Exploring the Role of the GABAergic Modulation in Pain Transmission in Human (NDMC-101)

Jules Desmeules

Status and phase: Completed; Phase 1

Conditions: Neuropathic Pain

Treatments: Drug: NDMC 20mg; Drug: NDMC60mg; Drug: Placebo; Drug: Clonazepam 1.5mg

Study type: Interventional

Funder types: Other

Identifiers

NCT03375034

PB_2016-02140

Details and patient eligibility

About

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.

Enrollment: 56 patients

Sex: Male

Ages: 18 to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Male subject, age between 18 and 50 years old
• Caucasian
• Type 3 skin phototype (white skin that can tan gradually and burns moderately)
• Non smoker or moderate smoker (< 10 cigarettes/day)
• No clinically abnormal findings on history and/or on physical examination
• Positive minimal erythema dose (MED) determination

Exclusion criteria

• Any active significant illness
• Current or past history of drug and alcohol abuse or current intake of more than 3 glasses of alcohol a day or more than 21 glasses of alcohol per week
• Psychotropic drug intake during the last month
• Sun allergy or any skin disease
• Any regular drug intake
• CYP2C19 poor metabolizer (phenotype)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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56 participants in 4 patient groups, including a placebo group

NDMC 20mg

Experimental group

Description:

oral single dose

Treatment:

Drug: NDMC 20mg

NDMC 60mg

Experimental group

Description:

oral single dose

Treatment:

Drug: NDMC60mg

Clonazepam 1.5mg

Active Comparator group

Description:

oral single dose

Treatment:

Drug: Clonazepam 1.5mg

Placebo

Placebo Comparator group

Description:

oral single dose

Treatment:

Drug: Placebo