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Trial registered on ANZCTR


Registration number
ACTRN12616000859482
Ethics application status
Approved
Date submitted
6/04/2016
Date registered
30/06/2016
Date last updated
19/05/2020
Date data sharing statement initially provided
1/02/2019
Date results information initially provided
1/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The efficacy of mangosteen pericarp fruit extract for the treatment of schizophrenia.
Scientific title
The efficacy of adjunctive Garcinia mangostana Linn. (mangosteen) pericarp for the treatment of schizophrenia: A 24-week double blind randomised placebo controlled trial
Secondary ID [1] 286649 0
Nil
Universal Trial Number (UTN)
Trial acronym
MANGO SZ/CADENCE-M
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia 294982 0
Condition category
Condition code
Mental Health 295244 295244 0 0
Schizophrenia
Alternative and Complementary Medicine 298682 298682 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Total daily dose of 1000mg of Garcinia mangostana L. (mangosteen dried fruit pericarp encapsulated in gelatine capsules): 500mg 2 capsules once a day with food.
Duration of treatment: 24 weeks
Participants will be instructed to return unused medication which will be calculated and documented to determine medication adherence.
Intervention code [1] 291794 0
Treatment: Other
Comparator / control treatment
Total daily dose of 1000mg of rice flour weighted gelatine capsules: 500mg 2 capsules once a day with food.
Duration of treatment: 24 weeks
Control group
Placebo

Outcomes
Primary outcome [1] 294995 0
The primary outcome will be the change in schizophrenia symptom severity on PANSS total score.
Timepoint [1] 294995 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [1] 314537 0
The change in PANSS Positive subscale.
Timepoint [1] 314537 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [2] 314538 0
The change in depressive symptoms using MADRS.
Timepoint [2] 314538 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post discontinuation week 28
Secondary outcome [3] 314539 0
The change in participant life satisfaction rated on the self-reporting scale (Q-LES-Q)
Timepoint [3] 314539 0
Baseline, week 4,12,16,20, primary endpoint week 24 and post-discontinuation week 28.
Secondary outcome [4] 314540 0
The change in functioning measures using the Global Assessment of Functioning Scale (GAF)
Timepoint [4] 314540 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24 and post-discontinuation week 28.
Secondary outcome [5] 314541 0
The change in functioning measures using the LIFE-RIFT scale.
Timepoint [5] 314541 0
Baseline, week 4,8,12,16,20, primary outcome week 24 and post-discontinuation week 28.
Secondary outcome [6] 314542 0
The change in participant perception using the Patient Global Impression Scale (PGI).
Timepoint [6] 314542 0
Week 4,8,12,16,20, primary endpoint week 24 and post-discontinuation week 28.
Secondary outcome [7] 314543 0
The change in participant cognition using Cogstate computerised cognitive testing (Cogstate).
Timepoint [7] 314543 0
Baseline and primary endpoint week 24.
Secondary outcome [8] 314544 0
The changes in tobacco use will be recorded using the Opiate Treatment Index (OTI).
Timepoint [8] 314544 0
Baseline and primary endpoint week 24.
Secondary outcome [9] 314545 0
Blood samples are being collected at baseline and the end of the treatment phase (week 24). We expect to explore oxidative stress factors, including cytokines, thiobarbituric acid reactive substances and total antioxidant capacity. However, as the field of biological psychiatry is rapidly moving, these will be exploratory investigations for which the targets may change by the end of the trial. Participants are providing blood samples as an optional extra to the trial and have signed unspecified consent to allow all relevant and unforeseen investigations to occur at the completion of the study.
Timepoint [9] 314545 0
Baseline and primary endpoint week 24
Secondary outcome [10] 325159 0
The change in PANSS Negative subscale
Timepoint [10] 325159 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [11] 325160 0
The change in PANSS General Psychopathology subscale
Timepoint [11] 325160 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [12] 325161 0
The changes in alcohol use will be recorded using the Opiate Treatment Index (OTI).
Timepoint [12] 325161 0
Baseline and primary endpoint week 24.
Secondary outcome [13] 325162 0
The changes in heroin use will be recorded using the Opiate Treatment Index (OTI).
Timepoint [13] 325162 0
Baseline and primary endpoint week 24.
Secondary outcome [14] 325163 0
The changes in other opiates use will be recorded using the Opiate Treatment Index (OTI).
Timepoint [14] 325163 0
Baseline and primary endpoint week 24.
Secondary outcome [15] 325164 0
The changes in cannabis use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [15] 325164 0
Baseline and primary endpoint week 24.
Secondary outcome [16] 325165 0
The changes in amphetamine use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [16] 325165 0
Baseline and primary endpoint week 24.
Secondary outcome [17] 325166 0
The changes in cocaine use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [17] 325166 0
Baseline and primary endpoint week 24.
Secondary outcome [18] 325167 0
The changes in (illicit) benzodiazepine use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [18] 325167 0
Baseline and primary endpoint week 24.
Secondary outcome [19] 325168 0
The changes in barbiturates use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [19] 325168 0
Baseline and primary endpoint week 24.
Secondary outcome [20] 325169 0
The changes in hallucinogens use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [20] 325169 0
Baseline and primary endpoint week 24.
Secondary outcome [21] 325170 0
The changes in inhalants use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [21] 325170 0
Baseline and primary endpoint week 24.
Secondary outcome [22] 325171 0
The changes in synthetic drugs use will be recorded using the Opiate Treatment Index (OTI)
Timepoint [22] 325171 0
Baseline and primary endpoint week 24.
Secondary outcome [23] 325172 0
The changes in the occurence of tardive dyskinesia using the Abnormal Involuntary Movement Scale
Timepoint [23] 325172 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [24] 325173 0
The changes in overall illness severity, improvement or change and therapeutic response using the Clinical Global Impression
Timepoint [24] 325173 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [25] 325174 0
The changes in alcohol use using the Alcohol Use Disorders Identification Test
Timepoint [25] 325174 0
Baseline and primary endpoint week 24.
Secondary outcome [26] 325175 0
The changes in level of nicotine dependence using the Fagerstrom Test for Nicotine Dependence
Timepoint [26] 325175 0
Baseline and primary endpoint week 24.
Secondary outcome [27] 329393 0
Clinical Global Impressions (CGI) - Severity scale
Timepoint [27] 329393 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.
Secondary outcome [28] 329394 0
CGI - Improvement scale
Timepoint [28] 329394 0
Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Eligibility
Key inclusion criteria
1. Being 18 years or older
2. Have a DSM-V diagnosis of schizophrenia or schizoaffective disorder.
3. Score greater than or equal to 54 on the PANSS total score or have a CGI-S score of greater than or equal to 3.
4. Participants currently under therapy for schizophrenia or schizoaffective disorder will need to have been on that primary therapy for at least four weeks prior to randomization.
5. Have the capacity to consent to the study and comply with the procedures.
6. Be using effective contraception if female, sexually active and childbearing age.
7. Be able to speak, read, write and understand English language.
8. 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
Gender
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.
3. Participants currently enrolled in any other intervention study.
4. Individuals who are intolerant, allergic to or have had an anaphylactic reaction to any of the components of the preparation.
5. Inability to comply with either the requirements of informed consent or 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)
Participants will be recruited through various recruitment avenues including advertisements through local newspapers, flyers in medical waiting rooms, pharmacies and university campuses. Direct contact will be made with potential referral sources consisting of general practitioners, community mental health teams, the disability support sector, support groups, private psychiatrists and local psychiatric inpatient unit.
Trial clinicians will contact all participants referred to the trial to schedule an initial face-to-face screening interview to establish written consent, that inclusion criteria are satisfied and confirm the DSM-V diagnosis of schizophrenia or scizoaffective disorder with a PANSS total score of greater than or equal to 54 or CGI greater than or equal to 3. Participants will be randomised in the Garcinia mangostana Linn group or placebo group and will be allocated a study number for trial identification purposes. Packs will be allocated 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. The trial statistician and trial clinicians will be blinded to the group allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation to treatment arm will be randomly assigned using 1:1 ratio (active to placebo) using permutated block randomisation. An independent researcher will develop the computer-generated randomisation plan.
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
The statistical method used will be a likelihood based mixed-effect model and repeated measures approach (MMRM). The MMRM model includes the fixed, categorical effects of treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-visit interaction. 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 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 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 two groups. Using Fisher's z transformation, we will test whether the correlations obtained for each group are statistically different in terms of strength. Sample size: Pilot study data indicated that effect sizes depicting treatment group differences in change between baseline to endpoint, ranged from moderate (e.g., GAF, Cohen’s d=0.59), to large (PANSS Total, Cohen’s d=1.41). Power and sample size calculations for the proposed study were conservative and based on the smallest effect observed in the pilot study (i.e. medium effect for GAF). With power (1-ß) set at 0.90, alpha (a) at the 0.05 level, a sample size of 50 per group is required. As effect sizes are typically smaller in follow up studies and to allow for attrition, total sample size was increased to 150, to enable confident detection of PANSS Total group differences.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 5573 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 5574 0
Ipswich Hospital - Ipswich
Recruitment hospital [3] 5575 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 5576 0
Gold Coast Hospital - Southport
Recruitment hospital [5] 5577 0
Logan Hospital - Meadowbrook
Recruitment hospital [6] 5578 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [7] 5579 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [8] 5580 0
The Geelong Clinic - St Albans Park
Recruitment postcode(s) [1] 9637 0
3220 - Geelong
Recruitment postcode(s) [2] 13028 0
4305 - Ipswich
Recruitment postcode(s) [3] 13029 0
4006 - Herston
Recruitment postcode(s) [4] 13030 0
4032 - Chermside
Recruitment postcode(s) [5] 13031 0
4215 - Southport
Recruitment postcode(s) [6] 13032 0
4122 - Upper Mount Gravatt
Recruitment postcode(s) [7] 13033 0
4131 - Meadowbrook
Recruitment postcode(s) [8] 13494 0
3219 - St Albans Park
Recruitment postcode(s) [9] 13495 0
3214 - Corio
Recruitment postcode(s) [10] 13496 0
3215 - Bell Park
Recruitment postcode(s) [11] 13497 0
3228 - Torquay
Recruitment postcode(s) [12] 13498 0
3216 - Belmont

Funding & Sponsors
Funding source category [1] 291229 0
Other
Name [1] 291229 0
The Stanley Medical Research Institute
Address [1] 291229 0
8401 Connecticut Avenue, Suite 200
Chevy Chase, MD 20815
Country [1] 291229 0
United States of America
Primary sponsor type
Hospital
Name
University Hospital-Barwon Health
Address
P.O. Box 281
Geelong VIC 3220
Country
Australia
Secondary sponsor category [1] 289906 0
University
Name [1] 289906 0
University of Queensland, Queensland Brain Institute
Address [1] 289906 0
The University of Queensland
QBI Building 79, University of Queensland,
St Lucia QLD 4072
Country [1] 289906 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292789 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 292789 0
Research Ethics Office
University Hospital-Barwon Health
P.O.Box 281
Geelong, Victoria
3220
Ethics committee country [1] 292789 0
Australia
Date submitted for ethics approval [1] 292789 0
29/06/2015
Approval date [1] 292789 0
10/03/2016
Ethics approval number [1] 292789 0
15/26
Ethics committee name [2] 294671 0
Metro South Human Research Ethics Committee
Ethics committee address [2] 294671 0
Metro South HREC Office
PAH Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [2] 294671 0
Australia
Date submitted for ethics approval [2] 294671 0
08/01/2016
Approval date [2] 294671 0
15/02/2016
Ethics approval number [2] 294671 0
HREC/16/QPAH/15

Summary
Brief summary
There is evidence of anomalies in redox biology in schizophrenia; (i) the presence of oxidative stress (where the levels of antioxidants are decreased or the levels of free radicals are increased to a point that is damaging to the function of the cell, increasing inflammation) particularly implicating the glutathione system ; (ii) changes in oxidative status with treatment; and (iii) evidence that other glutathione and redox active agents have therapeutic value.
Garcinia mangostana Linn, known colloquially as mangosteen, is a tropical evergreen fruit tree originating from Indonesia. Its rind or pericarp contains an exudate containing a large number of bioactive compounds called xanthones that have robust effects on the glutathione system and many other pathways germane to schizophrenia. Motivated by the results of the first pilot randomised, double blind placebo trial of adjunctive Garcinia mangostana Linn for the treatment of schizophrenia we speculate that this research may uncover a new class of agents for the treatment of the disorder, and uncover novel pathophysiological pathways.
The trial involves 150 participants aged 18 years or older with a DSM-V diagnosis of schizophrenia or schizoaffective disorder. Participants referred to the trial will have an initial face–to-face screening interview. All randomised participants will receive two 500mg mangosteen pericarp capsules once a day to a total dose of 1000mg daily or placebo, in addition to treatment as usual, for 24 weeks. Assessment will occur at regular 4 weekly intervals throughout the 24 weeks and 1 month after completion of the study. The primary outcome will be the change in schiaophrenia symptom severity using the PANSS total scale at the end of the 24-week treatment phase. The secondary outcomes will include changes in depressive symptoms, quality of life, functioning and life satisfaction which will be measured using the PANSS subscales, Q-LES-Q scale, GAF, LIFE-RIFT, PGI and Cogstate. Blood biomarkers will also be analysed. Blood samples will be obtained at baseline and week 24. Blood will be analysed for relevant markers based on preclinical evidence including markers of antioxidant defence, oxidative stress and markers of inflammation. The research will have immediate and direct translational benefits. The safety and tolerability of Garcinia mangostana Linn, its affordability and accessibility and that the general public are accepting of plant-derived compounds, raise its attraction as a potential therapeutic agent.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 57018 0
Prof Michael Berk
Address 57018 0
IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220
Country 57018 0
Australia
Phone 57018 0
+61 3 42153330
Fax 57018 0
+61 3 42153491
Email 57018 0
michael.berk@deakin.edu.au
Contact person for public queries
Name 57019 0
Prof Michael Berk
Address 57019 0
IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220
Country 57019 0
Australia
Phone 57019 0
+61 3 42153330
Fax 57019 0
+61 3 42153491
Email 57019 0
michael.berk@deakin.edu.au
Contact person for scientific queries
Name 57020 0
Prof Michael Berk
Address 57020 0
IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220
Country 57020 0
Australia
Phone 57020 0
+61 3 42153330
Fax 57020 0
+61 3 42153491
Email 57020 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?
Overall summary data for participants who took part in the trial. This includes scales of symptoms, functioning, quality of life, substance use and adverse events.
When will data be available (start and end dates)?
The data will be available once data lock has occurred and data has been uploaded to the Stanley Medical Research Institute repository. No end date determined.
Available to whom?
The data will be available to any researcher who applies for access to the data and has the relevant approvals.
Available for what types of analyses?
Any statistical analysis on the data set, and potentially pooling data will be available.
How or where can data be obtained?
We are waiting to hear from the SMRI on the full process on data access.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 7995 0
Study protocol
Citation [1] 7995 0
Clinical Psychopharmacology and Neuroscience 2019; 17(2): 297-307 https://doi.org/10.9758/cpn.2019.17.2.297
Protocol and Rationale: A 24-week Double-blind, Randomized, Placebo Controlled Trial of the Efficacy of Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia
Email [1] 7995 0
Other [1] 7995 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary