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

NCT03375034 | Completed Phase 1

• 1 other identifier: PB_2016-02140
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuropathic Pain

Keywords

Chronic pain; Benzodiazepine; Central sensitization; Selective compound; GABAA receptors; Antihyperalgesia; RCT

Outcome Measures

Primary Outcomes (1)

• Change in the area of secondary hyperalgesia from baseline

  The mapping of the area of secondary hyperalgesia is determined by pricking the skin surrounding the erythema with a hand-held von Frey filament (235 mN), normally felt as non-painful. The punctuated probe is moved along the 8 radial lines defined by the center (erythema) and the corners of a regular octagon. Testing starts outside the hyperalgesic area and the probe is moved towards the center in steps of 5 mm. The position is marked where the pin-prick sensation changes to become painful. Once complete boundaries had been defined, the areas are transcribed onto clear film and weighed. The surface area will then be calculated based on a standard measure of the weight of an area of 100cm2.

  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 (6)

• Change in static mechanical pain threshold (SMPT) from baseline

  Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration

• Change in dynamic mechanical sensory VAS (DMSV) from baseline

  Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration

• Change in subjective feeling of sedation from baseline

  Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration

• Change in memory test score from baseline

  Hour 4 and Hour 10 following drug administration

• Change in AUC of N-desmethylclobazam from Baseline following administration of single dose (20mg, 40mg and 60mg) of N-desmethylclobazam

  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

Study Arms (4)

NDMC 20mg

EXPERIMENTAL

oral single dose

Drug: NDMC 20mg

NDMC 60mg

EXPERIMENTAL

oral single dose

Drug: NDMC60mg

Clonazepam 1.5mg

ACTIVE COMPARATOR

oral single dose

Drug: Clonazepam 1.5mg

Placebo

PLACEBO COMPARATOR

oral single dose

Drug: Placebo

Interventions

NDMC 20mg DRUG

Oral administration of one NDMC 20mg capsule and two Placebo capsules

NDMC 20mg

NDMC60mg DRUG

Oral administration of three NDMC 20mg capsules

NDMC 60mg

Clonazepam 1.5mg DRUG

Oral administration of three clonazepam 0.5mg capsules

Clonazepam 1.5mg

Placebo DRUG

Oral administration of three Placebo capsules

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Jules Desmeules: lead

Study Sites (1)

UGeneva

Geneva, 1211, Switzerland

Location

MeSH Terms

Conditions

Neuralgia; Chronic Pain

Interventions

Clonazepam

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: September 8, 2017
• First Posted: December 15, 2017
• Study Start: March 30, 2017
• Primary Completion: December 28, 2017
• Study Completion: January 31, 2018
• Last Updated: April 19, 2019

Record last verified: 2019-04

Locations

CH (1)