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Trial registered on ANZCTR


Registration number
ACTRN12615000617561
Ethics application status
Approved
Date submitted
24/05/2015
Date registered
15/06/2015
Date last updated
7/07/2021
Date data sharing statement initially provided
3/07/2019
Date results provided
3/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of glutamate modulation on anxiety symptoms
Scientific title
Effect of ketamine on anxiety ratings in patients with anxiety disorders
Secondary ID [1] 286794 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety Disorders 295168 0
Condition category
Condition code
Mental Health 295413 295413 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study has three Phases
1. Open label within-subject ascending single dosing of ketamine (dose range 0.25, 0.5, 1 mg/kg subcutaneously (SC)) in patients with Generalized Anxiety Disorder (GAD) or Social Phobia (SP) (n=6/diagnosis). Unless there are individual toleration problems, it is anticipated all patients will receive all doses. There will be approximately 1 week between doses.
2. Double-blind within-subject ascending single dosing of ketamine (dose range 0.25, 0.5, 1 mg/kg subcutaneously) plus double blind active control (midazolam 0.01mg/kg SC) in a separate group of patients with GAD or SP (n=6/diagnosis). The timing of the midazolam dose will be randomized within the ascending ketamine doses. There will be approximately 1 week between doses.
3. Patients will be eligible to enter Phase 3 once they have completed either Phase 1 or Phase 2; entry to Phase 3 will be immediately after completing Phase 1 or Phase 2. They must also have had at least 50% reduction in anxiety ratings in response to any dose of ketamine are eligible to receive 1-2x weekly ketamine dosing for up to 3 months to help maintain improvement in anxiety symptoms. The Phase 3 dose will be individualized based on the balance between optimal tolerability and efficacy.
Intervention code [1] 291952 0
Treatment: Drugs
Comparator / control treatment
Single dose of midazolam 0.01mg/kg sc in Phase 2.
Control group
Active

Outcomes
Primary outcome [1] 295150 0
Change in anxiety rating scales (GAD: Hamilton Anxiety Scale (HAM-A); SP: Spielberger State Anxiety Inventory (SSAI) plus Fear Questionnaire (FQ) items 3, 7, 9, 11, & 14h)– predose, 1h, 2h, 24h, 72h, 168h. Primary endpoint is change at 24h.
Timepoint [1] 295150 0
Primary endpoint is change at 24h.
Secondary outcome [1] 314877 0
Safety: vital signs (blood pressure, heart rate, O2 sats)
Timepoint [1] 314877 0
Screening and predose, 0:15, 0:30, 0:45, 1:00, 1:30, 2:00h and 24h post-dosing at each dose.
Secondary outcome [2] 314878 0
Tolerability: reported adverse events. Most commonly patients report feeling woozy or dissociated 10-20mins post dosing. These can be assessed by self-report, or via use of the CADSS scale.
Timepoint [2] 314878 0
Wooziness and dissociation will be assessed predose until 1h post dose. Adverse events will be recorded throughout the study.
Secondary outcome [3] 314879 0
Blood samples for plasma ketamine and metabolite concentrations, after each dose
Timepoint [3] 314879 0
predose, 15, 30, 60 and 120mins, and at 24h post each dose
Secondary outcome [4] 314880 0
Clinician Administered Dissociative Symptoms Scale (CADSS)
Timepoint [4] 314880 0
predose, 30 and 60mins post- each dose
Secondary outcome [5] 314881 0
Montgomery Asberg Depression rating Scale (MADRS)
Timepoint [5] 314881 0
at screening, predose and 24h post- each dose
Secondary outcome [6] 314988 0
Blood samples for plasma BDNF concentrations
Timepoint [6] 314988 0
Predose, 15, 30, 60 and 120mins, and at 24h post each dose

Eligibility
Key inclusion criteria
GAD patients must have a Hamilton Anxiety Scale (HAM-A) score >20
SP patients must have a Liebowitz Social Anxiety Scale (LSAS) self-report score >50.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Female patients 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.Current use of MAOIs, thyroxine or stimulants (amphetamine/methyphenidate). Use of antidepressants or other anxiolytics at stable doses > 4 weeks is acceptable.
5.Patients with severe acute or chronic medical illnesses.
6.Patients with current active suicidal ideation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
In Phase 1 dosing will be sequential (lowest dose first, then ascending doses); in Phase 3 the most effective and best tolerated dose from Phase 1 will be used. There is no allocation concealment in Phases 1 and 3.

In Phase 2 dosing will be sequential (lowest ketamine dose first, then ascending doses), with a dose of midazolam (active control) randomly inserted within this sequence. Allocation concealment will be managed by having medication prepared by a pharmacist who is not involved with dosing or rating patients.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Phase 1/3 - n/a
Phase 2: computer generated random code
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
Other
Other design features
Phase 1 and Phase 3 have open label dosing. Blinding is only for Phase 2.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
This is a pilot proof of concept study and subject numbers have been chosen pragmatically rather than based on statistical power considerations.

Changes in anxiety ratings will be modelled along with ketamine and metabolite blood concentrations, and changes in plasma BDNF levels

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/08/2015
Actual
10/11/2015
Date of last participant enrolment
Anticipated
16/12/2016
Actual
11/10/2017
Date of last data collection
Anticipated
Actual
15/12/2017
Sample size
Target
24
Accrual to date
Final
25
Recruitment outside Australia
Country [1] 6899 0
New Zealand
State/province [1] 6899 0

Funding & Sponsors
Funding source category [1] 291336 0
Self funded/Unfunded
Name [1] 291336 0
Country [1] 291336 0
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin, 9054
Country
New Zealand
Secondary sponsor category [1] 290015 0
None
Name [1] 290015 0
Address [1] 290015 0
Country [1] 290015 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292899 0
NZ Health and Disability Ethics Committee
Ethics committee address [1] 292899 0
Ethics committee country [1] 292899 0
New Zealand
Date submitted for ethics approval [1] 292899 0
25/05/2015
Approval date [1] 292899 0
28/08/2015
Ethics approval number [1] 292899 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 57550 0
Prof Paul Glue
Address 57550 0
Dunedin School of Medicine,
University of Otago
PO Box 913, Dunedin 9054
Country 57550 0
New Zealand
Phone 57550 0
64 3 470 3867
Fax 57550 0
64 3 474 7934
Email 57550 0
paul.glue@otago.ac.nz
Contact person for public queries
Name 57551 0
Paul Glue
Address 57551 0
Dunedin School of Medicine,
University of Otago
PO Box 913, Dunedin 9054
Country 57551 0
New Zealand
Phone 57551 0
64 3 470 3867
Fax 57551 0
64 3 474 7934
Email 57551 0
paul.glue@otago.ac.nz
Contact person for scientific queries
Name 57552 0
Paul Glue
Address 57552 0
Dunedin School of Medicine,
University of Otago
PO Box 913, Dunedin 9054
Country 57552 0
New Zealand
Phone 57552 0
64 3 470 3867
Fax 57552 0
64 3 474 7934
Email 57552 0
paul.glue@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Pilot data


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders.2017https://dx.doi.org/10.1177/0269881117725685
EmbaseKetamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders.2017https://dx.doi.org/10.1177/0269881117705089
EmbaseKetamine effects on EEG during therapy of treatment-resistant generalized anxiety and social anxiety.2018https://dx.doi.org/10.1093/ijnp/pyy032
EmbaseSafety and efficacy of maintenance ketamine treatment in patients with treatment-refractory generalised anxiety and social anxiety disorders.2018https://dx.doi.org/10.1177/0269881118762073
EmbaseEffects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study.2020https://dx.doi.org/10.1177/0269881119874457
N.B. These documents automatically identified may not have been verified by the study sponsor.