Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000321448p
Ethics application status
Submitted, not yet approved
Date submitted
4/04/2025
Date registered
17/04/2025
Date last updated
17/04/2025
Date data sharing statement initially provided
17/04/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Testing a new treatment regime involving behavioural activation therapy alongside a combination of two medicines for people with Treatment-Resistant Depression.
Scientific title
Dextromethorphan plus Bupropion for Treatment-resistant Depression-Does adding Behavioural Activation Therapy improve outcomes?
Secondary ID [1] 314119 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment-Resistant Depression 336921 0
Condition category
Condition code
Mental Health 333388 333388 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In this study, all patients will receive Dextromethorphan + Bupropion (D+B) for 8 weeks, with approximately half randomized to receive 12 sessions of Behavioral Activation Therapy (BAT) as well. All participants will receive D+ B (50 mg + 150 mg) once daily for 3 days, followed by twice daily for the remainder of the study. In Day 1, initial dosing with D+B will be in the clinic to establish tolerance. Subsequently, we would give patients take home tablets. All participants will receive nursing contact and oversight on dosing days in clinic and by telephone as needed over the study period. Mood ratings and assessments of safety and tolerability will be collected at each visit. Safety data will be monitored for at least 2 hours after initial D+B dosing and at visits 3-6. Adverse events will be monitored throughout the study. Safety data will consist of a baseline assessment of general well-being, including systems enquiry, vital signs (blood pressure, heart rate, and temperature). At initial dosing, vital signs (blood pressure, heart rate, respiratory rate, O2 saturation) will be obtained pre-dose, 30, 60 and 120 mins post dosing. At visits 3-6, vital signs will be recorded once. To monitor adherence to the intervention, participants will be given enough medicine for the duration from one visit to the next visit.
BAT consists of 12 sessions provided at twice-weekly intervals for 4 weeks, then weekly intervals for 4 weeks (8 weeks in total). BAT will be provided in a clinic or via Zoom, depending on participant’s preference. 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 sessions will be scheduled within 24 hours of D+B dosing. This timing is intended to benefit from the anticipated improved mental state following D+B treatment and to enhance the potential for change. The approximate duration of BAT sessions is 50 Minutes.
BAT will be provided by a psychologist. Supervision of the BAT therapist and fidelity checks of BAT delivery will occur.
Intervention code [1] 330698 0
Treatment: Drugs
Intervention code [2] 330699 0
Treatment: Other
Comparator / control treatment
This study will test the benefits of adding BAT to D+B on depression mood ratings. For this assessment, patients who receive D+B in group A, will be compared to another group of patients who receive both D+B and BAT. This assessment is randomised open-label comparison of;
A) D+B (50 mg + 150 mg) daily for 8 weeks; or
B) D+B (50 mg + 150 mg) daily plus BAT for 8 weeks
All participants will receive 50+150mg for the first 3 days, followed by 100+300mg for the remainder of the study.
Control group
Active

Outcomes
Primary outcome [1] 340962 0
Depression
Timepoint [1] 340962 0
Visit 1-6 (Screening, Days 1, 8, 15, 29, 57 post-commencement of intervention) predose and at 3 month follow up visit 7 (Day 147 post-commencement of intervention)
Secondary outcome [1] 445620 0
Clinical Global Impression
Timepoint [1] 445620 0
at the beginning and end of the trial
Secondary outcome [2] 445621 0
Patient Global Impression
Timepoint [2] 445621 0
at the beginning and end of the trial
Secondary outcome [3] 445622 0
Participant adherence to BAT
Timepoint [3] 445622 0
All therapy sessions will be recorded and a random sample of two sessions/participant will be selected for review with a checklist to ensure all relevant therapy elements have been delivered at each session

Eligibility
Key inclusion criteria
• Male or female aged between 18 and 65 years
• In good general health
• Capable of understanding and signing an informed consent. Good general use of English.
• Participants will receive the DSM-5 MINI Diagnostic Interview at screening to provide conventional DSM-5 diagnoses and will have moderate to severe treatment-resistant depression (TR-MDD). We will also quantify the severity of treatment resistance using the Maudsley staging method. At screening, patients will have a MADRS score of greater than or equal to 20, 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.

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, cerebrovascular disease).
• Past or current diagnoses of schizophrenia, bipolar disorder, or current psychotic symptoms; moderate-severe personality disorder
• Female patients who are intending to become pregnant or breastfeeding
• Current or recent significant suicidal ideation (Score of greater than or equal to 4 on the MADRS suicide item).
• Current or recent (past 6 months) substance use disorder.
• Current or prior history of seizures.
• Prior history of serious head injury or other neurological condition resulting in ongoing cognitive impairment.
• 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 D+B treatment.
• Treatment with Electroconvulsive Therapy (ECT) in the last 6 months.
• Current or prior diagnosis of bulimia or anorexia nervosa.
• Use of a Monoamine Oxidase Inhibitor (MAOI) within 14 days of study entry.
• Known hypersensitivity to bupropion and/or dextromethorphan.
• Current use of medications that are strong inhibitors (e.g. ticlodipine, voriconazole) or inducers (e.g. evafirenz, carbamazepine, artemisinin, rifampin) of CYP2B6.
• Current use of medications that are strong inhibitors (e.g. fluoxetine, tiparoxetine, quinidine) of CYP2D6.

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)
Central Randomisation to D+B plus BAT or D+B only, Randomisation will be carried out by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
permuted block randomisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We plan to recruit 36 participants over 2 years. We believe recruiting 36 participants over 2 years is realistic and achievable. With N = 36 patients (N = 18 per group) and an expected effect size (Cohen’s d = 1.2), we should have 80% > power at p < 0.05 to detect changes in MADRS total score from baseline in a group comparison.

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. 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. 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 score of less than or equal to 10 on two consecutive measurements during treatment) and relapsed (MADRS score of greater than or equal to 22 after previously responding). 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 end of the trial 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. The secondary outcomes including the Clinical Global Impression (CGI) and Patient Global Impression (PGI-C) which will be undertaken at the beginning and end of the trial, 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 as appropriate to the measurement timing of each outcome. Trends in MADRS scores will be assessed with repeated measures ANOVA including orthogonal polynomial components of time for the 8-week period.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2025
Actual
Date of last participant enrolment
Anticipated
31/10/2026
Actual
Date of last data collection
Anticipated
31/03/2027
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment outside Australia
Country [1] 26934 0
New Zealand
State/province [1] 26934 0
Otago

Funding & Sponsors
Funding source category [1] 318628 0
Government body
Name [1] 318628 0
New Zealand Lottery Grant Board-Lottery Health
Country [1] 318628 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Country
New Zealand
Secondary sponsor category [1] 321042 0
None
Name [1] 321042 0
Address [1] 321042 0
Country [1] 321042 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 317229 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 317229 0
Ethics committee country [1] 317229 0
New Zealand
Date submitted for ethics approval [1] 317229 0
02/04/2025
Approval date [1] 317229 0
Ethics approval number [1] 317229 0

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

Contacts
Principal investigator
Name 140418 0
Dr Neda Nasrollahi
Address 140418 0
Department of Psychological Medicine (DSM)-Fraser Building, 464 Cumberland Street, Dunedin ,PO Box 56, Dunedin, 9054
Country 140418 0
New Zealand
Phone 140418 0
+64 3 556 5042
Fax 140418 0
Email 140418 0
[email protected]
Contact person for public queries
Name 140419 0
Prof Paul Glue
Address 140419 0
Department of Psychological Medicine (DSM)-Fraser Building, 464 Cumberland Street, Dunedin ,PO Box 56, Dunedin, 9054
Country 140419 0
New Zealand
Phone 140419 0
+64 3 556 6094
Fax 140419 0
Email 140419 0
[email protected]
Contact person for scientific queries
Name 140420 0
Neda Nasrollahi
Address 140420 0
Department of Psychological Medicine (DSM)-Fraser Building, 464 Cumberland Street, Dunedin ,PO Box 56, Dunedin, 9054
Country 140420 0
New Zealand
Phone 140420 0
+64 3 556 5042
Fax 140420 0
Email 140420 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: Need to discuss with co-investigators



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.