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

December 13, 2011 updated by: Jules Desmeules, University Hospital, Geneva

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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 :

  1. 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.
  2. 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
25

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • 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

  • Switzerland
      • Geneva, Switzerland, 1211
        • University Hospitals

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Determination of the impact of clobazam on the change in the area of secondary hyperalgesia (in cm2) mapped with a Von Frey filament (256mN).
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
3 single days spaced out with at least two weeks wash-out periods

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in the pain threshold (heat (°C) static mechanical (g) and dynamic mechanical (Numerical rating scale NAS) in the area of secondary hyperalgesia
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
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
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
3 single days spaced out with at least two weeks wash-out periods
Change in Nociceptive Flexion Reflex
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
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
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
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.
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
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.
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
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
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
Clobazam and N-desmethylclobazam concentrations (µg/mL)
3 single days spaced out with at least two weeks wash-out periods
Pharmacokinetic/ pharmacodynamic modelling.
Time Frame: 3 single days spaced out with at least two weeks wash-out periods
3 single days spaced out with at least two weeks wash-out periods

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Geneva

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

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2010

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2011

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 1, 2011

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 7, 2011

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 7, 2011

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 8, 2011

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 14, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 13, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2011

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • GABA-SPUM

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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