorrhagic stroke. The fever prevention intervention utilizes the Arctic Sun System and will be compared to standard care patients in whom fever may spontaneously develop. Ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage patients will be included within disease-specific time-windows. Both awake and sedated patients will be included, and treatment is initiated immediately upon enrollment. Eligible patients are expected to require intensive care for at least 72 h post-injury, will not be deemed unlikely to survive without severe disability, and will be treated for up to 14 days, or until deemed ready for discharge from the ICU, whichever comes first. Fifty sites in the USA and worldwide will participate, with a target enrollment of 1176 patients (1000 evaluable). The target temperature is 37.0 °C. The primary efficacy outcome is the total fever burden by °C-h, defined as the area under the temperature curve above 37.9 °C. The primary secondary outcome, on which the sample size is based, is the modified Rankin Scale Score at 3 months. All efficacy analyses including the primary and key secondary endpoints will be primarily based on an intention-to-treat population. Analysis of the as-treated and per protocol populations will also be performed on the primary and key secondary endpoints as sensitivity analyses.

Discussion

The INTREPID trial will provide the first results of the impact of a pivotal fever prevention intervention in patients with acute stroke (www.clinicaltrials.gov; NCT02996266; registered prospectively 05DEC2016).

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Abbreviations

AE:

Adverse event

ASPECTS:

Alberta Stroke Program Early CT Score

CEC:

Clinical Events Committee

DMC:

Data Monitoring Committee

EC:

Ethics Committee

FDA:

United States Food and Drug Administration

F/U:

Follow-up

ICDSC:

Intensive Care Delirium Screening Checklist

ICF:

Informed Consent Form

ICH:

Intracerebral hemorrhage

ICU:

Intensive care unit

IRB:

Institutional Review Board

IS:

Ischemic stroke

LAR:

Legally Authorize Representative

MAE:

Major adverse event

mRS:

Modified Rankin Scale

NIHSS:

National Institutes of Health Stroke Scale

MoCA:

Montreal Cognitive Assessment

PP:

Per protocol

SAE:

Serious adverse event

SAH:

Subarachnoid hemorrhage

SAP:

Statistical analysis plan

SCA:

Sudden cardiac arrest

SOC:

Standard of care

TBI:

Traumatic brain injury

TH:

Therapeutic hypothermia

TTM:

Targeted temperature management

WBC:

White blood cell

WFNS:

World Federation of Neurological Societies grading system for subarachnoid hemorrhage

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Acknowledgements

Funding was provided by the study sponsor, C. R. Bard.

Funding

This study was supported by funding from Becton Dickinson (Franlin Lakes, NJ).

Conflict of interest

Dr. Greer has received research support to his institution as PI for the INTREPID study from Becton Dickenson. Ms. Ritter is an employee of Becton Dickenson, the study sponsor. Dr. Helbok has received travel grants and lecture fees from Bard Medical, Zoll Medical, Fresenius Kabi, and Integra Life Sciences outside of the submitted work. Dr. Badjatia has received research funding from Becton Dickinson, and has received research funding from Zoll Inc, the Department of Defense and Maryland Industrial Partnerships. Dr. Ko has nothing to disclose. Ms. Guanci has nothing to disclose. Dr. Sheth has received research support to his institution as co-PI for the INTEPID study from Becton Dickinson. He has consulted for Zoll Medical as DSMB chair for another study. He reports receiving funding from Ncontrol for ad board consulting, and from Alva Equity.

Ethical Approval/Informed Consent

The study was approved by the local Ethics Committee (Date 01/2017). Informed consent was obtained from the patient or LAR prior to inclusion. The inclusion/exclusion criteria are included in detail in the manuscript.

Author information

Authors and Affiliations

  1. Department of Neurology, Boston University School of Medicine, Boston Medical Center, Collamore 3, Suite 338, 72 East Concord Street, Boston, MA, USA

    David M. Greer & Sang-Bae Ko

  2. Becton Dickenson & Company, Franklin Lakes, NJ, USA

    Jaime Ritter

  3. Department of Neurology, Neurology Medical University of Innsbruck, Anichstreet 65, 6020, Innsbruck, Austria

    Raimund Helbok

  4. Program in Trauma, Department of Neurology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD, USA

    Neeraj Badjatia

  5. Neurocritical Care Unit, Massachusetts General Hospital, Lunder Building 6th Floor, 55 Fruit Street, Boston, MA, USA

    Mary Guanci

  6. Department of Neurology, Yale University School of Medicine, 15 York Street, LCI 1003, New Haven, CT, USA

    Kevin N. Sheth

Authors
  1. David M. Greer
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  2. Jaime Ritter
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  3. Raimund Helbok
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  4. Neeraj Badjatia
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  5. Sang-Bae Ko
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  6. Mary Guanci
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  7. Kevin N. Sheth
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Contributions

The study concept and design were given by DG, KS and JR. Data acquisition and analysis not applicable (protocol manuscript). DG prepared the first draft of the manuscript. Interpretation of the data not applicable (protocol manuscript). All authors provided critical feedback of the manuscript and approved the final version.

Corresponding author

Correspondence to David M. Greer.

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Clinical trial registration

The study is now on version 7.0, last updated March 2020. Recruitment began in March 2017, and recruitment is estimated to be completed by April 2022.

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Greer, D.M., Ritter, J., Helbok, R. et al. Impact of Fever Prevention in Brain-Injured Patients (INTREPID): Study Protocol for a Randomized Controlled Trial. Neurocrit Care 35, 577–589 (2021). https://doi.org/10.1007/s12028-021-01208-1

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  • DOI: https://doi.org/10.1007/s12028-021-01208-1

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