Early survival of comatose patients after severe traumatic brain injury with the dual cannabinoid CB1/CB2 receptor agonist KN38-7271: a randomized, double-blind, placebo-controlled phase II trial.
BACKGROUND AND STUDY OBJECT: Despite many drug trials, no substance has yet been identified that improves the outcome of severe head injury. The dual cannabinoid CB1/CB2 receptor agonist KN38-7271 mediates potent neuroprotection in animal models. We describe here the first randomized, double-blind, prospective, placebo-controlled clinical phase IIa proof-of-concept trial to investigate the safety, pharmacokinetics, and potential efficacy of a cannabinoid receptor agonist in humans.


METHODS
Out of the 439, 97 comatose patients at 14 European neurosurgical centers met the inclusion criteria. KN38-7271 was administered within 4.5 hours of the injury, and the patients received 1000, 500 μg, or placebo. The primary analysis was pharmacokinetic; efficacy was measured by survival and by neurological improvement or deterioration 7 and 14 days and 1, 3, and 6 months after the injury. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were analyzed from start of treatment to end of day 7.


RESULTS
Survival rates within 1 month of the injury were significantly better in the treatment groups than in the placebo group (high-dose, Kaplan-Meier difference on day 30 + 0.12 with p = 0.043; low-dose, difference +0.15 with p = 0.011) but this effect was not seen after 6 months. Critical ICP and CPP were less extreme and less frequent in the treatment group. There were no severe and no serious adverse effects that could be attributed to KN38-7271.


CONCLUSIONS
KN38-7271 appeared beneficial in the acute early phase of the comatose patient after a head injury. Its use was safe and well tolerated by patients. These results may provide the basis for further phase II/III trials in larger study populations.
Klinik für Neurochirurgie, Universitätsklinikum, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany. raimund.firsching@med.ovgu.de
Raimund
R
Firsching
Jürgen
J
Piek
Martin
M
Skalej
Veit
V
Rohde
Uwe
U
Schmidt
Frank
F
Striggow
D000293:Adolescent; D000328:Adult; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D003128:Coma / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007189:Indans / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009460:Neurologic Examination; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012025:Reflex, Pupillary; D013451:Sulfonic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013534:Survival; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult
C459384:3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate; D007189:Indans; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013451:Sulfonic Acids