The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.
BACKGROUND
Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor.


METHODS
Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS).


RESULTS
228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures.


CONCLUSIONS
This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness.


BACKGROUND
This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128.
Shakur
Haleema
H
Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. haleema.shakur@lshtm.ac.uk
Andrews
Peter
P
Asser
Toomas
T
Balica
Laura
L
Boeriu
Cristian
C
Quintero
Juan Diego Ciro
JD
Dewan
Yashbir
Y
Druwé
Patrick
P
Fletcher
Olivia
O
Frost
Chris
C
Hartzenberg
Bennie
B
Mantilla
Jorge Mejia
JM
Murillo-Cabezas
Francisco
F
Pachl
Jan
J
Ravi
Ramalingam R
RR
Rätsep
Indrek
I
Sampaio
Cristina
C
Singh
Manmohan
M
Svoboda
Petr
P
Roberts
Ian
I
D000328:Adult; D065094:Bradykinin B2 Receptor Antagonists; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D015600:Glasgow Coma Scale; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000009:adverse effects; D009017:Morbidity; D015990:Placebo Effect; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors
D065094:Bradykinin B2 Receptor Antagonists; D018836:Inflammation Mediators; C403051:LF 16-0687; D011804:Quinolines