Clinical trial NCT03375034: Exploring the Role of the GABAergic Modulation in Pain Transmission in Human
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuropathic Pain
Keywords: Chronic pain
Benzodiazepine
Central sensitization
Selective compound
GABAA receptors
Antihyperalgesia
RCT
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2017-12-15
Enrollment: 56
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Change in the area of secondary hyperalgesia from baseline
timeFrame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
Secondary outcomes:
measure: Change in static mechanical pain threshold (SMPT) from baseline
timeFrame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
measure: Change in dynamic mechanical sensory VAS (DMSV) from baseline
timeFrame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
measure: Change in subjective feeling of sedation from baseline
timeFrame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
measure: Change in memory test score from baseline
timeFrame: Hour 4 and Hour 10 following drug administration
measure: Change in AUC of N-desmethylclobazam from Baseline following administration of single dose (20mg, 40mg and 60mg) of N-desmethylclobazam
timeFrame: Hour 0.5, Hour 1, Hour 2, Hour 4, Hour 6, Hour 8, Hour 10, Hour 12, Hour 24, Hour 32, DAY 3, DAY 4, DAY 5, DAY 6, DAY 7, DAY 8, DAY 9, DAY 10, DAY 14 following drug administration
measure: Change in AUC of N-desmethylclobazam from Baseline following administration of repeated doses (20mg) of N-desmethylclobazam
timeFrame: Hour 0.5, Hour 1, Hour 2, Hour 4, Hour 6, Hour 8, Hour 10, Hour 12, Hour 24 following drug administration
Other outcomes:
Locations:
city: Geneva
country: Switzerland
facility: UGeneva
Study officials:
References: