ANZCTR - Registration

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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]

Nil

Universal Trial Number (UTN)

Trial acronym

MANGO SZ/CADENCE-M

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Schizophrenia

Condition category

Condition code

Mental Health

Schizophrenia

Alternative and Complementary Medicine

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]

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]

The primary outcome will be the change in schizophrenia symptom severity on PANSS total score.

Timepoint [1]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [1]

The change in PANSS Positive subscale.

Timepoint [1]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [2]

The change in depressive symptoms using MADRS.

Timepoint [2]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post discontinuation week 28

Secondary outcome [3]

The change in participant life satisfaction rated on the self-reporting scale (Q-LES-Q)

Timepoint [3]

Baseline, week 4,12,16,20, primary endpoint week 24 and post-discontinuation week 28.

Secondary outcome [4]

The change in functioning measures using the Global Assessment of Functioning Scale (GAF)

Timepoint [4]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24 and post-discontinuation week 28.

Secondary outcome [5]

The change in functioning measures using the LIFE-RIFT scale.

Timepoint [5]

Baseline, week 4,8,12,16,20, primary outcome week 24 and post-discontinuation week 28.

Secondary outcome [6]

The change in participant perception using the Patient Global Impression Scale (PGI).

Timepoint [6]

Week 4,8,12,16,20, primary endpoint week 24 and post-discontinuation week 28.

Secondary outcome [7]

The change in participant cognition using Cogstate computerised cognitive testing (Cogstate).

Timepoint [7]

Baseline and primary endpoint week 24.

Secondary outcome [8]

The changes in tobacco use will be recorded using the Opiate Treatment Index (OTI).

Timepoint [8]

Baseline and primary endpoint week 24.

Secondary outcome [9]

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]

Baseline and primary endpoint week 24

Secondary outcome [10]

The change in PANSS Negative subscale

Timepoint [10]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [11]

The change in PANSS General Psychopathology subscale

Timepoint [11]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [12]

The changes in alcohol use will be recorded using the Opiate Treatment Index (OTI).

Timepoint [12]

Baseline and primary endpoint week 24.

Secondary outcome [13]

The changes in heroin use will be recorded using the Opiate Treatment Index (OTI).

Timepoint [13]

Baseline and primary endpoint week 24.

Secondary outcome [14]

The changes in other opiates use will be recorded using the Opiate Treatment Index (OTI).

Timepoint [14]

Baseline and primary endpoint week 24.

Secondary outcome [15]

The changes in cannabis use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [15]

Baseline and primary endpoint week 24.

Secondary outcome [16]

The changes in amphetamine use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [16]

Baseline and primary endpoint week 24.

Secondary outcome [17]

The changes in cocaine use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [17]

Baseline and primary endpoint week 24.

Secondary outcome [18]

The changes in (illicit) benzodiazepine use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [18]

Baseline and primary endpoint week 24.

Secondary outcome [19]

The changes in barbiturates use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [19]

Baseline and primary endpoint week 24.

Secondary outcome [20]

The changes in hallucinogens use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [20]

Baseline and primary endpoint week 24.

Secondary outcome [21]

The changes in inhalants use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [21]

Baseline and primary endpoint week 24.

Secondary outcome [22]

The changes in synthetic drugs use will be recorded using the Opiate Treatment Index (OTI)

Timepoint [22]

Baseline and primary endpoint week 24.

Secondary outcome [23]

The changes in the occurence of tardive dyskinesia using the Abnormal Involuntary Movement Scale

Timepoint [23]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [24]

The changes in overall illness severity, improvement or change and therapeutic response using the Clinical Global Impression

Timepoint [24]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [25]

The changes in alcohol use using the Alcohol Use Disorders Identification Test

Timepoint [25]

Baseline and primary endpoint week 24.

Secondary outcome [26]

The changes in level of nicotine dependence using the Fagerstrom Test for Nicotine Dependence

Timepoint [26]

Baseline and primary endpoint week 24.

Secondary outcome [27]

Clinical Global Impressions (CGI) - Severity scale

Timepoint [27]

Baseline, weeks 4,8,12,16,20, primary endpoint week 24, post-discontinuation week 28.

Secondary outcome [28]

CGI - Improvement scale

Timepoint [28]

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

Sex

Both males and females

Can healthy volunteers participate?

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

6/07/2016

Actual

28/07/2016

Date of last participant enrolment

Anticipated

1/09/2018

Actual

2/08/2018

Date of last data collection

Anticipated

13/02/2019

Actual

15/02/2019

Sample size

Target

150

Accrual to date

Final

150

Recruitment in Australia

Recruitment state(s)

QLD,VIC

Recruitment hospital [1]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [2]

Ipswich Hospital - Ipswich

Recruitment hospital [3]

The Prince Charles Hospital - Chermside

Recruitment hospital [4]

Gold Coast Hospital - Southport

Recruitment hospital [5]

Logan Hospital - Meadowbrook

Recruitment hospital [6]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [7]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [8]

The Geelong Clinic - St Albans Park

Recruitment postcode(s) [1]

3220 - Geelong

Recruitment postcode(s) [2]

4305 - Ipswich

Recruitment postcode(s) [3]

4006 - Herston

Recruitment postcode(s) [4]

4032 - Chermside

Recruitment postcode(s) [5]

4215 - Southport

Recruitment postcode(s) [6]

4122 - Upper Mount Gravatt

Recruitment postcode(s) [7]

4131 - Meadowbrook

Recruitment postcode(s) [8]

3219 - St Albans Park

Recruitment postcode(s) [9]

3214 - Corio

Recruitment postcode(s) [10]

3215 - Bell Park

Recruitment postcode(s) [11]

3228 - Torquay

Recruitment postcode(s) [12]

3216 - Belmont

Funding & Sponsors

Funding source category [1]

Other

Name [1]

The Stanley Medical Research Institute

Address [1]

8401 Connecticut Avenue, Suite 200
Chevy Chase, MD 20815

Country [1]

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]

University

Name [1]

University of Queensland, Queensland Brain Institute

Address [1]

The University of Queensland
QBI Building 79, University of Queensland,
St Lucia QLD 4072

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Barwon Health Human Research Ethics Committee

Ethics committee address [1]

Research Ethics Office
University Hospital-Barwon Health
P.O.Box 281
Geelong, Victoria
3220

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

29/06/2015

Approval date [1]

10/03/2016

Ethics approval number [1]

15/26

Ethics committee name [2]

Metro South Human Research Ethics Committee

Ethics committee address [2]

Metro South HREC Office
PAH Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

08/01/2016

Approval date [2]

15/02/2016

Ethics approval number [2]

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

Attachments [1]

/AnzctrAttachments/368490-MANGO S StudyProtocol-V1-12-5-15-update.doc

Contacts

Principal investigator

Name

Prof Michael Berk

Address

IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220

Country

Australia

Phone

+61 3 42153330

Fax

+61 3 42153491

[email protected]

Contact person for public queries

Name

Prof Michael Berk

Address

IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220

Country

Australia

Phone

+61 3 42153330

Fax

+61 3 42153491

[email protected]

Contact person for scientific queries

Name

Prof Michael Berk

Address

IMPACT Strategic Research Centre
Swanston Centre
University Hospital-Barwon Health
P.O.Box 281
Geelong
Victoria 3220

Country

Australia

Phone

+61 3 42153330

Fax

+61 3 42153491

[email protected]

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
7995	Study protocol	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	http://www.cpn.or.kr/journal/view.html?uid=937&vmd=Full			368490-(Uploaded-07-01-2020-10-36-30)-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

Source	Title	Year of Publication	DOI
Embase	The Effect of Adjunctive Mangosteen Pericarp on Cognition in People With Schizophrenia: Secondary Analysis of a Randomized Controlled Trial.	2021	https://dx.doi.org/10.3389/fpsyt.2021.626486
Embase	Adjunctive Garcinia mangostana Linn. (Mangosteen) Pericarp for Schizophrenia: A 24-Week Double-blind, Randomized, Placebo Controlled Efficacy Trial: Pericarpe d'appoint Garcinia mangostana Linn (mangoustan) pour la schizophrenie : un essai d'efficacite de 24 semaines, a double insu, randomise et controle par placebo.	2021	https://dx.doi.org/10.1177/0706743720982437

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically