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Trial registered on ANZCTR


Registration number
ACTRN12616000028404
Ethics application status
Approved
Date submitted
17/12/2015
Date registered
18/01/2016
Date last updated
27/09/2023
Date data sharing statement initially provided
28/03/2019
Date results information initially provided
28/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The efficacy of adjunctive Garcinia mangostana linn (mangosteen) pericarp for bipolar depression: A 24-week double-blind, randomised, placebo controlled trial.
Scientific title
The efficacy of adjunctive Garcinia mangostana linn (mangosteen) pericarp for bipolar depression: A 24-week double-blind, randomised, placebo controlled trial.
Secondary ID [1] 288135 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
MANGO BD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bipolar depression 297013 0
Condition category
Condition code
Mental Health 297260 297260 0 0
Depression
Mental Health 297261 297261 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1000mg/day of oral (2 capsules, once a day) of adjunctive Garcinia Mangostana Linn. (mangosteen) pericarp will be trialled against placebo for 24 weeks to determine the efficacy of mangosteen pericarp for the treatment of bipolar depression. Adherence will be monitored by participants returning all bottles of investigational product, including any unused capsules.
Intervention code [1] 293444 0
Treatment: Drugs
Comparator / control treatment
Placebo (inactive starch)
Control group
Placebo

Outcomes
Primary outcome [1] 296851 0
Change in severity of mood symptoms, measured using the Montgomery Åsberg Depression Rating Scale (MADRS).
Timepoint [1] 296851 0
Conducted at all trial visits - Baseline (week 0) and every four weeks after that (week 4, 8, 12, 16, 20, 24)
Secondary outcome [1] 319518 0
Change in Clinical Global Impressions - Improvement Scale (CGI-I)
Timepoint [1] 319518 0
Conducted at all trial visits post Baseline - week 4, 8, 12, 16, 20, 24 and week 28 (4 weeks post discontinuation).
Secondary outcome [2] 319519 0
Change in Clinical Global Impressions - Severity Scale (CGI-S)
Timepoint [2] 319519 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [3] 319520 0
Change in anxiety symptoms based on the Hamilton Anxiety Rating Scale (HAM-A).
Timepoint [3] 319520 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [4] 319521 0
Change in bipolar symptomology as measured by Bipolar Depression Rating Scale (BDRS)
Timepoint [4] 319521 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [5] 319522 0
Change in mania symptomology measured by the Young Mania Rating Scale (YMRS)
Timepoint [5] 319522 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and four weeks post-discontinuation at week 28
Secondary outcome [6] 319523 0
Change in Patient Global Impression Scale (PGI)
Timepoint [6] 319523 0
Conducted every four weeks after baseline (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [7] 319524 0
Change in quality of life measured by Quality of life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF).
Timepoint [7] 319524 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [8] 319525 0
Change in Functioning measured by Social Occupational Functioning Scale (SOFAS)
Timepoint [8] 319525 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [9] 319526 0
Change in Functioning measured by Range of Impaired Functioning Tool (LIFE-RIFT)
Timepoint [9] 319526 0
Conducted at all trial visits - Baseline (week 0), every four weeks after that (week 4, 8, 12, 16, 20, 24) and week 28 (4 weeks post discontinuation).
Secondary outcome [10] 319527 0
Change in oxidative stress (malondialdehyde) markers
Timepoint [10] 319527 0
Bloods collected from consenting participants at baseline and week 24, where participant contact is allowable.
Secondary outcome [11] 319575 0
Changes in severity of mood symptoms following discontinuation of trial medication, measured using MADRS
Timepoint [11] 319575 0
The post-discontinuation of treatment (week 28) will be analysed both between week 24 and week 28.
Secondary outcome [12] 319888 0
Change in inflamatory (IL-6, TNF-alpha and CRP) markers
Timepoint [12] 319888 0
Bloods collected from consenting participants at baseline and week 24
Secondary outcome [13] 319889 0
Change in neuroprotection (BDNF) markers
Timepoint [13] 319889 0
Bloods collected from consenting participants at baseline and week 24
Secondary outcome [14] 342081 0
Change in RNA expression
Timepoint [14] 342081 0
Bloods collected from consenting participants at baseline and week 24
Secondary outcome [15] 342082 0
Change in other relevant biological markers not yet identified, this is an exploratory outcome.
Timepoint [15] 342082 0
Bloods collected from consenting participants at baseline and week 24
Secondary outcome [16] 342083 0
Economic evaluation of adjunctive mangosteen pericarp treatment compared to placebo, where $50,000 per quality adjusted life year (QALY) is the accepted benchmark for cost-effectiveness. Measured using the Health Service Use Questionnaire and the Assessment of Quality of Life (AQoL-4D).
Timepoint [16] 342083 0
Conducted at 3 trial visits - Baseline (week 0), week 12, and week 24
Secondary outcome [17] 342084 0
Changes in cognition as measured on pen and paper tasks (forward and backward digit span, trail making and symbol digit task)
Timepoint [17] 342084 0
comparison between baseline and week 24

Eligibility
Key inclusion criteria
1. Must be required to meet DSM-5 criteria for bipolar disorder I or II, or bipolar disorder not elsewhere classified (NEC) and be currently be in a major depressive episode on SCID-5-RV

2. Have a current episode of depressive illness with a MADRS score greater than or equal to 20

3. Have capacity to consent to the study and comply with study procedures

4. Any form of therapy must be stable for the last month

5. Using effective contraception if female, sexually active and of child bearing potential

6. Be able to speak, read, write and understand the English language,

7. Participants will be required to nominate a current treating physician and will not be eligible to enter the study until one is identified.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants with a known or suspected active systemic medical disorder,

2. Individuals who are pregnant or lactating (participants will be requested to conduct a urine pregnancy test if sexually active and of child-bearing age),

3. Participants currently enrolled in any other intervention study will be excluded,

4. Individuals who are intolerant, allergic to or have had an anaphylactic reaction to any components of the preparation,

5. Inability to comply with either the requirements of informed consent or the treatment protocol.

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)
An independent researcher utilising a block design will develop the computer-generated randomisation plan. Trial clinicians will allocate packs sequentially, and bottles are identical so as to conceal treatment allocation and blinding. To facilitate the double-blinding process, the trial medications will be dispensed by an independent pharmacist in identical numbers and capsule forms in sealed containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
All analyses will be conducted in accordance with the International Conference on Harmonization E9 statistical principles, and are based on all randomised participants with at least one post-baseline observation (intention to treat population). Reporting of research findings will be done in accordance to CONSORT guidelines. The statistician responsible for the analysis of outcome data will be blind to group allocation. The primary efficacy analysis will assess average treatment group differences for the primary outcome measure MADRS total score over the entire study period and will use a likelihood based mixed-effects model, repeated measures approach (MMRM). The MMRM model includes the fixed, categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. The MMRM includes all available data at each time point and is the preferred method of analyzing clinical trial data in psychiatry as compared to more traditional repeated measures analysis of variance (ANOVA) and analysis of covariance models (ANCOVA). Planned comparisons will be done with the MMRM models to determine between group differences in change of symptoms measures from baseline to week 24. Results from the analysis of dichotomous data will be presented as proportions, with 95% confidence interval, and Fisher’s exact p-value where appropriate. Non-parametric statistics will be used when assumptions for parametric methods are violated. Effect sizes will be calculated using Cohen’s guidelines. All tests of treatment effects will be conducted using a two-sided alpha level of 0.05 and 95% confidence intervals. Baseline characteristics of each treatment arm will be summarised using descriptive statistics and will be formally tested using chi square for categorical variables or independent t-test for continuous variables. We will consider adjusting for one or more predictors in our multivariable analysis to account for any imbalance that may have occurred by chance between the randomized groups. Change scores in symptoms and in biological markers will be derived. Pearson Product Moment Correlations will be used to examine the relationships between the change scores for symptoms and the change scores for biological markers in the two groups. Using Fisher’s z transformation, we will test whether the correlations obtained for each group are statistically different in terms of strength.

We are aiming for a target sample size of 150 participants. For a two tailed analysis with alpha=0.05, Z alpha = 1.96 and with ß=0.2, Zß = 0.8, N=120, the study should be powered at 80% to detect a true difference in MADRS scale score between the mangosteen pericarp and placebo groups if the effect size is Cohen’s d=0.362 or greater. This is a conservative estimate, based on the results of the pilot data. However, in our previous trial of N-acetylcysteine specifically investigating bipolar depression, effect sizes for depressive symptoms (BDRS, MADRS), clinical global impression of depressive severity (CGI BP-depression), as well as all functional measures have shown effects similar to or above the effect size the sample has been calculated for. Based on our previous trials we typically have an attrition rate of 20%. Therefore, although power calculations indicated 120 participants will be sufficient to detect between group differences, we plan to recruit 150 participants to account for attrition.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/02/2016
Actual
6/06/2016
Date of last participant enrolment
Anticipated
30/09/2020
Actual
3/11/2020
Date of last data collection
Anticipated
13/11/2020
Actual
26/05/2021
Sample size
Target
150
Accrual to date
Final
152
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 4938 0
The Melbourne Clinic - Richmond
Recruitment hospital [2] 4939 0
Albert Road Clinic - Melbourne
Recruitment hospital [3] 9812 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 17212 0
Toowong Specialist Clinic - Toowong
Recruitment postcode(s) [1] 12446 0
3004 - Melbourne
Recruitment postcode(s) [2] 12445 0
3121 - Richmond
Recruitment postcode(s) [3] 18590 0
3220 - Geelong
Recruitment postcode(s) [4] 18589 0
4066 - Toowong

Funding & Sponsors
Funding source category [1] 292543 0
University
Name [1] 292543 0
Deakin University, IMPACT SRC Seed Funding Grant
Country [1] 292543 0
Australia
Funding source category [2] 296560 0
Government body
Name [2] 296560 0
NHMRC
Country [2] 296560 0
Australia
Primary sponsor type
Hospital
Name
Barwon Health
Address
Research Ethics, Governance and Integrity (REGI) Unit
PO BOX 281
Geelong Victoria 3220
Country
Australia
Secondary sponsor category [1] 291260 0
None
Name [1] 291260 0
Address [1] 291260 0
Country [1] 291260 0
Other collaborator category [1] 278731 0
University
Name [1] 278731 0
University of Melbourne
Address [1] 278731 0
The University of Melbourne
Victoria 3010
Country [1] 278731 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294018 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 294018 0
Research Ethics, Governance and Integrity (REGI) Unit
PO BOX 281
Geelong Victoria 3220
Ethics committee country [1] 294018 0
Australia
Date submitted for ethics approval [1] 294018 0
26/08/2015
Approval date [1] 294018 0
18/11/2015
Ethics approval number [1] 294018 0
Ethics committee name [2] 294019 0
The Melbourne Clinic Research Ethics Committee
Ethics committee address [2] 294019 0
130 Church St
RICHMOND, VIC 3121
Ethics committee country [2] 294019 0
Australia
Date submitted for ethics approval [2] 294019 0
31/07/2015
Approval date [2] 294019 0
26/08/2015
Ethics approval number [2] 294019 0
Ethics committee name [3] 294057 0
Deakin University Human Research Ethics Committee
Ethics committee address [3] 294057 0
Burwood Campus
Postal: 221 Burwood Highway
Burwood Victoria 3125
Ethics committee country [3] 294057 0
Australia
Date submitted for ethics approval [3] 294057 0
02/12/2015
Approval date [3] 294057 0
16/12/2015
Ethics approval number [3] 294057 0

Summary
Brief summary
Aims
The primary aim of this study is to investigate the efficacy of adjunctive mangosteen pericarp 1000mg/day for the treatment of bipolar depression using a 24 Week randomised, placebo controlled trial. The primary outcome measure will be the change in severity of mood symptoms, measured using the Montgomery Asberg Depression Rating Scale (MADRS). Secondary outcomes include global psychopathology, substance use, functioning, quality of life, and safety and tolerability data. A follow-up interview will be conducted 4 weeks posttreatment to determine any outcomes following cessation of the trial agent.

Method
We plan to recruit a total of 150 participants aged 18+years with moderate to severe bipolar depression (having a DSM5 diagnosis of bipolar I or II or bipolar disorder not elsewhere classified (NEC), determined using the Structured Clinical Interview for DSM Disorders 5 (SCID5), currently be in a major depressive episode on SCID5, and meeting criteria of a Montgomery Asberg Depression Rating Scale (MADRS) score of greater than or equal to 20.

Participants will attend a screening visit to ascertain suitability and once randomized they will receive a month’s supply of either 1000mg/day of mangosteen or matched placebo to be taken in addition to their treatment as usual. Participants take two capsules per day.

Participants will visit the study site at weeks 4, 8, 12, 16, 20 24 and 28 (4 weeks posttreatment discontinuation) where a battery of validated outcome measures will be administered by trained research staff. Participants will be asked to discuss their symptoms, side effects and any issues the participant would like to raise regarding the trial. Participants will be notified of which arm of the study they took part in and a summary of results at the completion of the study.
Trial website
https://mangosteenbipolar.com/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61838 0
A/Prof Olivia Dean
Address 61838 0
IMPACT SRC
P.O. Box 281
Geelong, Victoria
3220
Country 61838 0
Australia
Phone 61838 0
+61 3 4215 3300
Fax 61838 0
+61 3 4215 3491
Email 61838 0
oliviad@barwonhealth.org.au
Contact person for public queries
Name 61839 0
A/Prof Olivia Dean
Address 61839 0
IMPACT SRC
P.O. Box 281
Geelong, Victoria
3220
Country 61839 0
Australia
Phone 61839 0
+61 3 4215 3300
Fax 61839 0
+61 3 4215 3491
Email 61839 0
oliviad@barwonhealth.org.au
Contact person for scientific queries
Name 61840 0
A/Prof Olivia Dean
Address 61840 0
IMPACT SRC
P.O. Box 281
Geelong, Victoria
3220
Country 61840 0
Australia
Phone 61840 0
+61 3 4215 3300
Fax 61840 0
+61 3 4215 3491
Email 61840 0
oliviad@barwonhealth.org.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 participant data will be available following publication of the primary 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?
Data are potentially available to:
* researchers from not-for profit organisations;
* commercial organisations; or
* other research staff with appropriate Human Research and Ethics Approval;
based in any location.
Available for what types of analyses?
Data are potentially available for all types of analysis, both patient-level analyses as well as meta-analyses.

All data requests will be considered on a case-by-case basis. Please contact Olivia Dean at Deakin University.
https://impact-trials.deakin.edu.au/
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
1721Study protocol    369695-(Uploaded-10-08-2023-14-23-04)-Study-related document.pdf
20514Data dictionary    369695-(Uploaded-15-09-2023-16-45-15)-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
EmbaseThe therapeutic potential of mangosteen pericarp as an adjunctive therapy for bipolar disorder and schizophrenia.2019https://dx.doi.org/10.3389/fpsyt.2019.00115
N.B. These documents automatically identified may not have been verified by the study sponsor.