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

April 18, 2019 updated by: Jules Desmeules

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

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

56

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: NDMC 20mg
oral single dose
Oral administration of one NDMC 20mg capsule and two Placebo capsules
EXPERIMENTAL: NDMC 60mg
oral single dose
Oral administration of three NDMC 20mg capsules
ACTIVE_COMPARATOR: Clonazepam 1.5mg
oral single dose
Oral administration of three clonazepam 0.5mg capsules
PLACEBO_COMPARATOR: Placebo
oral single dose
Oral administration of three Placebo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the area of secondary hyperalgesia from baseline
Time Frame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in static mechanical pain threshold (SMPT) from baseline
Time Frame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
Increasing pressure will be manually delivered at a constant rate of 10 g / sec with a von Frey electronic device (Bioseb, Id-Tech Bioseb, Chaville, France). SMPT is defined as the lowest pressure that produces a sensation of pain. This threshold will be determined at DAY1 before UVB exposition and at DAY2 on the primary area of hyperalgesia prior to the administration of the study drug to document hyperalgesia/allodynia.
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
Time Frame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
Dynamic mechanical sensory is a good correlate of central sensitization and will be determined by gently stroking a hand-held cotton wool tip on the skin at a rate of approximately 1 cm/sec. Following a series of 10 strokes, the subject will be asked to score the intensity of the tactile sensation he experienced on a visual analogue scale (VAS; 0-100mm). This parameter will be determined at DAY1 before UVB exposition to document the integrity of the nociceptive fibres and at DAY2 on the primary area of hyperalgesia prior to the administration of the study drug to document hyperalgesia/allodynia.
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
Time Frame: Hour 1, Hour 2, Hour 3, Hour 4, Hour 5, Hour 6, Hour 7, Hour 8, Hour 9, Hour 10 following drug administration
The subjective degree of sedation will be evaluated on a Visual Analog Scale (VAS). The subject is asked to rate on a 100 mm scale (0=not at all and100 extremely) his level of drowsiness: "How sleepy do you feel now?"
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
Time Frame: Hour 4 and Hour 10 following drug administration
Short term anterograde memory will be tested by memorizing a list of 20 words and 30 minutes later retrieve as many of them as possible.
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
Time Frame: 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
Venous blood sample will be collected to assess N-desmethylclobazam basic pharmacokinetic parameters following single dose administration
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
Change in AUC of N-desmethylclobazam from Baseline following administration of repeated doses (20mg) of N-desmethylclobazam
Time Frame: Hour 0.5, Hour 1, Hour 2, Hour 4, Hour 6, Hour 8, Hour 10, Hour 12, Hour 24 following drug administration
Venous blood sample will be collected to assess N-desmethylclobazam basic pharmacokinetic parameters following the administration of repeated doses of N-desmethylclobazam 20mg over 14 days
Hour 0.5, Hour 1, Hour 2, Hour 4, Hour 6, Hour 8, Hour 10, Hour 12, Hour 24 following drug administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 30, 2017

Primary Completion (ACTUAL)

December 28, 2017

Study Completion (ACTUAL)

January 31, 2018

Study Registration Dates

First Submitted

September 8, 2017

First Submitted That Met QC Criteria

December 14, 2017

First Posted (ACTUAL)

December 15, 2017

Study Record Updates

Last Update Posted (ACTUAL)

April 19, 2019

Last Update Submitted That Met QC Criteria

April 18, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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