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

Raimund Firsching; Jürgen Piek; Martin Skalej; Veit Rohde; Uwe Schmidt; Frank Striggow; the KN38-7271 Study Group

doi:10.1055/s-0032-1304815

Journal of Neurological Surgery Part A: Central European Neurosurgery, Table of Contents

J Neurol Surg A Cent Eur Neurosurg 2012; 73(04): 204-216
DOI: 10.1055/s-0032-1304815

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Raimund Firsching

¹Klinik für Neurochirurgie, Universitätsklinikum, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany

,

Jürgen Piek

²Abteilung für Neurochirurgie, Chirurgische Universitätsklinik Rostock, Rostock, Germany

,

Martin Skalej

³Zentrum für Radiologie, Institut für Neuroradiologie, Universitätsklinikum, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany

,

Veit Rohde

⁴Klinik und Poliklinik für Neurochirurgie, Georg-August-Universität Göttingen, Göttingen, Germany

,

Uwe Schmidt

⁵Biometrie, StatConsult Gesellschaft für klinische und Versorgungsforschung mbH, Magdeburg, Germany

,

Frank Striggow

⁶KeyNeurotek Pharmaceuticals Ag, Magdeburg, Germany

⁷Arbeitsgruppe Neurodegeneration und Interventionsstrategien, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Magdeburg, Germany

,

the KN38-7271 Study Group

› Author Affiliations

Abstract

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.

Patients and 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.

Keywords

traumatic brain injury - severe head trauma - cannabinoids - cannabinoid receptor agonist

Full Text

References

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Supplementary Material

Complete Inclusion Criteria