The results of the INTREPID trial, led by Dr. David Greer, Professor and Chair at Boston University, were announced August 16, 2023 in the Clinical Trials session at the Neurocritical Care Society meeting in Phoenix, Arizona. 

The INTREPID (Impact of Fever Prevention in Brain Injured Patients) trial, an international multicenter randomized controlled clinical trial, compared standard “reaction to fever” management to “surface cooling to prevent fever” with target temperature 37 degrees Celsius, using the Becton-Dickinson Corporation’s Arctic Sun 5000 device.

Each year, millions of people suffer from strokes secondary to ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage. Unfortunately, 31% of people who suffer from strokes are below 65 years of age and a third are discharged to skilled nursing facilities. Fever can cause secondary brain injury as a result of increased inflammatory responses which increase cerebral metabolism. It is not known whether preventing fever from occurring is beneficial or not. This was the premise of the INTREPID trial.

The trial planned to enroll 1176 patients with one of 3 diagnoses of stroke (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage).  Unfortunately, the trial was stopped at the interim analysis for futility of the principal secondary outcome.

The primary outcome was the daily average fever burden, defined as the area under the temperature curve above 37.9˚C. The secondary outcomes were functional outcome, principally the 90-day modified Rankin scale (mRS), but included other functional outcome scales (GOS-E, NIHSS, Barthel Index, MOCA) as well as mortality, ICU and hospital length of stay and major adverse events, infection and shivering. 

The trial included 30 US sites, 10 international sites and ran from March 2017 through 2021.  Participants included adults functionally independent prior to onset.  Exclusions included both poor likelihood of survival to 6 months as well as poor likelihood of being in the ICU for > 72 hours.  Participants were enrolled prior to fever onset but were allowed one instance of fever prior to enrollment.  The study intervention was permitted for up to 14 days but was stopped at ICU discharge.

The intention to treat analysis included 677 patients of whom 433 completed the study.  The proportion of subjects in the 3 diagnostic groups was approximately one third in each, and patient severity was high with median NIHSS of 17.

The primary outcome was met with patients in the fever prevention arm having a significantly lower fever burden than patients in the standard care arm (relative risk of positive fever burden 0.73; 95% confidence interval 0.65,0.82; P<0.0001).  Daily average fever burden was also significantly lower in the fever prevention group overall and in each disease category, as was the total fever duration in hours.

Functional outcomes, using a dichotomized mRS 0-3 (vs 4-6) was not different between treatment groups at 3, 6 or 12 months either overall or by disease subgroup. Other secondary functional outcomes did not show significant differences between groups including mortality.  There were similarly no differences in number of days with delirium, days on ventilator, ICU or hospital stay.

Fortunately, adverse events did not differ between groups including pneumonia and other infections.  Shivering incidence was not unexpectedly greater in the fever prevention group but was well managed in the trial.

INTREPID demonstrated safety and feasibility of fever prevention after acute vascular brain injury although a beneficial effect on outcome remains to be found.  Important considerations for future studies according to Dr. Greer include patient selection, duration of therapy and management of shivering.

Dr. Greer recognized the INTREPID Steering Committee which included Kevin Sheth, MD (co-PI), Neeraj Badjatia, MD, Mary Guanci, MD, Raimund Helbok, MD, and Sang-Bae KO, MD.

For more information on the INTREPID trial, please visit: https://clinicaltrials.gov/ct2/show/NCT02996266