NCT03375034

Exploring the Role of the GABAergic Modulation in Pain Transmission in Human

Exploring the Role of the GABAergic Modulation in Pain Transmission in Human. Effects of the GABAA Agonist N-desmethylclobazam on Central Sensitization: a Pharmacodynamic and Pharmacokinetic Study in Healthy Volunteers

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 56 (actual)
• Sponsor: Jules Desmeules · Academic / Other
• Sex: Male
• Age: 18 Years – 50 Years
• Healthy volunteers: Accepted

Summary

Neuropathic pain affects about 7% of the general population in European countries. Meta-analyses indicate that only a minority of neuropathic pain patients has adequate response to drug therapy and management of neuropathic pain is still an unmet medical need. New insights into the contribution of defined subtypes of GABAA receptors (GABAARs) to the different clinical effects of benzodiazepines, including analgesia, have suggested that α1-sparing selective benzodiazepines, such as N-desmethylclobazam (NDMC), may be a new realistic alternative for the treatment of neuropathic pain. Results from our previous study in healthy volunteers assessing the antihyperalgesic and sedative effects of benzodiazepines on a UVB-induced pain model of central sensitization showed that, at the time of maximum effect, clobazam and clonazepam antihyperalgesic effect was greater than placebo by respectively 15.7% (95% CI 0.8 - 30.5) and 28.6% (95% CI 4.5 - 52.6), p\<0.05. Moreover difference in sedation (VAS), as compared to placebo, was only significant for clonazepam 26.3mm (95%CI 15.0-37.7), p\<0.001. Our preclinical data also demonstrate that, in recombinant receptors, NDMC has a better α2- over α1GABAARs activity ratio than clobazam and diazepam. And, unlike diazepam, NDMC caused no or modest sedation at antihyperalgesic doses in two strains of wild-type mice. In addition NDMC α2/α1 in vitro activity profile and long term clinical experience from its marketed parent compound (clobazam) make it an advisable clinical candidate for further proof-of-concept assessments in human. Therefore the Geneva University Hospitals have manufactured a new chemical entity and initiated a drug development program for NDMC starting with this proof-of-concept phase 1b randomized double-blind crossover (4 arms) study that will assess the analgesic and sedative effects of NDMC 20mg and 60mg compared to clonazepam 1.5 mg or placebo on a UVB-induced erythema pain model in healthy volunteers.

Conditions

• Neuropathic Pain

Interventions

Type	Name	Description
DRUG	NDMC 20mg	Oral administration of one NDMC 20mg capsule and two Placebo capsules
DRUG	NDMC60mg	Oral administration of three NDMC 20mg capsules
DRUG	Clonazepam 1.5mg	Oral administration of three clonazepam 0.5mg capsules
DRUG	Placebo	Oral administration of three Placebo capsules

Timeline

• Start date: 2017-03-30
• Primary completion: 2017-12-28
• Completion: 2018-01-31
• First posted: 2017-12-15
• Last updated: 2019-04-19

Locations

1 site across 1 country: Switzerland