Neuroprotective effect of gacyclidine. A multicenter double-blind pilot trial in patients with acute traumatic brain injury.
The aim of this study was to assess the safety and efficacy of intravenous (IV) injections of gacyclidine, a novel NMDA receptor antagonist, for neurological and functional recovery following acute traumatic brain injury. This multicenter, prospective, randomized, placebo-controlled, double-blind study compared four parallel groups. Two IV doses were administrated (placebo, 2x0.005mg/kg, 2x0.001mg/kg, 2x0.02mg/kg): the first dose was given within 2 hours following the trauma, and the second dose 4 hours after the first. Fifty-one patients were enrolled and 48 studied between March 1995 and June 1997 in France. Evaluation criteria for safety were physical examination, cardiovascular parameters, blood chemistry, hematology, ECG, and neuropsychological changes monitored after medication. Primary evaluation criteria for efficacy was the Glasgow coma scale complemented by the initial CT-scan and Glasgow outcome scale, motor deficiencies, neuropsychological changes, and functional indenpendence at D90 and D365 or endpoint. Intracranial pressure (ICP) monitoring was not taken into account because all the clinical centers participating in this study did not use this technique in daily practice during the inclusion period. Twelve patients died during the follow-up period, none of these deaths being related to the drug. Serious adverse events (181) were reported by most of the patients with no significant differences between groups. Only 10 of these adverse events were considered to be drug-related. Safety-related laboratory tests did not show any relevant changes. Concerning efficacy, the predefined prognostic factors (initial CT-scan score, initial Glasgow Coma Scale and occurrence of low systolic blood pressure during the first 24 hours) largely determinated the patient's outcome. When the prognostic factors were taken into account together with the dose level in a logistic regression model, gacyclidine showed a beneficial long-term effect and a best dose-result in the 0.04mg/kg treated group. Data obtained in this clinical trial appeared sufficient to warrant a European multicenter study on gacyclidine using the same evaluation criteria and ICP monitoring.
Lepeintre
J-F
JF
Service de Neurochirurgie, CHU de Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France. jf.lepeintre@bct.ap-hop-paris.fr
D'Arbigny
P
P
Mathé
J-F
JF
Vigué
B
B
Loubert
G
G
Delcour
J
J
Kempf
C
C
Tadié
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy*; D003510:Cyclohexanes / Q000009:adverse effects / Q000627:therapeutic use*; D053138:Cyclohexenes; D004311:Double-Blind Method; D004562:Electrocardiography; D023381:Endpoint Determination; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007427:Intracranial Pressure; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D010808:Physical Examination; D010865:Pilot Projects; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D003510:Cyclohexanes; D053138:Cyclohexenes; D018696:Neuroprotective Agents; D010880:Piperidines; C070707:gacyclidine