TBI: Trials and Tribulations

March is Brain Injury Awareness Month in the United States, with this Wednesday set aside as Brain Injury Awareness Day by a US Congressional Brain Injury Task Force. (1)

In the United States, more than 2.5 million emergency department visits, hospitalisations, or deaths are associated with TBI each year. There is still no approved treatment for either severe or mild TBI (concussion) and recently released results of three large TBI studies have failed to offer any new solutions.

Results of two separate large clinical trials of progesterone in the treatment of TBI were published in the New England Journal of Medicine in December. The SyNAPse trial enrolled its projected number of 1180 patients with severe TBI across 21 countries. The trial was a failure, with progesterone showing no clinical benefit over placebo. (2) In the second trial, ProTECT 111, a total of 882 of the planned sample of 1140 patients underwent randomisation before the trial was stopped for futility with respect to the primary outcome. (3)  The NEJM editor pointed to problematic aspects of the Phase II Trials that preceded both trials, including modest effect sizes and better-than expected outcomes in the placebo group. (4) The researchers involved in the failed ProTECT 111 trial reflected

The ProTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI. To date, more than 30 clinical trials have investigated various compounds for the treatment of acute TBI, yet no treatment has succeeded at the confirmatory trial stage. Many reasons for the disappointing record of translating promising agents from the laboratory to the clinic have been postulated, including limited preclinical development work, poor drug penetration into the brain, delayed initiation of treatment, heterogeneity of injuries, variability in routine patient care across sites, and insensitive outcome measures. (4)


In the following month, researchers published the results of a 3 year retrospective study of the records of patients admitted to a trauma center with TBI. A common treatment to prevent progression of "traumatic intracranial haemorrhage" has been the transfusion of platelets and the administration of desmopressin, a naturally occurring hormone used to treat bleeding. The researchers compared the outcomes for the patients who received platelet transfusions and desmopressin and the patients who did not receive the therapies. Their comparison found no significant differences in mortality or haemorrhage progression between the two groups.(5)

There is a further, large Phase 3 TBI trial due to announce its results mid-year. The Australian study has been trialing one of Lance Armstrong’s favourite therapies, the red blood cell promoting hormone, erythropoietin (EPO). The prospective, multi-centre, randomised, double-blind, placebo-controlled, 600-patient, Phase 3 trial has been conducted in intensive care unit patients with moderate or severe TBI to determine whether EPO improves neurological function 6 months after injury. (6)

Perhaps not too long after, Neuren will announce its TBI clinical trial results. Neuren’s Phase 2 trial of NNZ-2566 (trofinetide) in moderate to severe TBI has an estimated August study completion date, while the study of NNZ-2566 in mild TBI is expected to be completed in October.

(1) http://www.biausa.org/brain-injury-awareness-month.htm

(2) http://www.nejm.org/doi/full/10.1056/NEJMoa1411090

(3) http://www.nejm.org/doi/full/10.1056/NEJMoa1404304

(4) http://neurocritic.blogspot.com.au/2015/01/the-futility-of-progesterone-for.html

(5) http://medicalxpress.com/news/2015-01-traumatic-brain-injury-treatment-ineffective.html

(6) https://clinicaltrials.gov/ct2/show/NCT00987454