Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000817640
Ethics application status
Approved
Date submitted
13/07/2023
Date registered
28/07/2023
Date last updated
3/04/2024
Date data sharing statement initially provided
28/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Ketamine and Behavioural Activation Therapy study
Scientific title
Ketamine versus Ketamine plus Behavioural Activation Therapy for Adults with Treatment Resistant Depression
Secondary ID [1] 310086 0
None
Universal Trial Number (UTN)
U1111-1294-9310
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment Resistant Depression 330636 0
Condition category
Condition code
Mental Health 327463 327463 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive oral ketamine plus Behavioural Activation Therapy (BAT) (the intervention) or oral ketamine plus Treatment As Usual (TAU) (the comparator).

Ketamine will commence at a dose of 0.5mg/kg diluted with 50 ml orange juice and sipped over 30-60 minutes. Initial dosing will be twice weekly (with gaps of 3 and 4 days between doses). If tolerated and if the Montgomery Asperg Depression Rating Scale (MADRS)>6 on follow-up (indicating mild depression or greater), dose can be increased to 1.5 mg/kg and then 2 mg/kg. If the MADRS is <6 on follow-up, dosing can be reduced to weekly intervals at participant request. Dosing will be individualised through discussion with nursing staff. All participants will receive nursing contact and oversight on Ketamine dosing days and by telephone as needed over the study period.

BAT consists of 12 sessions provided at twice-weekly intervals for 4 weeks, then weekly intervals for 4 weeks. Sessions will be timed to occur within 24 hours of Ketamine treatments. BAT will be based on the manual by Lejuez et al. and be adapted by Assoc. Prof Jordan, Dr Katie Douglas, and Prof Greg Murray to work synergistically with the Ketamine treatment.

BAT has already been adapted using He Puna Whakaata principles for use with Maori participants. BAT will provide an individual formulation for the participant and be a holistic treatment package alongside Ketamine therapy. BAT content includes psychoeducation about depression and the BAT model, values, goal setting, scheduling pleasant and mastery activities, negotiating support from others, dealing with rumination and worry, skills training as needed (e.g. problem solving, assertive communication) and managing early signs of relapse. BAT will include an initial focus on symptom reduction followed by maintenance of improvements and behavioural change to prevent relapse. BAT therapy session will be 40-50 minutes in duration and occur face-to-face unless specific circumstances such as sickness arise which mean a zoom session is desirable. BAT will be undertaken by nurses and psychologists trained in BAT and supervision of BAT therapists and fidelity checks of BAT delivery will occur.
Intervention code [1] 326485 0
Behaviour
Intervention code [2] 326487 0
Treatment: Drugs
Comparator / control treatment
Treatment as Usual (TAU) will consist of nursing contact and support on ketamine dosing days and by telephone as needed over the study period.
Control group
Active

Outcomes
Primary outcome [1] 335327 0
Study feasibility will be assessed by tracking weekly attendance with Ketamine and BAT, retention to the study follow-up protocol, and acceptability of treatment measures.
Timepoint [1] 335327 0
Weekly attendance with Ketamine and BAT will be assessed through recording attendance weekly.
Retention to the study follow-up protocol will be assessed by monitoring responses to the study phone calls occuring every two weeks from weeks 8-20.
Acceptability of treatment will be assessed by the Behavioural Activation for Depression Scale - Short Form (BADS-SF) at baseline, week 8, and week 20.
Primary outcome [2] 335328 0
Montgomery Asperg Depression Rating Scale (MADRS)
Timepoint [2] 335328 0
The MADRS will be measured weekly during the 8 weeks of active treatment and fortnightly between weeks 8 and 20 post-baseline.
Secondary outcome [1] 423955 0
The MATRICS Consensus Cognitive Battery. This is a series of memory, attention, and learning tests that take about one hour to complete.
Timepoint [1] 423955 0
This will be administered at baseline and 7 days following end of Ketamine treatment.
Secondary outcome [2] 423956 0
GENEActiv actigraphs (a small wrist-worn device) on the non-dominant wrist. The primary actigraphic outcome measure will be total waking activity count per waking day (averaged across 7 days of data collection).
Timepoint [2] 423956 0
Actigraphs will be worn for six weeks in total;
a) 1 week prior to and for 2 weeks after first ketamine treatment to test the acute impacts of ketamine
b) 1 week prior to and 1 week after completion of ketamine treatment to test the impact of ketamine withdrawal (weeks 8 and 9)
c) 1 week prior to week 20 to investigate maintenance of psychomotor benefits.

Secondary outcome [3] 423957 0
Depression Anxiety and Stress Scale (DASS-21 ): Depression subscale
Timepoint [3] 423957 0
Baseline, week 8, week 20 post-baseline
Secondary outcome [4] 423958 0
Functional impairment assessed using the Work and Social Adjustment Scale (WSAS)
Timepoint [4] 423958 0
Baseline, week 8, week 20 post-baseline
Secondary outcome [5] 423959 0
Bladder Pain Interstitial Cystitis (BPIC) questionnaire
Timepoint [5] 423959 0
Weekly for first 8 weeks, then week 20 post-baseline
Secondary outcome [6] 423960 0
Participant adherence to BAT will be assessed by the Behavioral Activation for Depression Scale – Short Form (BADS-SF).
Timepoint [6] 423960 0
Baseline, week 8, week 20 post-baseline
Secondary outcome [7] 424464 0
DASS-21: Anxiety Subscale
Timepoint [7] 424464 0
Baseline, week 8, week 20 post-baseline
Secondary outcome [8] 424465 0
DASS-21: stress subscale
Timepoint [8] 424465 0
Baseline, week 8, week 20 post-baseline

Eligibility
Key inclusion criteria
Participants aged between 18 and 65 years with treatment-resistant, DSM 5, Major Depressive Disorder (TR-MDD) are eligible for entry to the study. A standard definition for treatment resistance will be used: having trialled, and not responded to, at least two antidepressant medications at adequate doses for more than 6 weeks.

At screening, patients will have a Hamilton Depression Rating Scale-17 (HAMD) greater than 16, reflecting depression of at least moderate severity.

Participants will be required to be on stable medication treatment (or no treatment) for at least 1 month prior to screening for the study and commit to remaining on the same medication during active treatment to ensure treatment withdrawal or dose changes do not confound study effects.

Proficient in spoken English
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 conditions (e.g. diabetes, ischaemic heart disease, chronic obstructive airways disease, cerebro-vascular disease);

Past or current diagnoses of schizophrenia, bipolar disorder, or current psychotic symptoms; moderate-severe personality disorder;

Current or recent significant suicidal ideation;

Current or recent (past 6 months) substance use disorder;

Prior history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions; prior history of serious head injury or other neurological condition resulting in ongoing cognitive impairment;

Participants who are breast feeding or pregnant

Receiving active psychotherapy for MDD (supportive psychotherapy can be placed on hold during the study)

Having received a course of BAT in the last 12 months; previous non-response to BAT or Ketamine treatment

Electro-Convulsive Therapy (ECT) in the last 6 months.

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 concealed with allocation schedule held at a central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated permuted block randomisation, stratified by centre (Christchurch, Dunedin).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Standard descriptive statistics will be used to describe the presenting demographic and clinical features of the randomised sample. These will include means, medians, standard deviations and ranges for continuous measures and frequencies and percentages for categorical data.

Feasibility
A full flow chart will be generated showing the numbers of patients screened, recruited, randomised, attendance at treatment visits and attendance at follow-up. This will allow description of the degree to which the final sample is a subset of those referred or responding to advertisement. The details of any noncompliance with the treatment protocol including the BADS-SF results will be recorded and reported.

Efficacy
The primary efficacy outcome, MADRS, will be used to categorise patients as treatment non-response (never meeting response criteria during the active treatment phase (0-8 weeks)), responders ( greater than or equal to 50% reduction in the MADRS during treatment), remitters (MADRS less than or equal to 10 on two consecutive measurements during treatment) and relapsed (MADRS greater than or equal to 22 after previously responding or being in remission during follow-up (8–20 weeks)). These outcomes are not mutually exclusive so will each be analysed and compared between randomised groups using binary logistic regressions, with the effect sizes summarised as odds ratios with 95% confidence intervals. Additionally, the MADRS scores from baseline to follow-up will be further analysed using a linear mixed model, which will include patient as a random effect, baseline levels as a covariate, and time and treatment as fixed factors. The estimated means at each time for each treatment group will be summarised and presented with 95% confidence intervals. For a definitive followup RCT study to be recommended, the recruitment expectations will be met (60 participants over 3 years) and efficacy outcomes consistent with a >20% reduction in relapse rates favouring the BAT arm will be achieved.

The secondary and exploratory outcomes including the cognitive functioning, psychomotor functioning, activity count (Actigraphy), HADS and WSAS scales and measures will be compared between randomised groups using a linear mixed model, which will include patient as a random effect and time and treatment as fixed factors. These models will include specific comparisons of the changes from baseline to end of treatment and end of follow-up as appropriate to the measurement timing of each outcome.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/10/2023
Actual
5/02/2024
Date of last participant enrolment
Anticipated
2/03/2026
Actual
Date of last data collection
Anticipated
20/07/2026
Actual
Sample size
Target
60
Accrual to date
4
Final
Recruitment outside Australia
Country [1] 25630 0
New Zealand
State/province [1] 25630 0
Otago
Country [2] 25631 0
New Zealand
State/province [2] 25631 0
Canterbury

Funding & Sponsors
Funding source category [1] 314249 0
Government body
Name [1] 314249 0
Health Research Council
Country [1] 314249 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith Street Dunedin, Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 316228 0
None
Name [1] 316228 0
Address [1] 316228 0
Country [1] 316228 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313366 0
Health and Disability Ethics Committee
Ethics committee address [1] 313366 0
Ethics committee country [1] 313366 0
New Zealand
Date submitted for ethics approval [1] 313366 0
31/07/2023
Approval date [1] 313366 0
26/09/2023
Ethics approval number [1] 313366 0

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

Contacts
Principal investigator
Name 127902 0
Dr Ben Beaglehole
Address 127902 0
Department of Psychological Medicine
University of Otago, Christchurch
4 Oxford Terrace
Christchurch 8011
Country 127902 0
New Zealand
Phone 127902 0
+64 3 3726708
Fax 127902 0
+64 3 3720405
Email 127902 0
ben.beaglehole@otago.ac.nz
Contact person for public queries
Name 127903 0
Ben Beaglehole
Address 127903 0
Department of Psychological Medicine
University of Otago, Christchurch
4 Oxford Terrace
Christchurch 8011
Country 127903 0
New Zealand
Phone 127903 0
+64 3 3726700
Fax 127903 0
+64 3 3720405
Email 127903 0
ben.beaglehole@otago.ac.nz
Contact person for scientific queries
Name 127904 0
Ben Beaglehole
Address 127904 0
Department of Psychological Medicine
University of Otago, Christchurch
4 Oxford Terrace
Christchurch 8011
Country 127904 0
New Zealand
Phone 127904 0
+64 3 3726700
Fax 127904 0
+64 3 3720405
Email 127904 0
ben.beaglehole@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified individual participant data underlying published results only
When will data be available (start and end dates)?
immediately following publication; no end date determined.
Available to whom?
Researchers who provide a methodologically sound proposal
Available for what types of analyses?
to achieve the aims in the approved proposal and meta-analysis
How or where can data be obtained?
By email approach to the principal investigator on ben.beaglehole@otago.ac.nz


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
No additional documents have been identified.