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Trial registered on ANZCTR


Registration number
ACTRN12621000429853
Ethics application status
Approved
Date submitted
14/02/2021
Date registered
16/04/2021
Date last updated
16/04/2021
Date data sharing statement initially provided
16/04/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Oral Ketamine Trial on Adults with Treatment-Resistant Depression
Scientific title
An open-label clinical trial of oral ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist on depressive symptomatology in adults who are experiencing treatment-resistant depression
Secondary ID [1] 299994 0
Nil
Universal Trial Number (UTN)
Trial acronym
OKTOD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment-Resistant Depression 315484 0
Condition category
Condition code
Mental Health 313773 313773 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is an open-label, dose-ranging clinical trial aiming to explore the feasibility, tolerability, and safety of low-dose oral ketamine on treatment-resistant depression. In this 10-week trial, participants will undergo 6 weeks of active treatment followed by 2 follow-up assessments.

Participants (N = 25-50) will receive low-dose liquid oral ketamine (OK) in water or flavoured drink once a week over a 6-week period (6 OK treatments in total). The initial dose will be 0.5mg per kilogram of bodyweight, after which dose will be increased by 0.1mg – 1.0mg/kg in each treatment, with a maximum dose of 3.0mg/kg.

Oral ketamine will be administered on-site by the psychiatrist as per the dosage protocol on routine basis but can be administered by the mental health nurse practitioner as directed by the psychiatrist. The participants will be observed at Thompson Institute for up to two hours after the drug administration. An accountability logbook and controlled drug register (as per Queensland Governmental regulations) for ketamine will be maintained throughout the trial. If a participant is unable to attend or misses a ketamine treatment, details of the deviation will be recorded in the source documentation. Participants will be withdrawn from the study if they miss more than 2 ketamine treatments.
Intervention code [1] 319730 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326522 0
Clinician-rated depressive symptomatology will be assessed using the Hamilton Depression Rating Scale (HAM-D),
Timepoint [1] 326522 0
The HAM-D will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment) (primary endpoint)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Primary outcome [2] 326527 0
Participant-rated depression symptoms will be measured using the Inventory of Depressive Symptomatology Self-Rating (IDS-SR) as the primary outcome measure in this project.
Timepoint [2] 326527 0
The IDS-SR will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 30-60 minutes after ketamine treatment
• Phone call one: 24 hours post-ketamine treatment
• Phone call two: +4-5 days post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment) (primary endpoint)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [1] 391793 0
Neurobiological effects of ketamine treatment as measured by magnetic resonance imaging (MRI)
Timepoint [1] 391793 0
MRI will be collected at 3 timepoints:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [2] 391826 0
Psychiatric side effects of ketamine treatment as assessed using psychiatric safety scales: Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and Young Mania Rating Scale (YMRS).

This is a composite secondary outcome.
Timepoint [2] 391826 0
The CADSS, BPRS, YMRS will be administered at the following time points:
• Within 30-60 minutes pre-ketamine treatment
• Phone call one: 24 hours post-ketamine treatment
• Phone call two: +4-5 days post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [3] 391827 0
Clinically rated suicidality as assessed by the Beck Scale for Suicide Ideation (BSS).
Timepoint [3] 391827 0
The BSS will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [4] 391828 0
Social and occupational functioning as assessed by Social and Occupational Assessment Scale (SOFAS).
Timepoint [4] 391828 0
SOFAS will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [5] 391829 0
Depression, assessed using the Depression subscale of the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [5] 391829 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 30-60 minutes after receiving ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [6] 391830 0
Anxiety, assessed by anxiety subscale of the Depression, Anxiety and Stress Scale (DASS-21)
Timepoint [6] 391830 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 30-60 minutes after receiving ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [7] 391831 0
Self-rated stress, assessed through the stress subscale of the Depression, Anxiety and Stress Scale (DASS-21)
Timepoint [7] 391831 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 30-60 minutes after receiving ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [8] 391832 0
Global wellbeing, assessed using the World Health Organization Wellbeing Index (WHO-5).
Timepoint [8] 391832 0
The WHO-5 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [9] 391833 0
Electroencephalography (EEG) will be used to assess changes in neural network communication from BAS to FUP1 and FUP2
Timepoint [9] 391833 0
EEG will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [10] 391834 0
Cambridge Neuropsychological Test Automated Battery (CANTAB) will be used to assess cognitive functioning such as attention, working memory, speed of processing, and executive functioning.

This is a composite secondary outcome.
Timepoint [10] 391834 0
The computerized cognitive battery will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [11] 391835 0
Clinical side effects, assessed using the symptom tolerability scale: Frequency, Intensity, Burden of Side Effects Rating (FIBSER).
Timepoint [11] 391835 0
The FIBSER will be administered at the following time points:
• Within 30-60 minutes of receiving ketamine treatment
• Phone call one: 24 hours post-ketamine treatment
• Phone call two: +4-5 days post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [12] 391836 0
Clinical side effects, assessed using the symptom tolerability scale: Patient Rated Inventory of Side Effects (PRISE).
Timepoint [12] 391836 0
The PRISE will be administered at the following time points:
•Within 30-60 minutes of receiving ketamine treatment
• Phone call one: 24 hours post-ketamine treatment
• Phone call two: +4-5 days post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [13] 391837 0
Bladder pain and cystitis as measured by the Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS).

This is a composite secondary outcome.
Timepoint [13] 391837 0
The BPIC-SS will be administered at the following time points:
• Baseline
• Within 30-60 minutes of receiving ketamine treatment
• Phone call one: 24 hours post-ketamine treatment
• Phone call two: +4-5 days post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)

Eligibility
Key inclusion criteria
•Patients who suffer from TRD and determined by cut-off scores of: 17 for the HAM-D
•Persons (male/female/other) aged 18 years and over
•Participants must be able to understand the Participant Information Form (PIF) and provide written informed consent on the Participant Consent Form (PCF)

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Demographic
• Persons under 18 years of age
Psychiatric conditions
• Psychosis
• Mania/hypomania
• Acute suicidality requiring urgent psychiatric intervention
• History of ketamine use disorder
• Recovery from a substance use disorder within prior 6 months

Physical conditions
• Uncontrolled/severe symptomatic cardiovascular disease states including: recent myocardial infarction (within prior 6 months); history of stroke; and hypertension (resting blood pressure >150/100)
• History of intracranial mass, intracranial haemorrhage/stroke, cerebral trauma/traumatic brain injury or increased intracranial pressure (as assessed by referring general practitioner)
• Liver function test (LFT) results out of normal range, as specified below:
• ALT: >135 U/L
• AST: >123 U/
• GAMMA GT (GGT) male participants: >210 U/L
• GAMMA GT (GGT) – female participants: >135 U/L
• TOTAL BILIRUBIN (BIT): >60 umol/L
• ALBUMIN (A): <25g/L and >150g/L
• ALK PHOS (ALP): >345 U/L
• Previous reaction to ketamine (as reported by referring general practitioner and participant)
• Pregnant women
• Breastfeeding women
• History of epilepsy or unexplained seizures

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical Analyses will include generalised linear models (GLMs), analysis of the relative change index, Frequentist statistics, and Bayesian statistics. A significance level of .05 will be utilized where required. Data will be inspected for outliers and any spurious data will be corrected or removed prior to analysis. A detailed data analysis plan will be constructed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 300888 0
University
Name [1] 300888 0
Thompson Institute, University of the Sunshine Coast
Address [1] 300888 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway,
Birtinya QLD 4575
Country [1] 300888 0
Australia
Primary sponsor type
University
Name
Thompson Institute, University of the Sunshine Coast
Address
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway,
Birtinya QLD 4575
Country
Australia
Secondary sponsor category [1] 300452 0
None
Name [1] 300452 0
Address [1] 300452 0
Country [1] 300452 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301661 0
Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 301661 0
The Prince Charles Hospital
Building 14
Rode Road
Chermside, Qld , 4032
Ethics committee country [1] 301661 0
Australia
Date submitted for ethics approval [1] 301661 0
11/04/2019
Approval date [1] 301661 0
19/09/2019
Ethics approval number [1] 301661 0
HREC/2019/QPCH/53437

Summary
Brief summary
This study is an open-label, dose-ranging clinical trial aiming to explore the feasibility, tolerability, and safety of low-dose oral ketamine on treatment-resistant depression. In this 10-week trial, participants will undergo 6 weeks of active treatment followed by 2 follow-up assessments. Additionally to any changes in depressive symptomatology, this study will determine whether the intervention improves rates of anxiety, stress, suicidality, and social and occupational functioning. The study will also explore neurobiological effects of oral ketamine, assessing the treatment mechanisms of action and identifying predictors of response.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87702 0
Dr Adem Can
Address 87702 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway,
Birtinya QLD 4575
Country 87702 0
Australia
Phone 87702 0
+61 0754 565385
Fax 87702 0
Email 87702 0
acan@usc.edu.au
Contact person for public queries
Name 87703 0
Ms Megan Dutton
Address 87703 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway,
Birtinya QLD 4575
Country 87703 0
Australia
Phone 87703 0
+61 07 5456 5386
Fax 87703 0
Email 87703 0
mdutton@usc.edu.au
Contact person for scientific queries
Name 87704 0
Mrs Megan Dutton
Address 87704 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway,
Birtinya QLD 4575
Country 87704 0
Australia
Phone 87704 0
+61 07 5456 5386
Fax 87704 0
Email 87704 0
mdutton@usc.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results