Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001177347p
Ethics application status
Submitted, not yet approved
Date submitted
1/08/2017
Date registered
10/08/2017
Date last updated
10/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of brain glutamatergic mechanisms in patients with treatment resistant anxiety
Scientific title
Evaluation of brain glutamatergic mechanisms in patients with treatment resistant anxiety - comparative effects of ketamine vs fentanyl
Secondary ID [1] 292570 0
None
Universal Trial Number (UTN)
None
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 304237 0
Condition category
Condition code
Mental Health 303589 303589 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single doses of ketamine 1mg/kg as intramuscular injections
Intervention code [1] 298774 0
Treatment: Drugs
Comparator / control treatment
Single doses of fentanyl 50mcg as intramuscular injections
Control group
Active

Outcomes
Primary outcome [1] 302940 0
Exploratory outcome: Magnetic Resonance Imaging scans - data collected include resting state fMRI and magnetic resonance spectroscopy.

Spectroscopy picks up a glutamate/glycine signal in brain; this is well established; there are multiple (between 10-20) endpoints in terms of brain structure, blood flow, network patterns etc that could be determined from an MRI scan.
Timepoint [1] 302940 0
predose, 2 hours and 72 hours post dosing.
Secondary outcome [1] 337517 0
Electroencephalogram measuring on brain rhythmicity and coherence (connectivity) (composite outcome)
Timepoint [1] 337517 0
predose, 2 hours and 72 hours post dosing.
Secondary outcome [2] 337518 0
Plasma ketamine and norketamine concentrations (composite outcome)
Timepoint [2] 337518 0
0.5, 1, 2 and 3 hours post dose
Secondary outcome [3] 337519 0
Mood rating scales (Hamilton Anxiety Scale and Fear Questionnaire)
Timepoint [3] 337519 0
Predose, 1, 2, 24 and 72 hours after dosing
Secondary outcome [4] 337520 0
Safety and tolerability assessments, including adverse events, vital signs via clincal assessments, dissociation ratings using the CADSS rating scale
Timepoint [4] 337520 0
Predose, 1,2, 24 and 72 hours post dose

Eligibility
Key inclusion criteria
• Male or female aged 18-65y
• Diagnosed with DSM-5 Generalized Anxiety Disorder and/or Social Anxiety Disorder, with inadequate response to prior treatment i.e. unsuccessful with 1 or more prescribed antidepressants and prior failed psychotherapy
• Hamilton Anxiety Scale (HAM-A) score of >20, and/or a Liebowitz Social Anxiety Scale (LSAS) score of >60 at screening.
• Prior response to ketamine as demonstrated by a >50% decrease in HAMA and/or Fear Questionnaire (FQ) scores 24 hours after dosing.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• evidence of severe acute or chronic medical disorders,
• presence of implanted cardiac pacemakers, hearing aids, insulin pumps or neurostimulators; intracranial metal clips; or metallic bodies in the eye
• past or current diagnoses of schizophrenia, bipolar disorder, or current psychotic symptoms
• female patients who are pregnant or lactating
• drug abuse or dependence in the last 6 months
• current significant suicidal ideation
• current Major Depressive Disorder (MADRS >20 at screening).
• participants must be free of recreational drug and alcohol use at the time of testing

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)
Allocation involved contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerized randomization in blocks of 4, stratified by 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
N/A
Phase
Phase 1 / Phase 2
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
-fMRI data: FSL’s Multivariate Exploratory Linear Optimized Decomposition into Independent Components (MELODIC) will be used to decompose data from all participants into different spatial and temporal components using independent components analysis (ICA). Parameters for MELODIC will be as follows: no brain extraction, brain/non-brain threshold=10, TR=3, mixture modelling=0.5. A general linear model will then be created for use during dual regression. A factor effects general linear model will be set up to compare the mean of each group with the average mean across all groups. A post-hoc t-test will be used to determine the direction of the difference between groups for any statistically significant results arising from the ANOVAs.

Using FSL’s dual regression function, spatial maps from the group-average analysis will be used to generate individualised versions of the spatial maps and associated time series. An ANOVA comparing group differences over 5000 non-parametric permutations with threshold-free cluster enhancement will be undertaken using FSL's randomise permutation testing tool, following dual regression. The threshold for statistical significance will be set at p=0.05 [family-wise error corrected] and adjusted for multiple comparisons using the null distribution of the maximal voxel-wise test statistic.

-EEG data: The raw EEG will be downsampled to 128Hz, a bandpass of 1-30Hz applied, eye blink artefact components will be subtracted and remaining artefacts of all types deleted. The cleaned EEG will then be processed with a 1s overlapping Hanning window (0.5s steps), fast Fourier power transform, and log10 transform. Relaxation data will be processed for frontal and parietal alpha asymmetry and Higuchi’s fractal dimension.

-PK data: Descriptive statistics, noncompartmental analysis

-Safety/tolerability: Descriptive statistics.

-PK-PD: General linear models will be used to undertake regression analyses using the covariates of age, gender, diagnosis, mood rating scores and ketamine and norketamine exposure (AUC measurements) to compare the differences in functional connectivity between the 2 treatment arms.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2017
Actual
Date of last participant enrolment
Anticipated
1/10/2019
Actual
Date of last data collection
Anticipated
1/11/2019
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment outside Australia
Country [1] 9118 0
New Zealand
State/province [1] 9118 0
Otago

Funding & Sponsors
Funding source category [1] 297150 0
University
Name [1] 297150 0
University of Otago
Country [1] 297150 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 913, Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 296164 0
None
Name [1] 296164 0
Address [1] 296164 0
Country [1] 296164 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 298318 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 298318 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 298318 0
New Zealand
Date submitted for ethics approval [1] 298318 0
01/08/2017
Approval date [1] 298318 0
Ethics approval number [1] 298318 0

Summary
Brief summary
Low-dose ketamine has fast-acting positive effects on mood in patients with treatment resistant anxiety, similar to its effects in depression. This is a mechanistic study to assess changes in brain function in patients with treatment resistant anxiety treated with ketamine or a psychoactive control, using a range of assessment methods (brain imaging, EEG analysis, blood pharmacokinetic samples). Data from this study may help clarify the neurobiological basis of treatment-resistant anxiety.
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 76698 0
A/Prof Bruce Russell
Address 76698 0
School of Pharmacy
University of Otago
PO Box 56
Dunedin 9054
Country 76698 0
New Zealand
Phone 76698 0
+64 3 479 7272
Fax 76698 0
+64 3 479 7034
Email 76698 0
[email protected]
Contact person for public queries
Name 76699 0
Prof Paul Glue
Address 76699 0
School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 76699 0
New Zealand
Phone 76699 0
+64 21 243 3372
Fax 76699 0
+64 3 474 7934
Email 76699 0
[email protected]
Contact person for scientific queries
Name 76700 0
A/Prof Bruce Russell
Address 76700 0
School of Pharmacy
University of Otago
PO Box 56
Dunedin 9054
Country 76700 0
New Zealand
Phone 76700 0
+64 3 479 7272
Fax 76700 0
+64 3 479 7034
Email 76700 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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