Neuropathic PainPhase 1/2NCT01291316
GABAergic Modulation in Pain Transmission in Human: Effect of the GABAA Agonist Clobazam on Peripheral and Central Sensitisation
A Phase 1/2 study testing Clonazepam, Tolterodine and clobazam in people with Neuropathic Pain, run by University Hospital, Geneva at 1 site in Switzerland.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Neuropathic Pain
- What is being tested?
- Clonazepam, Tolterodine and clobazam
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteSwitzerland
- Study dates
- Apr 2010to Nov 2011
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Neuropathic Pain
- Being tested
- Clonazepam, Tolterodine, clobazam
- Medical subject headings
- Neuralgia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClonazepamDrug
clonazepam, 1 mg, single oral dose
TolterodineDrug
Tolterodine 1,37mg, single oral dose
clobazamDrug
clobazam 20 mg, single oral dose
| Study group | Role | What they receive |
|---|---|---|
| clobazam | Experimental | Not described Receives: Drug: clobazam |
| clonazepam | Active comparator | Not described Receives: Drug: Clonazepam |
| tolterodine | Placebo comparator | Not described Receives: Drug: Tolterodine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of the impact of clobazam on the change in the area of secondary hyperalgesia (in cm2) mapped with a Von Frey filament (256mN).
Measured: 3 single days spaced out with at least two weeks wash-out periods
Secondary outcomes (8)
Change in the pain threshold (heat (°C) static mechanical (g) and dynamic mechanical (Numerical rating scale NAS) in the area of secondary hyperalgesia
Measured: 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
Measured: 3 single days spaced out with at least two weeks wash-out periods
Change in Nociceptive Flexion Reflex
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Clobazam and N-desmethylclobazam concentrations (µg/mL)
Measured: 3 single days spaced out with at least two weeks wash-out periods
Pharmacokinetic/ pharmacodynamic modelling.
Measured: 3 single days spaced out with at least two weeks wash-out periods
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2011 (estimated)
- Study startApr 2010
- Primary completionNov 2011
- Study completionNov 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neuropathic PainStudies of the same condition, open and under way.
- More trials run by University Hospital, GenevaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Geneva
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jules Desmeules, University Hospital, Geneva
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01291316
- Sponsor's protocol ID
- GABA-SPUM
- Status last verified
- Dec 2011
- First submitted
- 7 Feb 2011
- Last updated
- 14 Dec 2011
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- GABAergic Modulation in Pain Transmission in Human: Effect of the GABAA Agonist Clobazam on Peripheral and Central Sensitisation
- ClinicalTrials.gov ID
- NCT01291316
- Acronym / sponsor ID
- GABA-SPUM
- Conditions
- Neuropathic Pain
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- University Hospital, GenevaUniversity, hospital or other
- Study start
- Apr 2010
- Primary completion
- Nov 2011 (actual)
- Study completion
- Nov 2011 (actual)
- First posted
- 8 Feb 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| clobazam | Experimental | Drug: clobazam |
| clonazepam | Active comparator | Drug: Clonazepam |
| tolterodine | Placebo comparator | Drug: Tolterodine |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Clonazepamclonazepam, 1 mg, single oral dose | Drug | clonazepam |
| TolterodineTolterodine 1,37mg, single oral dose | Drug | tolterodine |
| clobazamclobazam 20 mg, single oral dose | Drug | clobazam |
Primary outcome
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
8 secondary outcomes
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
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
Change in Nociceptive Flexion Reflex
Time frame: 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
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
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
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
Pharmacokinetic/ pharmacodynamic modelling.
Time frame: 3 single days spaced out with at least two weeks wash-out periods
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Clonazepam, Tolterodine and clobazam in people with Neuropathic Pain, run by University Hospital, Geneva at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2011.