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Trial registered on ANZCTR


Registration number
ACTRN12617000008325p
Ethics application status
Submitted, not yet approved
Date submitted
4/11/2016
Date registered
3/01/2017
Date last updated
3/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Using brain rhythms to assess anti-anxiety drug action
Scientific title
Using brain rhythms to assess anti-anxiety drug action in healthy adult volunteers
Secondary ID [1] 290468 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 300834 0
Condition category
Condition code
Mental Health 300661 300661 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single doses of one of the following anxiolytic medications: buspirone 5, 10 or 15mg, citalopram 10mg, clonidine 75mcg, pregabalin 25, 75 or 100mg, triazolam 0.125, 0.25 or 0.5mg, promethazine 10mg, quetiapine 25mg, venlafaxine 75mg. All medications will be encapsulated (i.e.administered as an oral capsule) to assist with blinding. Dosing will be directly observed by study staff.
Intervention code [1] 296320 0
Treatment: Drugs
Comparator / control treatment
Encapsulated microcellulose placebo capsule
Control group
Placebo

Outcomes
Primary outcome [1] 300082 0
Response inhibition, assessed using the Stop Signal Task.
Timepoint [1] 300082 0
Approximately 1 hour after dosing
Primary outcome [2] 300236 0
EEG frontal midline power,
Timepoint [2] 300236 0
Approximately 1 hour after dosing
Primary outcome [3] 300237 0
EEG left-right and frontal-posterior alpha asymmetry
Timepoint [3] 300237 0
Approximately 1 hour after dosing
Secondary outcome [1] 328982 0
Stop signal reaction time in the stop signal task
Timepoint [1] 328982 0
Over the first hour post-dose
Secondary outcome [2] 329443 0
Choice reaction time task; Subjects press mouse buttons in response to presented stimuli. The percent of left (outcome delivery) click responses out of left+right (no outcome) responses in the choice task are assessed separately for each condition (net gain, conflict, and net loss). This is a composite outcome for net gain, conflict and net loss conditions.
Timepoint [2] 329443 0
Over the first hour post-dose

Eligibility
Key inclusion criteria
1. Capable of understanding and signing an informed consent.
2. Aged 18-65 years on the day of consent.
3. Good general health.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Females who are or intend to become pregnant, or are lactating.
2. Participants who, in the opinion of the investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
3. Any participant for whom the investigator believes, for any reason, that participation would not be an acceptable risk.
4. Regular use of any drug that alters mood or is used to treat mental disorder, including daily use of alcohol or use of alcohol within 24 hours prior to testing.
5. Subjects with a prior history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Prof Glue will create the random codes and encapsulate all treatments. All study personnel involved with recruitment, dosing, data collection and analysis will have no access to the random codes until the databases are locked. All medications will be provided in opaque labelled envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random code, with stratification based on gender.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
There are four discrete dosing groups in this study, three of which are evaluating dose-response relationships in the study tasks for buspirone, triazolam and pregabalin. The fourth group will test single doses of other anxiolytic drugs not yet evaluated in the study task paradigm.
1. Placebo, buspirone (5, 10*, 15mg)
2. Placebo, triazolam (0.125, 0.25*, 0.375mg)
3. Placebo, pregabalin (25, 75*, 100 mg)
4. Placebo, buspirone (10*mg), citalopram (SSRI, 10mg), venlafaxine (SNRI, 75mg), clonidine (adrenergic agonist, 75mcg), quetiapine (atypical antipsychotic, 25mg), promethazine (antihistamine, 10mg)
Phase
Phase 1
Type of endpoint/s
Pharmacodynamics
Statistical methods / analysis
- Behaviour: Post-dosing behaviour changes will be compared between drug and placebo dosing using a mixed measures ANOVA with drug/dose as a between participants factor and, e.g., changes in measures across trials as repeated measures with polynomial contrasts extracted.
- Biomarker: Raw EEG will be converted to log Fourier power for an epoch centred on the 500ms after a stop signal. GCSR will be calculated as stop-go[linear] x delay[quadratic] for channel F8 and the resultant value submitted to ANOVA. Additional EEG analyses will assess polynomial components of anterior-posterior and left-right location of channels on the scalp. Significant results will be explored with post hoc split ANOVAs.
- Choice EEG: as for biomarker EEG analysis but with analysis centred on the trial start and GCSR calculated as payoff[quadratic].
- Resting EEG: log Fourier power will be calculated for eyes open and eyes closed periods separately for all electrodes. Frontal midline power, left-right alpha asymmetry, and frontal-posterior alpha asymmetry will be extracted as separate measures and each subjected to repeated measures ANOVA with effect of drug group and eyes open/closed as factors.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
190
Accrual to date
Final
Recruitment outside Australia
Country [1] 8372 0
New Zealand
State/province [1] 8372 0
Otago

Funding & Sponsors
Funding source category [1] 294880 0
University
Name [1] 294880 0
Otago University
Country [1] 294880 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin, 9054
Country
New Zealand
Secondary sponsor category [1] 293718 0
None
Name [1] 293718 0
None
Address [1] 293718 0
N/A
Country [1] 293718 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 296259 0
Southern HDEC
Ethics committee address [1] 296259 0
Ministry of Health
Ethics Department
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 296259 0
New Zealand
Date submitted for ethics approval [1] 296259 0
18/11/2016
Approval date [1] 296259 0
Ethics approval number [1] 296259 0

Summary
Brief summary
‘Anxiety disorders’ diagnosis is currently based on clinical symptom check lists and there are no biological markers to diagnose specific syndromal causes. We have described a detailed theory of the brain systems controlling anxiolytic-insensitive threat-avoidance and anxiolytic-sensitive threat-approach. This new biomarker should allow division of untreated ‘anxiety’ patients, with superficially similar clusters of symptoms, into distinct high scoring (syndromal) and low scoring groups with different treatment-responses. This would be the first theoretically-derived biomarker for any mental disorder and should: 1) predict treatment efficacy better than current symptom-based diagnoses; 2) provide a human single dose test of novel anxiolytics; 3) provide a starting point for developing biomarkers for other ‘anxiety’ syndromes; and so, 4) greatly improve treatment outcomes and cost-effectiveness.

Our previous work has shown that single doses of 3 types of anxiolytic drug all reduce goal-conflict-specific rhythmicity (GCSR) in a stop signal task despite sharing only anxiolytic and not panicolytic or antidepressant or other actions. Preliminary results indicate that this action is also seen in a variant of the stop signal task with targeted rather than speeded responses; but drug action has not been tested in the choice tasks, involving monetary gain and loss, in which GCSR was originally demonstrated and from which the money-free variant was developed. Generality of the results has also not been extended to other doses of the original anxiolytic drugs or to drugs with broader actions on panic and depression that share a capacity to reduce clinical anxiety.

There are several objectives in the proposed randomized double blind parallel group studies:
-To evaluate the dose-response relationship for drugs already known to affect an EEG biomarker of an anxiety-related process.
-To evaluate the generalisation of effect on the EEG biomarker of the anxiety-related process to drugs with broader anxiolytic-antipanic-antidepressant-antipsychotic actions.
-To evaluate the dose-response relationship of anxiolytic drugs on behaviour and potential EEG biomarkers in behavioural tasks involving explicit approach-avoidance conflict generated by gain and loss of money.
Trial website
none
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70174 0
Prof Neil McNaughton
Address 70174 0
Department of Psychology
University of Otago
William James Building
275 Leith Walk
Dunedin 9016
Country 70174 0
New Zealand
Phone 70174 0
+64 3 479 7634
Fax 70174 0
NA
Email 70174 0
[email protected]
Contact person for public queries
Name 70175 0
Neil McNaugthon
Address 70175 0
Department of Psychology
University of Otago
William James Building
275 Leith Walk
Dunedin 9016
Country 70175 0
New Zealand
Phone 70175 0
+64 3 479 7634
Fax 70175 0
NA
Email 70175 0
[email protected]
Contact person for scientific queries
Name 70176 0
Neil Mcnaughton
Address 70176 0
Department of Psychology
University of Otago
William James Building
275 Leith Walk
Dunedin 9016
Country 70176 0
New Zealand
Phone 70176 0
+64 3 479 7634
Fax 70176 0
NA
Email 70176 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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