Pitfalls and advances from the international tirilazad trial in moderate and severe head injury.
This manuscript reviews current experience with a large-scale clinical trial of the nonglucocorticoid 21-aminosteroid compound, tirilazad mesylate (U-74,006F). The trial itself now encompasses 15 countries with all central coordination conducted in the Data Coordinating Center at the University of California, San Diego. To date, the conduct of this trial has shown that diverse groups of clinicians in multiple countries have been able to work together to adhere to a tightly defined research protocol. Despite the success in initiating and conducting this trial, however, there have been several unanticipated problems that have complicated its progress. In this regard, difficulties have been associated with the use of mean Glasgow coma scores for data analysis. Similarly, a prospective identification of the risk variables was found necessary to preclude the potential for serious errors in data analysis. Lastly, a differential effect of the drug was noted in women compared to men in the European subarachnoid hemorrhage trial where a significant improvement in outcome was observed in males. This differential response appears to be linked to drug metabolism, but the problem may be further compounded by improper dosing because of failure to weigh many patients. Women appear to be routinely underdosed because their weights are routinely underestimated. Overall, this paper shows the feasibility of conducting such a large scale international trial, while also highlighting some of the potential pitfalls and problems that should be avoided in future trials of this nature.
Marshall
L F
LF
Neurosurgical Services, University of California, San Diego Medical Center 92103-8893, USA.
Marshall
S B
SB
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006259:Craniocerebral Trauma / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D011281:Pregnatrienes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011859:Radiography; D018570:Risk Assessment; D016896:Treatment Outcome
D000975:Antioxidants; D011281:Pregnatrienes; C053355:tirilazad