Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001379707
Ethics application status
Approved
Date submitted
21/09/2022
Date registered
27/10/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
27/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
RELEASE: Redressing long-term antidepressant use in general practice
Scientific title
RELEASE: REdressing Long-tErm Antidepressant uSE in adults: A 3-arm cluster RCT effectiveness-implementation hybrid type-1 in general practice
Secondary ID [1] 308006 0
None
Universal Trial Number (UTN)
Trial acronym
RELEASE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Long-term antidepressant use 327678 0
Condition category
Condition code
Public Health 324763 324763 0 0
Health service research

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
RELEASE and RELEASE+ are user-informed multi-modal interventions based in general practice that target both GPs and patients on long-term antidepressants. The interventions have the following guiding principles:
- All prescribing decisions are made as usual by the GP and patient together.
- Empowering patients.
- Acceptable and translatable in routine general practice.
- Resources developed to raise awareness, prompt medication review, support decision-making, and guide safe cessation of long-term antidepressants when these medications are no longer clinically indicated.

RELEASE for GPs includes:
1) Interactive e-Learning module for GPs (30-60 minutes). Content includes information about antidepressant use in Australia, clinical guideline recommendations, adverse effects and risks associated with long-term antidepressant use, withdrawal symptoms, hyperbolic tapering of drug dose to minimise withdrawal symptoms and safely stop long-term antidepressants, and other strategies to mitigate withdrawal symptoms.

2) Outreach visit to Practice and GPs by research Practice Liaison Officer to:
a. Update practice management software to include printable antidepressant drug-specific tapering protocols
b. Update practice management software to include bespoke prescriptions for antidepressant drug mini-doses for hyperbolic tapering
c. Provide the practice with a list of practice patients enrolled in the study
d. Provide to each GP:
i. The RELEASE study Pack that includes copies of printable resources including drug-specific tapering protocols, Decision Aid, Medicines Information Brochure and a reporting adverse events proforma.
ii. One-on-one training (15-30 minutes) in the 3-As informed ‘RELEASE conversation’ medication review process, and prescribing for hyperbolic tapering of antidepressant drug dose. The mode of training includes case-based discussion, evidence-based medicine discussion, and demonstration of prescribing for hyperbolic tapering protocols.
RELEASE for GPs will be scheduled soon after practice randomisation, with delivery completed by 4-weeks when patients are informed of allocation and receive the RELEASE pack for patients.
3) Local community pharmacists near intervention practices will be provided with a letter outlining the study and informing pharmacists that patients may inquire about compounding of min-doses of antidepressants.
4) GP prompts to initiate RELEASE AAA conversations with patients on long-term antidepressants, every 28 days x 6 from week 0.

RELEASE for patients includes:
1) RELEASE Study pack
- Letter informing patients of allocation to RELEASE intervention group and inviting patients to schedule a medication review appointment with their GP. Researchers will prompt patient participants via email to schedule the medication review with their GP 4-weekly for 6 months.
- RELEASE pen and fridge magnet.
- A tri-fold evidence-based Medicines Information Brochure to raise awareness of antidepressant adverse effects and physiological withdrawal effects.
- A Decision Aid (1 double-sided A4 sheet) to support shared decision making and to help patients weigh up the risks and potential benefits of stopping or continuing antidepressants.
- A drug-specific tapering protocol (1 double-sided A4 sheet), providing step by step guidance for slow tapering of antidepressant drug dose, including advice on flexibility of tapering speed and availability of drug mini-doses via compounding chemists. Tapering protocols advise patients that if withdrawal symptoms occur and are unbearable to return to previous drug dose for symptom relief and, when ready to try again, use a more gradual taper with smaller dose reductions and/or longer steps.
- A family and friends brochure to help patients communicate with family and friends by raising awareness of antidepressant adverse effects and physiological withdrawal effects, to address the common misconception that depression is a long-term condition caused by a chemical (serotonin) deficiency in the brain that requires long-term medication, and to provide ways in which to support someone stopping antidepressants as a friend or family member.

2) RELEASE conversation medication review with GP: Participants are invited to schedule and attend a medication review appointment with their GP. The duration is not specified, although the standard appointment is 15 minutes. Usual fee applies to ensure scalability. The medication review includes the RELEASE conversation and shared decision-making based around the RELEASE Decision Aid. If the patient decides to discontinue antidepressants, then the GP may provide the RELEASE drug-specific tapering protocol and prescriptions for requisite antidepressant drug mini-doses. Cost to the patient for the antidepressant drug mini-doses is 50c-$1 per capsule from compounding chemist depending on quantity. All prescribing decisions are made as usual by the GP and patient together.

3) Follow-up with GP: Follow-up with GP as determined by the GP and patient together.

Strategies used to monitor adherence to the intervention include data collected from the patients’ GP electronic health record (number of GP visits, prescriptions etc), and interviews with both GPs and patients.

The RELEASE+ intervention is a more intensive intervention and in addition to the above includes:
For GPs - additional outreach visit from researcher Practice liaison officer supported by audit and feedback of practice prescribing data, and
For patients - use of an App that includes the RELEASE resources and links to e-mental health support sites, and that provides prompts to patients to see their GP for medication review. The app is specifically designed for this study. Patients will be provided an opportunity to access the app for the duration of the intervention, during which they will be free to use the app as they wish. There is no minimum frequency of use.
Intervention code [1] 324459 0
Treatment: Other
Comparator / control treatment
Practice as usual in the control practices. That is, all doctors in control practices will participate as usual in any quality improvement initiatives, audit activities, continuing medical education activities, and any other practice activities. All prescribing decisions will be made as usual by the doctor in discussion with the patient.
Control group
Active

Outcomes
Primary outcome [1] 332585 0
Antidepressant discontinuation self-reported by patients via study-specific online questionnaire. Discontinuation is defined as 0mg antidepressant maintained for at least 2 weeks.
Timepoint [1] 332585 0
At 12 months post participant allocation
Secondary outcome [1] 413977 0
Proportion of participants achieving 75% reduction of antidepressants self-reported by patients via study-specific online questionnaire
Timepoint [1] 413977 0
12-months post participant allocation
Secondary outcome [2] 413978 0
Health-related quality of life assessed via the 12-Item Short Form Survey (SF-12).
Timepoint [2] 413978 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [3] 413979 0
Antidepressant side effects assessed via the 12-item Antidepressant Side Effect Checklist (ASEC-12)
Timepoint [3] 413979 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [4] 413980 0
Wellbeing assessed via the Warwick Edinburgh Mental Well-being Scale (WEMWBS-14)
Timepoint [4] 413980 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [5] 413981 0
Beliefs about antidepressants assessed via the Beliefs about Medications Questionnaire-Specific.
Timepoint [5] 413981 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [6] 413982 0
Antidepressant withdrawal symptoms assessed via the 15-item Distinctive Antidepressant Withdrawal Scale.
Timepoint [6] 413982 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [7] 413983 0
Depressive symptoms assessed via the Patient Health Questionnaire (PHQ-9)
Timepoint [7] 413983 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [8] 413984 0
Anxiety symptoms assessed via the Generalized Anxiety Disorder measure (GAD-7).
Timepoint [8] 413984 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [9] 414689 0
Emotional numbing assessed via the Emotional Reactivity and Numbing Questionnaire (ERNQ).
Timepoint [9] 414689 0
Baseline, 6-months post-randomisation, 12-months post-randomisation
Secondary outcome [10] 414808 0
Acceptability, appropriateness and feasibility (e.g., whether RELEASE is a ‘good’ fit for practice workflows and could be translated into routine care) will be assessed via semi-structured interviews conducted face-to-face or via telephone/zoom with a purposive sub-sample of GPs and patients.

Timepoint [10] 414808 0
Recruitment for interviews with GPs and patients will commence at about 6-months post the first practice randomisation.
Secondary outcome [11] 414809 0
Adoption will be assessed by reviewing the number of practices and GPs approached to take part, interested in taking part, and taking part, number of patients de-selected by GPs and why (recorded by GPs on a GP log), percentage of eligible patients that enrolled in the study.
Timepoint [11] 414809 0
Adoption will be assessed 12-months post the last practice randomisation.
Secondary outcome [12] 414810 0
Fidelity will be assessed by reviewing the number of GPs who attended the one-on-one outreach training. Website analytics will be used to assess fidelity to training.
Timepoint [12] 414810 0
Fidelity will be assessed 12-months post the last practice randomisation.
Secondary outcome [13] 417542 0
Aggregated practice level antidepressant prescribing data. This data will be collected via TorchRecruit. (TorchRecruit is the software used to generate the lists at baseline and so will be the same process at 12m, done remotely via TorchRecruit).
Timepoint [13] 417542 0
at baseline and 12-months follow-up.

Eligibility
Key inclusion criteria
18 years or older AND

Currently on antidepressant medication AND

On any combination of antidepressant medication with a total duration of longer than 12 months including selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and other antidepressants including Mirtazapine, Vortioxetine, Mianserin, Moclobemide, Reboxetine, Agomelatine.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
GP considers the patient not suitable for medication review (for example, recent personal crisis)

Bipolar disorder

History of psychotic or obsessive-compulsive disorder

Currently under care of a psychiatrist

Current substance use disorder

Non-psychiatric indication for antidepressant (for example, neuropathic pain)

Dementia or unable to give informed consent

Not on antidepressants

Not on antidepressants for longer than 12 months

Aged care residents

Study design
Purpose of the study
Educational / counselling / training
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will occur via an off-site web-based randomisation service.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation using web-based interactive program.
Randomisation is clustered at the practice level to avoid contamination between intervention and usual care arms. Practice randomization occurs after baseline data collection is closed for each practice to avoid bias in GP de-selection. Randomisation occurs in a 1.5:1:1 usual care:RELEASE:RELEASE+ ratio via a central web-based randomisation service. Practices are stratified by size (>5 / <5 FTE GPs). Randomisation occurs in blocks of size 7 or 14, with block size randomly assigned in a 1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
3-arm pragmatic cluster randomised controlled trial (effectiveness-implementation hybrid type 1). The ratio chosen for allocation is 1.5:1:1 Usual care:RELEASE:RELEASE+.
The unit of randomisation is the practice to avoid contamination between intervention and control arms, and the unit of analysis is the individual patient
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A full statistical analysis plan will be developed prior to the final analysis of trial data. The unit of analysis is the individual patient. Analyses will account for the clustering at practice level. Outcomes will be analysed on an intention-to-treat basis. Summary statistics will be described using either mean (standard deviation) or median (25th-75th percentile) for continuous variables, according to distribution, or as frequency (percentage) for categorical variables.
The primary outcome will be assessed using mixed-effects logistic regression, with effect estimates presented as odds ratio and 95% confidence interval (95% CI). Treatment group (RELEASE/RELEASE+/Usual care) will be included as the main fixed effect and the practice will be included as a random effect to account for probable non-independence of results from participants who attend the same practice. The primary outcomes of interest are the between-group comparisons of RELEASE versus Usual care and RELEASE+ versus Usual care. Secondary outcomes will similarly be analysed using mixed-effects models, using linear regression for interval outcomes, logistic regression for binary outcomes, and Poisson regression for count outcomes. All models will include the practice as a random effect. Longitudinal associations will be investigated using analyses that account for the multiple observations per participant, with the particular analysis determined by data structure, for example, three-level hierarchical mixed-effects models with ‘patient’ nested within ‘GP’ nested within ‘practice’ where appropriate. With regard to missing data, sensitivity analyses will be conducted using imputation models. Patients who drop out before assessment will be classified as ‘not able to stop’.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/01/2023
Actual
14/03/2023
Date of last participant enrolment
Anticipated
31/07/2024
Actual
Date of last data collection
Anticipated
31/07/2025
Actual
Sample size
Target
653
Accrual to date
242
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 312269 0
Government body
Name [1] 312269 0
Commonwealth Department of Health (MRFF Clinician Researchers Applied Research in Health - MRFAR000079)
Country [1] 312269 0
Australia
Funding source category [2] 314778 0
Government body
Name [2] 314778 0
Australian Government National Health and Medical Research Council
Country [2] 314778 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
ST LUCIA QLD 4067
Australia
Country
Australia
Secondary sponsor category [1] 313815 0
None
Name [1] 313815 0
Address [1] 313815 0
Country [1] 313815 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311643 0
The University of Queensland Human Research Ethics Committee
Ethics committee address [1] 311643 0
ST LUCIA QLD 4067
Australia
Ethics committee country [1] 311643 0
Australia
Date submitted for ethics approval [1] 311643 0
14/09/2022
Approval date [1] 311643 0
18/10/2022
Ethics approval number [1] 311643 0
2022/HE001667

Summary
Brief summary
This 3-arm pragmatic effectiveness-implementation hybrid type-1 cluster randomised controlled trial in general practice will determine effectiveness and cost-effectiveness of two multi-strategy interventions, RELEASE and RELEASE+, in supporting safe cessation of long-term antidepressants when there is no clinical indication for continued use. Implementation strategies will be evaluated and assessed for scale up to improve primary health care and outcomes for patients.
All prescribing decisions are made as usual by patient and GP together.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121826 0
Prof Katharine Wallis
Address 121826 0
Medical School
The University of Queensland
Level 8, Health Sciences Building 901/813
Brisbane Qld 4029 Australia
Country 121826 0
Australia
Phone 121826 0
+61 7 3365 5545
Fax 121826 0
Email 121826 0
k.wallis@uq.edu.au
Contact person for public queries
Name 121827 0
Prof Katharine Wallis
Address 121827 0
Medical School
The University of Queensland
Level 8, Health Sciences Building 901/813
Brisbane Qld 4029 Australia
Country 121827 0
Australia
Phone 121827 0
+61 7 3365 5545
Fax 121827 0
Email 121827 0
k.wallis@uq.edu.au
Contact person for scientific queries
Name 121828 0
Prof Katharine Wallis
Address 121828 0
Medical School
The University of Queensland
Level 8, Health Sciences Building 901/813
Brisbane Qld 4029 Australia
Country 121828 0
Australia
Phone 121828 0
+61 7 3365 5545
Fax 121828 0
Email 121828 0
k.wallis@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
Only to achieve the aims in the approved proposal.
How or where can data be obtained?
Access to data is subject to approval by the Principal Investigator Professor Katharine Wallis. Requests for access to data can be sent to Professor Katharine Wallis via email (k.wallis@uq.edu.au). Individuals will be required to sign a data access agreement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17156Ethical approval    384692-(Uploaded-04-01-2023-13-25-09)-Study-related document.pdf
17157Informed consent form    384692-(Uploaded-29-08-2023-14-28-20)-Study-related document.pdf
17158Study protocol    384692-(Uploaded-16-01-2024-15-31-54)-Study-related document.pdf
18054Ethical approvalEthics approval for Amendment 1   384692-(Uploaded-09-01-2023-15-07-24)-Study-related document.pdf



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRELEASE (REdressing Long-tErm Antidepressant uSE): protocol for a 3-arm pragmatic cluster randomised controlled trial effectiveness-implementation hybrid type-1 in general practice.2023https://dx.doi.org/10.1186/s13063-023-07646-w
N.B. These documents automatically identified may not have been verified by the study sponsor.