title: The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.
abstract: 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 During the course of the trial, funding was withdrawn by the sponsor.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.
authors: Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. haleema.shakur@lshtm.ac.uk
authors: Haleema
authors: H
authors: Shakur
authors: Peter
authors: P
authors: Andrews
authors: Toomas
authors: T
authors: Asser
authors: Laura
authors: L
authors: Balica
authors: Cristian
authors: C
authors: Boeriu
authors: Juan Diego Ciro
authors: JD
authors: Quintero
authors: Yashbir
authors: Y
authors: Dewan
authors: Patrick
authors: P
authors: Druwé
authors: Olivia
authors: O
authors: Fletcher
authors: Chris
authors: C
authors: Frost
authors: Bennie
authors: B
authors: Hartzenberg
authors: Jorge Mejia
authors: JM
authors: Mantilla
authors: Francisco
authors: F
authors: Murillo-Cabezas
authors: Jan
authors: J
authors: Pachl
authors: Ramalingam R
authors: RR
authors: Ravi
authors: Indrek
authors: I
authors: Rätsep
authors: Cristina
authors: C
authors: Sampaio
authors: Manmohan
authors: M
authors: Singh
authors: Petr
authors: P
authors: Svoboda
authors: Ian
authors: I
authors: Roberts
mesh_terms: 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
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D018836:Inflammation Mediators; C403051:LF 16-0687; D011804:Quinolines