GABAergic Modulation in Pain Transmission in Human: Effect of the GABAA Agonist Clobazam on Peripheral and Central Sensitisation

Sponsor

University Hospital, Geneva (Other)

Overall Status

Completed

CT.gov ID

NCT01291316

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In animal, the GABAergic system modulates central sensitisation, which is a key phenomenon in pain processing. The development of GABAA agonists targeting the subunits of the GABAA receptor implicated in nociception, but not the subunit implicated in sedation is attractive as it opens new perspectives of testing the role of GABAergic modulation of pain processing in human volunteers. The purpose of this subproject is to test the effect of the specific α2 and α3 agonist but sparing α1 effect TPA023 on a human model of peripheral and central sensitisation and to correlate its pharmacodynamic effect with the pharmacokinetic of the compound.

The results would contribute to clarify the potential role of these α2/α3 agonist but sparing α1drugs in clinical pain conditions.

Condition or Disease	Intervention/Treatment	Phase
Neuropathic Pain	Drug: Clonazepam Drug: Tolterodine Drug: clobazam	Phase 1/Phase 2

Detailed Description

Objectives:

To assess the effect of the GABAA agonist clobazam on central sensitisation (change in the size of the area of secondary hyperalgesia) in healthy volunteers.
To assess the effect of the GABAA agonist clobazam on peripheral sensitisation.
To assess the effect of the GABAA agonist clobazam on sedation.
To correlate the pharmacokinetic of clobazam to its effect (PK-PD modelling)
To describe the role of the polymorphisms of CYP450 2C19 in the pharmacokinetic and dynamic of clobazam.

Methodology :

phase II , exploratory, three arms randomised placebo-controlled, double blind cross-over study in healthy volunteers

Number of patients : 25

Test product,Dose, Route of administration :

Clobazam,20 mg,oral intake

Duration of treatment :

Single dose administration of each compound

Reference therapy :

Clonazepam 1mg, oral intake Tolterodine 1, 37mg, oral intake

Other therapy :

Flumazenil 0.2mg, intravenous

Efficacy evaluation :

Determination of the impact of clobazam:

on the size of the area of secondary hyperalgesia induced by an UVB irradiation of the skin (sunburn model). The area is mapped with an electronical Von Frey filament
on the pain threshold (heat, static and mechanical threshold) in the primary and secondary area of hyperalgesia
on the nociceptive flexion reflex
on tolerance pain threshold (cold pressor test)
on the degree of sedation measured by saccadic eye movements, digit substation symbols test (DSST) and numerical rating scale.

Determination of the concentration-time curve of clobazam and PK-PD modelling.

Statistical Methods :

Based on the results of a previous study done in our unit, assessing the effect of the association of paracetamol and ketorolac on the sunburn model30, the number of volunteers required to detect a 30% reduction in the area of hyperalgesia is 4830. However we chose a lower intensity of UVB irradiation than in previous studies. Using a dose of irradiation of 3 med , this number falls to 18, adopting a 5% level for statistical significance and a 80% power. Taking these two results in account we will go for 25 volunteers.

Data will be analysed by multifactorial analysis of variance (MANOVA) and by analysis of variance (ANOVA) with repeated measures In the case of withdrawal, the data obtained will not be used in the analysis. Data set will however be completed by enrolling a substitute volunteer.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Study Start Date :

Apr 1, 2010

Actual Primary Completion Date :

Nov 1, 2011

Actual Study Completion Date :

Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: clobazam	Drug: clobazam clobazam 20 mg, single oral dose
Active Comparator: clonazepam	Drug: Clonazepam clonazepam, 1 mg, single oral dose
Placebo Comparator: tolterodine	Drug: Tolterodine Tolterodine 1,37mg, single oral dose

Arm

Intervention/Treatment

Experimental: clobazam

Drug: clobazam

clobazam 20 mg, single oral dose

Active Comparator: clonazepam

Drug: Clonazepam

clonazepam, 1 mg, single oral dose

Placebo Comparator: tolterodine

Drug: Tolterodine

Tolterodine 1,37mg, single oral dose

Outcome Measures

Primary Outcome Measures

Determination of the impact of clobazam on the change in the area of secondary hyperalgesia (in cm2) mapped with a Von Frey filament (256mN). [3 single days spaced out with at least two weeks wash-out periods]

Secondary Outcome Measures

Change in the pain threshold (heat (°C) static mechanical (g) and dynamic mechanical (Numerical rating scale NAS) in the area of secondary hyperalgesia [3 single days spaced out with at least two weeks wash-out periods]
Change in the pain threshold (heat (°C ) static mechanical (g) and dynamic mechanical (NAS)) in the area of primary hyperalgesia [3 single days spaced out with at least two weeks wash-out periods]
Change in Nociceptive Flexion Reflex [3 single days spaced out with at least two weeks wash-out periods]
Change in the latency and in the area under the pain intensity/time curve in cold pressor test [3 single days spaced out with at least two weeks wash-out periods]
Change in mean target saccades peak velocity, target saccades acceleration and deceleration, in saccade latency (msec), in saccadic accuracy, in smooth pursuit lead time and in the number of saccadic intrusions in the smooth pursuit. [3 single days spaced out with at least two weeks wash-out periods]
Change in the total number and in the correct number of symbols drawn in the DDST challenge. [3 single days spaced out with at least two weeks wash-out periods]
Time concentration curve evaluation: blood samples at 0,5, 1, 2, 4, 6, 8,12, and at 24 hours post-dose [3 single days spaced out with at least two weeks wash-out periods]
Clobazam and N-desmethylclobazam concentrations (µg/mL)
Pharmacokinetic/ pharmacodynamic modelling. [3 single days spaced out with at least two weeks wash-out periods]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Male subject, age between 18 and 60 year old
Caucasian
Type 3 skin phototype
Non smoker or moderate smoker (< 10 cigarettes/day)
No clinically abnormal findings on history and/or on physical examination
Presence of an area of secondary hyperalgesia after UVB irradiation

Exclusion Criteria:

Any concomitant 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
Current and regular intake of any drugs that might affect nociception Paracetamol, or NSAIDS with a short half lives are permitted but should be stopped at least 48 h before the UVB session

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospitals	Geneva		Switzerland	1211

Sponsors and Collaborators

University Hospital, Geneva

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Jules Desmeules, MD, University Hospital, Geneva

ClinicalTrials.gov Identifier:

NCT01291316

Other Study ID Numbers:

GABA-SPUM

First Posted:

Feb 8, 2011

Last Update Posted:

Dec 14, 2011

Last Verified:

Dec 1, 2011

Additional relevant MeSH terms:

Study Results

No Results Posted as of Dec 14, 2011