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Trial registered on ANZCTR


Registration number
ACTRN12622001345774
Ethics application status
Approved
Date submitted
6/09/2022
Date registered
19/10/2022
Date last updated
24/03/2024
Date data sharing statement initially provided
19/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Enhancing the clinical effectiveness of deep TMS treatment of depression
Scientific title
Examining the clinical effectiveness of deep TMS treatment on depressive symptoms in adults with major depressive disorder (ACHIEVE)
Secondary ID [1] 307805 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
ACHIEVE Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 327391 0
Condition category
Condition code
Mental Health 324514 324514 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To aim of this study is to investigate the efficacy of a novel dual target deep transcranial alternating current stimulation (dTMS) treatment approach for major depressive disorder. To do this, we conduct a randomized parallel design study with blinded assessment of treatment outcomes across three treatment groups:
1. patients who receive standard lateral stimulation with the H1 coil and sham stimulation
2. patients who receive one application of stimulation with the H1 coil at the lateral prefrontal stimulation site and then a second application of stimulation at the same site, using the same coil.
3. patients who receive stimulation with both the H1 coil applied to lateral prefrontal cortex and the H7 coil applied to medial prefrontal cortex.

H1 and H7 coils will look the same. However, the placement of magnets differ between the two types of coils.

All patients will receive 35 sessions of one of two forms of dTMS: standard or dual target. Each treatment course will consist of 30 sessions, 5 days per week with an additional five sessions applied after this - three in the seventh week and two in the eighth week. Treatment sessions will involve the application of intermittent theta burst stimulation (iTBS) at 120% of the RMT as assessed by standard visual means. Sham stimulation will be applied at 25% of RMT. All iTBS will be applied in triplet burst of 3 pulses at 50Hz repeated at 5Hz in 2 second trains with an eight second inter-train interval (total of 600 pulses). All treatments will occur at a Monarch Mental Health Group clinic, administered by a TMS practitioner.

For treatment arm 1 and 3 there will be no break between stimulation at sites and for treatment arm 2, there will be a 5 minute break between stimulations. The overall session will run for approximately 20 minutes.

Clinical outcomes will be performed at baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, end of treatment and at 1, 3 and 6 month follow up. These include an interview with trained research staff via video conference call, and self report questionnaires conducted via electronic links.

Participants will be provided with a personalised schedule for their time in the study and the treatment and study teams will keep record of the number of treatments and days they attend.
Intervention code [1] 324268 0
Treatment: Devices
Comparator / control treatment
All participants will either receive at least standard iTBS treatment, this acts as the active control group (Group 1).

There will be no break between stimulation at the separate sites for this arm of stimulation.

Participants will be provided with a personalised schedule for their time in the study and the treatment and study teams will keep record of the number of treatments and days they attend.
Control group
Active

Outcomes
Primary outcome [1] 332343 0
Total score on the 17 item Hamilton Depression Rating Scale (HAMD) between any of the 2 groups.
Timepoint [1] 332343 0
The primary analysis will be on mean HAMD scores from baseline to treatment end (week 8 post-treatment commencement) for each primary comparison.
Secondary outcome [1] 413106 0
Patient Health Questionnaire-9 (PHQ-9)
Timepoint [1] 413106 0
Baseline compared to study timepoints: week 1 of treatment, week 2 of treatment, week 3 of treatment, week 4 of treatment, end of treatment (week 8 post-treatment commencement), and 1, 3 and 6 months post-treatment completion
Secondary outcome [2] 413531 0
Beck Anxiety Inventory (BAI)– self rated anxiety
Timepoint [2] 413531 0
Baseline compared to study timepoints: week 2 of treatment, week 4 of treatment, end of treatment (week 8 post-treatment commencement), and 1, 3 and 6 months post-treatment completion
Secondary outcome [3] 413532 0
Patient Global Impression of Improvement (PGI-I) Scale - self rated
Timepoint [3] 413532 0
Week 2 of treatment, week 4 of treatment, end of treatment (completion of 35 treatment sessions), and 1, 3 and 6 months post-treatment completion.
Secondary outcome [4] 413533 0
Assessment of Quality of Life (AQoL-8D) - self rated
Timepoint [4] 413533 0
Baseline assessment, end of treatment (week 8 post-treatment commencement), and 1, 3 and 6 months post-treatment completion
Secondary outcome [5] 413534 0
A custom questionnaire in regards to TMS tolerability and side effects - self rated
Timepoint [5] 413534 0
Conducted during treatment at week 4 and at the end of treatment (week 8 post-treatment commencement)
Secondary outcome [6] 418424 0
Patient Global Impression of Severity (PGI-S) Scale
Timepoint [6] 418424 0
Baseline compared to study timepoints: week 2 of treatment, week 4 of treatment, end of treatment (week 8 post-treatment commencement), and 1, 3 and 6 months post-treatment completion
Secondary outcome [7] 418425 0
Inventory of Depression and Anxiety Symptoms –II (IDAS-II)
Timepoint [7] 418425 0
Baseline

Eligibility
Key inclusion criteria
- Diagnosis of major depressive episode (MDE), in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context of unipolar major depressive disorder or bipolar affective disorder.
- 18-85 years of age.
- Treatment resistant depression at Stage II of the Thase and Rush classification.
- Hamilton Depression Rating Scale (HAMD) score of >17 (moderate – severe depression).
- No increase or initiation of new antidepressant therapy in the four weeks prior to screening.
- Demonstrated capacity to give informed consent.
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to provide informed consent
- Medically unstable patients
- Concomitant neurological disorder or a history of a seizure disorder.
- Patients who are pregnant or breastfeeding.
- Active suicidal intent
- Any psychotic disorder or current active psychotic symptoms
-Patients who have intracranial implants deemed unsafe for TMS.
- Significant difficulties understanding or communicating in English

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 to treatment group is concealed; by the research staff contacting the study investigators who have a computer-generated random sequence for treatment groups after the participant is deemed eligible and has consented for the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly allocated to study group using simple randomisation techniques i.e. using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
We ultimately aim to recruit a total of 240 subjects (80 per group). The power analysis was developed based on comparing 2 groups at a time (80 versus 80) based on the analysis plan as described below – the dual treatment group versus the single site group and the dual stimulation DLPFC group versus the single stimulation DLPFC group. A sample of 148 (7.5% attribution from 160 or 2 groups of 80, which is conservative based on our previous studies) will provide power of 0.805 to detect a four-point greater reduction in HAMD score from baseline to end of treatment between any of the 2 groups (repeated measured model, unstructured covariance matrix, significance level of 0.05). A greater than three-point difference on the HAMD is regarded as clinically significant.

Two main analyses will be conducted (each using the same method):

We will compare outcomes for the dual site treatment group (DLPFC + DMPFC) versus the single site treatment group (DLPFC stim with 1 train of iTBS): this will be to answer the question as to whether dual site stimulation produces better outcomes than standard treatment

We will compare outcomes for the dual site treatment group (DLPFC + DMPFC) versus the single site treatment group who receive 2 bursts of iTBS (DLPFC stim with 2 trains of iTBS): this will be to answer the question as to whether dual site stimulation produces better outcomes than single site treatment when dose of iTBS is controlled for.

The primary outcome measure (HAMD) will be analysed via the fitting of linear mixed models. The repeated measurements of the primary outcome variable will be analysed by fitting linear mixed models using restricted maximum likelihood (REML) – this will allow all available data to be used without the need for imputation of missing values, the selection of the most suitable variance-covariance model for the repeated measures, using Akaike’s Information Criterion, and the investigation of commonality of any nonlinear trends over time via smoothing splines. The F-test will be used to test for a treatment by time interaction and comparisons between treatment groups at each time point will be based on t-tests that utilize the predicted means and standard errors of difference that are recovered from the fitted mixed model. Categorical outcomes (response and remission rates) will be compared using chi-squared analysis based on last observation carried forward data.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/02/2023
Actual
29/03/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
240
Accrual to date
14
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 312075 0
Government body
Name [1] 312075 0
NHMRC Investigator Grant
Country [1] 312075 0
Australia
Primary sponsor type
University
Name
Australian National University
Address
The Australian National University
Canberra ACT 2600 Australia
Country
Australia
Secondary sponsor category [1] 313584 0
None
Name [1] 313584 0
n/a
Address [1] 313584 0
n/a
Country [1] 313584 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311483 0
ACT Health Human Research Ethics Committee
Ethics committee address [1] 311483 0
PO Box 11 Woden ACT 2606, Canberra Hospital Building 10 Level 6
Ethics committee country [1] 311483 0
Australia
Date submitted for ethics approval [1] 311483 0
10/10/2022
Approval date [1] 311483 0
06/12/2022
Ethics approval number [1] 311483 0
2022.ETH.00181

Summary
Brief summary
Deep Transcranial magnetic stimulation (dTMS) is a form of repetitive transcranial magnetic stimulation (rTMS) which has been established as a safe, effective and well-tolerated treatment for depression, especially in patients who do not respond to initial antidepressant medication treatment. Although dTMS, and other forms of rTMS, are effective treatments, only about 50% of patients get a substantial clinical response and for some this can take a considerable period of time. Over recent years we have conducted extensive research developing methods to enhance treatment response to forms of rTMS including exploring whether improving the targeting of treatment into relevant brain areas can improve clinical outcomes. dTMS involves the application of repetitive pulses using a coil that has a deeper and wider area of stimulation of the brain. There are a number of dTMS coils commercially available which allow for stimulation of different areas of the brain. For example, H1 coil is typically used to stimulate a relatively large area of the lateral prefrontal cortex. In contrast, the H7 coil is applied to stimulate medial prefrontal regions. Evidence suggests that meaningful therapeutic benefits in patients with depression can be achieved with stimulation of both lateral and medial prefrontal cortex although there may be differences in the clinical characteristics of patients who respond to treatment at these two locations. The aim of the current research is to explore whether clinical outcomes may be improved using an approach which combines stimulation of these two sites. Specifically, we will compare treatment at the lateral prefrontal cortex with the H1 coil alone (current standard treatment) to a dual approach stimulating both lateral prefrontal cortex with the H1 coil and medial prefrontal cortex with the H7 coil.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121258 0
Prof Paul Fitzgerald
Address 121258 0
Florey Building, 54 Mills Road, The Australian National University, Canberra ACT 2601
Country 121258 0
Australia
Phone 121258 0
+61 2 6125 2622
Fax 121258 0
Email 121258 0
paul.fitzgerald@anu.edu.au
Contact person for public queries
Name 121259 0
Ms Gemma Lamp
Address 121259 0
Monarch Mental Health Group,
Level 4, 131 York Street Sydney NSW 2000
Country 121259 0
Australia
Phone 121259 0
+61 2 9072 2855
Fax 121259 0
Email 121259 0
monarchri_brainstimulation@mmhg.com.au
Contact person for scientific queries
Name 121260 0
Prof Paul Fitzgerald
Address 121260 0
Florey Building, 54 Mills Road, The Australian National University, Canberra ACT 2601
Country 121260 0
Australia
Phone 121260 0
+61 2 6125 2622
Fax 121260 0
Email 121260 0
paul.fitzgerald@anu.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
The PI has not yet decided whether IPD will be made available on public directories.


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.