UNLABELLED: 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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
RCT Entities:
UNLABELLED: 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 comatosepatients 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 comatosepatient 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. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Authors: Patricia B de la Tremblaye; Darik A O'Neil; Megan J LaPorte; Jeffrey P Cheng; Joshua A Beitchman; Theresa Currier Thomas; Corina O Bondi; Anthony E Kline Journal: Neurosci Biobehav Rev Date: 2017-05-30 Impact factor: 8.989
Authors: Anton Reiner; Scott A Heldt; Chaela S Presley; Natalie H Guley; Andrea J Elberger; Yunping Deng; Lauren D'Surney; Joshua T Rogers; Jessica Ferrell; Wei Bu; Nobel Del Mar; Marcia G Honig; Steven N Gurley; Bob M Moore Journal: Int J Mol Sci Date: 2014-12-31 Impact factor: 5.923
Authors: Wei Bu; Huiling Ren; Yunping Deng; Nobel Del Mar; Natalie M Guley; Bob M Moore; Marcia G Honig; Anton Reiner Journal: Front Neurosci Date: 2016-10-06 Impact factor: 4.677
Authors: Alexandra Vogel; Annett Wilken-Schmitz; Regina Hummel; Manuel Lang; Robert Gurke; Yannick Schreiber; Michael K E Schäfer; Irmgard Tegeder Journal: Sci Rep Date: 2020-09-10 Impact factor: 4.379