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Trial registered on ANZCTR


Registration number
ACTRN12622000474752
Ethics application status
Approved
Date submitted
15/03/2022
Date registered
25/03/2022
Date last updated
20/07/2023
Date data sharing statement initially provided
25/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
TIDE (Trimetazidine in bipolar depression): A double-blind, randomised, placebo-controlled trial
Scientific title
TIDE (Trimetazidine in bipolar depression): A double-blind, randomised, placebo-controlled trial to evaluate the effect of trimetazidine on depressive symptoms in patients with bipolar disorder
Secondary ID [1] 306682 0
None
Universal Trial Number (UTN)
U1111-1275-6995
Trial acronym
TIDE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar depression 325631 0
Condition category
Condition code
Mental Health 322986 322986 0 0
Depression
Mental Health 323100 323100 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
8 weeks of adjunctive trimetazidine 35 mg oral tablet, twice a day. Treatment adherence will be assessed by tablet count of returned trial medication bottles.
Intervention code [1] 323133 0
Treatment: Drugs
Comparator / control treatment
Placebo (starch) tablets matched in appearance and weight.
Control group
Placebo

Outcomes
Primary outcome [1] 330752 0
Change in severity of mood symptoms, measured using Montgomery-Åsberg Depression Rating Scale (MADRS).
Timepoint [1] 330752 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement. Week 8 is the primary endpoint.
Secondary outcome [1] 407438 0
Change in severity of global symptomology, measured using Clinical Global Improvement for Bipolar Disorder (CGI-BP).
Timepoint [1] 407438 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [2] 407439 0
Change in severity of perceived symptomology, measured using Patient Global Impression Scale, (PGI).
Timepoint [2] 407439 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [3] 407440 0
Change in severity of mania symptomatology, measured using Young Mania Rating Scale (YMRS).
Timepoint [3] 407440 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [4] 407441 0
Change in severity of anxiety symptoms, measured using Hamilton Anxiety Rating Scale (HAM-A).
Timepoint [4] 407441 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [5] 407442 0
Change in the level of perceived quality of life measured by Quality of Life in Bipolar Disorder (QoL-BD).
Timepoint [5] 407442 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [6] 407457 0
Change in the level of day-to-day functioning measured by Functioning Assessment Short Test (FAST).
Timepoint [6] 407457 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [7] 407468 0
Change in the level of cognitive function measured by the COGSTATE battery.
Timepoint [7] 407468 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [8] 407472 0
Change in the level of functional impairments measured by Range of Impaired Functioning Tool (LIFE-RIFT).
Timepoint [8] 407472 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [9] 407473 0
Change in the level of clinical fatigue measured by Fatigue Severity Scale (FSS).
Timepoint [9] 407473 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.
Secondary outcome [10] 407474 0
The EuroQol-5 dimension (EQ-5D) will be used to measure preference-based utility to calculate Quality Adjusted Life Years (QALYs), which will be analysed for the trial population and also be incorporated into the modelled economic evaluation, where $50,000 per QALY is the accepted benchmark for cost-effectiveness. Cost-effectiveness are measured using the Resource Use Questionnaire (RUQ), Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH).
Timepoint [10] 407474 0
Conducted at all trial visits - Baseline (week 0 - pre-intervention) and Weeks 2, 4, and 8 post-intervention commencement.

Eligibility
Key inclusion criteria
I. Aged 18-65 years;
II. Have a DSM-V diagnosis of bipolar disorder I or II, or bipolar disorder not elsewhere classified (NEC);
III. Currently be in a major depressive episode on Structured Clinical Interview for DSM Disorders (SCID-5-RV);
IV. Score greater than or equal to 20 on the Montgomery Åsberg Depression Rating Scale (MADRS);
V. have the capacity to consent to the study and to follow its instructions and procedures;
VI. be using effective contraception if a sexually active woman of a childbearing age;
VII. be able to speak, read, write, and understand their national language;
VIII. have been on stable pre-existing pharmacological or psychotherapy regimens for 4 weeks prior to study entry (to mitigate the risk of induction of mania all participants will also need to be on an accepted mood stabiliser);
IX. Participants will be required to nominate a current treating physician prior to randomization.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
I. have a known or suspected active systemic medical disorder;
II. have a primary clinical diagnosis of another disorder such as borderline personality disorder, assessed using the SCID-5-RV;
III. have a diagnosis of another psychotic disorder and/or current substance use disorder, assessed using the SCID-5-RV;
IV. be undergoing electroconvulsive or transcranial magnetic stimulation therapy;
V. have contraindications or intolerance or allergy to trimetazidine or any of the trial preparations;
VI. have a concurrent enrolment in another psychiatric clinical trial;
VII. are pregnant or lactating (participants will be requested to conduct a urine pregnancy test if sexually active and of child-bearing age);
VIII. Inability to comply with either the requirements of informed consent or the treatment protocol;
IX. Any history of renal disease/impairment, Parkinson’s disease, restless legs syndrome or other movement disorders.

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)
After the baseline assessment has been completed, the participant will be randomised to either the trimetazidine group or the placebo group. The Coordinating Investigator will randomise participants using computerised number generator and retain the random allocation list. Copies of the randomisation list will be sealed in an opaque envelope in a locked filing cabinet with the Principal Investigator and in pharmacy at each site. Drug bottles are identical to conceal treatment allocation and the containers will be numbered. To facilitate the double-blinding process, the trial medications will be dispensed by an independent pharmacist in identical numbers and tablet forms in sealed containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to treatment arms will be randomly assigned in a 1:1 ratio (active to placebo) using permutated block randomisation. Permutated block randomisation utilising a block design on a computer-generated randomisation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be based on all randomised participants. Reporting of research findings will be in accordance with CONSORT guidelines. The biostatistician will be blinded to group allocation until analysis stage. To examine the primary hypothesis, generalised estimating equation (GEE) four continuous outcomes will be used. The GEE model will include the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariate of baseline MADRS score. The two-way treatment-by-visit interaction at post intervention follow-ups will estimate baseline adjusted between-group mean differences and hence are the primary comparisons. The GEE includes all available data at each time point and is the preferred method of analysing longitudinal clinical trial data to deal with missingness assuming missing at random (i.e. an intention to treat approach). Within-participant autocorrelation will be accounted for by an unstructured working correlation matrix. Planned comparisons will be done with the GEE models to determine baseline-adjusted between-group mean differences in symptom change from baseline to week 8. Sensitivity analysis to evaluate missing at random assumption for missing follow-up data is planned. Multiple imputation of missing data will be considered where necessary. All secondary continuous outcome measures will be analysed using the same approach as the primary outcome. Dichotomous data will be presented as proportions, with their respective 95% confidence intervals (CIs), and reporting Chi-square or Fisher’s exact p-value where appropriate. GEE approach with logit link will be used to compare dichotomous outcomes. Non-parametric statistics will be used when parametric assumptions are violated. Effect sizes will be calculated using Cohen’s guidelines. Pearson Product Moment Correlations will be used to examine the relationships between symptom and biological markers change. All tests will be conducted using a two-sided alpha level of 0.05 and 95% CIs will be reported. A detailed statistical analysis plan will be developed prior to unblinding of data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2023
Actual
Date of last participant enrolment
Anticipated
30/09/2026
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
260
Accrual to date
Final
Recruitment outside Australia
Country [1] 24663 0
India
State/province [1] 24663 0
Bengaluru
Country [2] 24664 0
India
State/province [2] 24664 0
Ranchi
Country [3] 24665 0
Spain
State/province [3] 24665 0
Barcelona

Funding & Sponsors
Funding source category [1] 311013 0
Charities/Societies/Foundations
Name [1] 311013 0
Stanley Medical Research Institute
Country [1] 311013 0
United States of America
Primary sponsor type
University
Name
Deakin University
Address
Locked Bag 20000
GEELONG VIC 3220
Australia
Country
Australia
Secondary sponsor category [1] 312342 0
Other Collaborative groups
Name [1] 312342 0
National Institute of Mental Health and Neurosciences
Address [1] 312342 0
No.29, Hosur Rd
Ayappa Garden, Adugodi
Bengaluru,
Karnataka 560030
India
Country [1] 312342 0
India
Secondary sponsor category [2] 312343 0
Hospital
Name [2] 312343 0
Central Institute of Psychiatry
Address [2] 312343 0
Kanke, Ranchi
Jharkhand
Pin-834006
India
Country [2] 312343 0
India
Secondary sponsor category [3] 312345 0
Hospital
Name [3] 312345 0
Hospital Clinic De Barcelona
Address [3] 312345 0
170 C. de Villarroel
Barcelona 08036
Spain
Country [3] 312345 0
Spain

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310561 0
Deakin University Human Research Ethics Committee (DUHREC)
Ethics committee address [1] 310561 0
Human Research Ethics Office
Deakin University
221 Burwood Hwy
Burwood, VIC 3125
Ethics committee country [1] 310561 0
Australia
Date submitted for ethics approval [1] 310561 0
17/03/2022
Approval date [1] 310561 0
18/07/2022
Ethics approval number [1] 310561 0
2022-114

Summary
Brief summary
Bipolar disorder is a highly debilitating illness characterized by two illness phases - mania and depression. It is the depressive phase that confers the greatest burden of disease and is associated with the highest risk of suicide. Only 3 evidence based medications approved by the Food and Drug Administration (FDA) are available for treating acute bipolar depression. Despite these therapies, patients spend more than half of their symptomatic periods depressed.

The failure in bipolar depression treatment discovery is largely due to its complex pathophysiology with many known and unknown biological and environmental factors. Typical drug development paradigms that target single proteins insufficiently address this challenge. We have bypassed this obstacle using an entirely novel in silico approach, which identified trimetazidine as having effects that mimic a combination of current bipolar disorder medications.

Trimetazidine’s ability in optimising energy generation dovetails with our research highlighting bipolar depression as a state of decreased energy generation and mania of increased energy generation. Trimetazidine is also highly accessible, affordable, and has regulatory approval to treat angina in India and Europe. It is then logical to clinically evaluate trimetazidine in a double-blind, randomised, placebo-controlled trial in people with bipolar depression. We have assembled a world-class investigator team to test trimetazidine’s efficacy in reducing bipolar depression in a Phase 2 clinical trial to be conducted in India and Spain, as the agent is registered and widely used in those countries. A positive outcome here would have immediate clinical relevance, providing a novel therapy for bipolar depression and providing concrete evidence for a novel mechanism of disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118090 0
Prof Michael Berk
Address 118090 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 118090 0
Australia
Phone 118090 0
+61 3 4215 3330
Fax 118090 0
Email 118090 0
michael.berk@deakin.edu.au
Contact person for public queries
Name 118091 0
Prof Michael Berk
Address 118091 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 118091 0
Australia
Phone 118091 0
+61 3 4215 3330
Fax 118091 0
Email 118091 0
michael.berk@deakin.edu.au
Contact person for scientific queries
Name 118092 0
Prof Michael Berk
Address 118092 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 118092 0
Australia
Phone 118092 0
+61 3 4215 3330
Fax 118092 0
Email 118092 0
michael.berk@deakin.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 de-identified clinical trial data will be available following publication of the primary data and a-priori secondary data.
When will data be available (start and end dates)?
Data will be available following publication of primary and a-priori secondary outcomes. No end date.
Available to whom?
Available to research staff with appropriate Human Research and Ethics approval (if requesting directly to TIDE principal investigator) or National Database for Clinical Trials related to Mental Illness (NDCT) approval (if accessing through NDCT).
Available for what types of analyses?
All types, both individual-level analyses as well as meta-analyses.
How or where can data be obtained?
Data can be directly requested (via email: impact@deakin.edu.au) from the Investigators and will be approved on a case-by-case arrangement. Data can also be requested to National Database for Clinical Trials related to Mental Illness (NDCT), which will also be approved on a case-by-case arrangement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15424Study protocolWill be published once ethics is approved.  



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseMetabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine.2023https://dx.doi.org/10.1038/s41380-023-02134-8
N.B. These documents automatically identified may not have been verified by the study sponsor.