Impact of Fever Prevention in Brain Injured Patients (INTREPID)

This study will assess the impact of fever prevention on fever burden and short- and long-term neurologic outcomes in brain injured patients. Half of the subjects will undergo fever prevention using a targeted temperature management system and half of the subjects will be treated for fever should it develop.

Study Overview

• Status: Terminated
• Conditions: Ischemic Stroke; Fever; Subarachnoid Hemorrhage; Intracerebral Hemorrhage
• Intervention / Treatment: Device: Targeted Temperature Management; Other: Standard Care

Detailed Description

Multiple studies demonstrate that fever / elevated temperature is associated with poor outcomes in brain injured patients; however, there are no conclusive studies that demonstrate that fever prevention/controlled normothermia is associated with better outcomes. This study will be conducted to assess the impact of advanced temperature control to prevent fever in brain injured patients. The fever prevention group will use the Arctic Sun Temperature Management System and will be compared to standard care patients in whom fever may spontaneously develop. If fever develops in a patient in the standard care group, they will be treated with standard fever care measures according to a step-wise algorithm, consisting primarily of intermittent antipyretics (e.g., acetaminophen) and cooling blankets and, when necessary, advanced targeted temperature management devices.

• Study Type: Interventional
• Enrollment (Actual): 686
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
• Austria
  • Innsbruck, Austria, A-6020
    • Medizinische Universität Innsbruck
• Germany
  • Berlin, Germany, D-10117
    • Charité - Universitätsmedizin Berlin
  • Dresden, Germany, 01062
    • Technische Universität Dresden
  • Jena, Germany, 07747
    • Universitätsklinikum Jena
  • Munich, Germany, 81377
    • LMU München, Klinikum Großhadern
• Korea, Republic of
  • Daegu, Korea, Republic of
    • Keimyung University Dongsan Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University Bundang Hospital
• Switzerland
  • Zürich, Switzerland, 8091
    • UniversitätsSpital Zürich
• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Palo Alto, California, United States, 94304
      • Stanford University Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Englewood, Colorado, United States, 80113
      • Swedish Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University
  • Kentucky
    • Louisville, Kentucky, United States, 40241
      • Norton Neuroscience Institute
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Worcester
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49506
      • Spectrum Health Hospitals
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • The University of New Mexico Health Science Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10032
      • Columbia University, New York - Presbyterian Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97225
      • Providence St Vincent Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Erlanger Health System Baroness Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Admitted with a primary neurological diagnosis of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage
2. Prior to onset of acute symptoms, was considered functionally independent (mRS 0-2)
3. Meets disease-specific criteria

Exclusion Criteria:

1. Fever (≥38°C) prior to study enrollment
2. Pre-existing neurological, psychiatric, or other condition that would confound neurological assessment or would make it difficult to accurately assess neurologic and/or functional outcome
3. Has a pre-morbid condition with poor likelihood of survival to 6 months
4. Has a pre-morbid mRS ≥3
5. Diagnosed with brain death
6. Is undergoing therapeutic hypothermia therapy
7. Has sustained neurological injury felt to be catastrophic with little chance of recovery
8. Has a skin condition in which the use of the ArcticGel Pads is contraindicated (i.e., skin that has signs of ulceration, burns, hives, or rash)
9. Has poor skin integrity or poor tissue perfusion
10. Participation in a concurrent investigational / interventional study (medical device or drug)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fever Prevention; Fever will be prevented using a surface targeted temperature management system	Device: Targeted Temperature Management; Prophylactic normothermia; Other Names: Arctic Sun 5000 Temperature Management System
Active Comparator: Standard Care; Standard care in which fever may spontaneously develop	Other: Standard Care; No intervention to control temperature unless fever occurs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fever Burden	Daily average fever burden (°C-hour)	Up to 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	An untoward medical occurrence, unintended disease or injury, or unanticipated complication	From date of randomization until hospital discharge, assessed up to 30 days
Primary Neurologic Outcome: Modified Rankin Scale Short-Term	Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.	3-months post injury
Other Neurologic Outcomes: NIH Stroke Scale Short-Term	NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome.	3-months post injury
Other Neurologic Outcomes: Barthel Index Short-Term	Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome.	3-months post injury
Other Neurologic Outcomes: Glasgow Outcome Scale Extended Short-Term	Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome.	3-months post injury
Other Neurologic Outcomes: Montreal Cognitive Assessment Short-Term	Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome.	3-months post injury
Primary Neurologic Outcome: Modified Rankin Scale Mid-Term	Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.	6-months post injury
Other Neurologic Outcomes: NIH Stroke Scale Mid-Term	NIH Stroke Scale is a systematic, quantitative assessment tool to measure stroke-related neurological deficit. Scores range from 0 to 42, with higher scores indicating worse outcome.	6-months post injury
Other Neurologic Outcomes: Barthel Index Mid-Term	Barthel Index is an assessment of functional independence. Scores range from 0 to 100, with lower scores indicating worse outcome.	6-months post injury
Other Neurologic Outcomes: Glasgow Outcome Scale Extended Mid-Term	Glasgow Outcome Scale assesses functional outcome after acute brain injury. Scores range from 1-8, with lower scores indicating worse outcome.	6-months post injury
Other Neurologic Outcomes: Montreal Cognitive Assessment Mid-Term	Montreal Cognitive Assessment assesses for cognitive impairment. Scores range from 0-30, with lower scores indicating worse outcome.	6-months post injury
Primary Neurologic Outcome: Modified Rankin Scale Long-Term	Modified Rankin Scale is a 6-category outcome measurement with 0 = no limitations, no symptoms and 6 = death.	12-months post injury
Major Adverse Events	MAEs defined as one of the following: pneumonia, sepsis, malignant cerebral edema, death	From date of randomization until end of study, assessed up to 12 months
Number of Participants With Infection	Healthcare associated infection	From date of randomization until hospital discharge, assessed up to 30 days
Number of Subjects With Shivering	Shivering greater than or equal to 1 on the Bedside Shivering Assessment Scale (BSAS). BSAS scores range from 0-3 with 0 indicating no shivering noted and 3 indicating severe shivering involving gross movements of the trunk and upper and lower extremities.	Up to 14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality	7-day (or hospital discharge); 3-, 6-, and 12-months
Hospital Length of Stay	Overall hospitalization duration	From date of randomization until hospital discharge, assessed up to 90 days
ICU Length of Stay	ICU Duration	From date of randomization until ICU discharge

Collaborators and Investigators

• Sponsor: C. R. Bard
• Collaborators: Boston University; Yale University
• Investigators: Principal Investigator: David M. Greer, MD, MA, Boston University; Principal Investigator: Kevin N. Sheth, MD, Yale University

Publications and helpful links

General Publications

• Greer DM, Ritter J, Helbok R, Badjatia N, Ko SB, Guanci M, Sheth KN. Impact of Fever Prevention in Brain-Injured Patients (INTREPID): Study Protocol for a Randomized Controlled Trial. Neurocrit Care. 2021 Oct;35(2):577-589. doi: 10.1007/s12028-021-01208-1. Epub 2021 Mar 24.
• Cronberg T, Greer DM, Lilja G, Moulaert V, Swindell P, Rossetti AO. Brain injury after cardiac arrest: from prognostication of comatose patients to rehabilitation. Lancet Neurol. 2020 Jul;19(7):611-622. doi: 10.1016/S1474-4422(20)30117-4.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): May 12, 2022
• Study Completion (Actual): May 12, 2022

Study Registration Dates

• First Submitted: December 5, 2016
• First Submitted That Met QC Criteria: December 14, 2016
• First Posted (Estimated): December 19, 2016

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Targeted Temperature Management
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Body Temperature Changes; Intracranial Hemorrhages; Ischemic Stroke; Hemorrhage; Fever; Subarachnoid Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: BMD-1111

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO