title: Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding.
abstract: BACKGROUND
  Clinical research in trauma patients poses multiple challenges in study design. These reflect the heterogeneity of injury and treatment, the paucity of acceptable study endpoints aside from mortality, and the difficulties inherent in obtaining informed consent in acutely ill populations. A current example of this problem is the study of recombinant factor VIIa (rFVIIa), which has attracted considerable interest as a systemic procoagulant agent for use in trauma patients with exsanguinating hemorrhage.
  
  
  OBJECTIVE
  To report on the implementation of an international trial - CONTROL - intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience.
  
  
  METHODS
  The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in an acutely injured population with altered levels of consciousness, (3) avoiding futile care, while recruiting subjects with incompletely diagnosed injuries, (4) standardizing trauma intensive care across different investigating sites and countries, and (5) establishing study endpoints that were both clinically relevant and convincing to regulatory authorities. The resulting study methodology is reported.
  
  
  RESULTS
  The CONTROL trial began active recruitment in October 2005, and was halted on June 11, 2008 because the observed mortality in the 576 enrolled patients was so far below expectations that the study would lack sufficient statistical power at the planned number of subjects to demonstrate a benefit. The utility of the endpoints selected for study will not be known until completion of data analysis.
  
  
  CONCLUSIONS
  Any clinical trial in trauma patients must cope with the urgency of care required, issues of patient heterogeneity, standardization of care across multiple centers, and the difficulties of obtaining informed consent.
  
  
  CONCLUSIONS
  Research in acutely hemorrhaging trauma patients presents numerous scientific and ethical challenges. The methodology of the CONTROL study is presented as an example of how some of these challenges can be approached and managed, and of the pitfalls that may arise.
authors.affiliation: Division of Trauma Anesthesiology, University of Maryland, USA. rdutton@anes.umm.edu
authors.forename: Richard
authors.initials: R
authors.lastname: Dutton
authors.forename: Carl
authors.initials: C
authors.lastname: Hauser
authors.forename: Kenneth
authors.initials: K
authors.lastname: Boffard
authors.forename: Jeannett
authors.initials: J
authors.lastname: Dimsitts
authors.forename: Gordon
authors.initials: G
authors.lastname: Bernard
authors.forename: John
authors.initials: J
authors.lastname: Holcomb
authors.forename: Ari
authors.initials: A
authors.lastname: Leppäniemi
authors.forename: Bartholemew
authors.initials: B
authors.lastname: Tortella
authors.forename: Bertil
authors.initials: B
authors.lastname: Bouillon
mesh_terms: D015942:Factor VIIa / Q000627:therapeutic use*; D019983:Guideline Adherence; D006470:Hemorrhage / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007258:Informed Consent; D015337:Multicenter Studies as Topic; D017063:Outcome Assessment, Health Care; D018579:Patient Selection; D017410:Practice Guidelines as Topic; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012107:Research Design; D013997:Time Factors; D014947:Wounds and Injuries / Q000145:classification / Q000188:drug therapy* / Q000401:mortality
chemical_list: D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa