title: A clinical trial of progesterone for severe traumatic brain injury.
abstract: BACKGROUND
  Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial.
  
  
  METHODS
  We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury.
  
  
  RESULTS
  Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo.
  
  
  CONCLUSIONS
  Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).
authors.affiliation: From the Department of Neurosurgery, Cushing Neuroscience Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY (B.E.S., R.K.N.); the Department of Neurosurgery, University Hospital Antwerp and University of Antwerp, Edegem, Belgium (A.I.M.); BHR Pharma, Herndon (R.G.H., T.M., N.R.N.), and the Department of Neurosurgery, Virginia Commonwealth University, Richmond (J.D.W.) - both in Virginia; and the Department of Physiopathology and Transplantation, Milan University and Neuro Intensive Care Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Cà Granda Ospedale Maggiore Policlinico, Milan (N.S.).
authors.forename: Brett E
authors.initials: BE
authors.lastname: Skolnick
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Maas
authors.forename: Raj K
authors.initials: RK
authors.lastname: Narayan
authors.forename: Roland Gerritsen
authors.initials: RG
authors.lastname: van der Hoop
authors.forename: Thomas
authors.initials: T
authors.lastname: MacAllister
authors.forename: John D
authors.initials: JD
authors.lastname: Ward
authors.forename: Neta R
authors.initials: NR
authors.lastname: Nelson
authors.forename: Nino
authors.initials: N
authors.lastname: Stocchetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001930:Brain Injuries / Q000188:drug therapy*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015600:Glasgow Coma Scale; D023261:Glasgow Outcome Scale; D006801:Humans; D007262:Infusions, Intravenous; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011374:Progesterone / Q000008:administration & dosage* / Q000009:adverse effects; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D011374:Progesterone