TY - JOUR
T1 - Scientific and logistical challenges in designing the CONTROL trial
T2 - recombinant factor VIIa in severe trauma patients with refractory bleeding
AU - Dutton, Richard
AU - Hauser, Carl
AU - Boffard, Kenneth D.
AU - Dimsitts, Jeannett
AU - Bernard, Gordon
AU - Holcomb, John
AU - Leppäniemi, Ari K.
AU - Tortella, Bartholemew
AU - Bouillon, Bertil
AU - CONTROL Steering Committee
AU - Croce, Martin A.
AU - Vincent, Jean Louis
AU - Parr, Michael
PY - 2009/11/16
Y1 - 2009/11/16
N2 - 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. Purpose: 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. Limitations 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. Conclusion: 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.
AB - 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. Purpose: 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. Limitations 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. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=71049192309&partnerID=8YFLogxK
U2 - 10.1177/1740774509344102
DO - 10.1177/1740774509344102
M3 - Article
C2 - 19737846
AN - SCOPUS:71049192309
SN - 1740-7745
VL - 6
SP - 467
EP - 479
JO - Clinical Trials
JF - Clinical Trials
IS - 5
ER -