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Trial registered on ANZCTR
Registration number
ACTRN12622000900718
Ethics application status
Approved
Date submitted
15/06/2022
Date registered
23/06/2022
Date last updated
4/06/2024
Date data sharing statement initially provided
23/06/2022
Type of registration
Prospectively registered
Titles & IDs
Public title
Effects of clozapine on autophagy in people with treatment-resistant psychosis.
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Scientific title
Effects of clozapine on autophagy in people with treatment-resistant psychosis.
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Secondary ID [1]
306897
0
Nil known
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Psychosis
325998
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Schizophrenia
325997
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Autophagy
326002
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Condition category
Condition code
Mental Health
323309
323309
0
0
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Schizophrenia
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Mental Health
323954
323954
0
0
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Psychosis and personality disorders
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Intervention/exposure
Study type
Observational
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Patient registry
False
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Target follow-up duration
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Target follow-up type
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Description of intervention(s) / exposure
The study is a non-randomised trial conducted in psychiatric hospital and community settings. The intervention will be the prescribed treatment of treatment-resistant psychosis with the pharmaceutical agent clozapine. This study will be utilising an existing workflow and established manner of care, and will not be assigning treatment to individuals. Rather, the study will be recruiting participants as they commence or have commenced their treatment in the routine clinical and community setting. Due to the nature of the psychosis and the established care routine, patients are required to be seen monthly, with routine blood collections necessary for monitoring the health of patients taking clozapine. This study integrates these standard blood measures and clinical assessments that occur during the existing routine care of clozapine patients.
The aim of this study is investigate the effects of clozapine on host autophagy to understand potential mechanisms contributing to clozapine's clinical effectiveness, and its side-effect profile (including metabolic, constipation, and inflammatory).
The study will include two groups:
Group 1: Includes 25 clozapine-naive participants. These participants will be asked to provide blood and stool samples on 4 occasions; at baseline (enrolment), 2 weeks after commencement of clozapine, and 3 and 6 months after commencing clozapine. All patients commencing clozapine are required to be admitted to the in-patient site for pre-work up (2 weeks) commencement of clozapine, then a minimum of 2 weeks for titration and monitoring for clinical effect and side effects. For Group 1, blood (and stool) samples will be collected at baseline, 3 and 6 months. The questionnaires BPRS, PANSS and GAF will be administered at these same time points by the psychiatrist or registrar without requiring time or effort by the participant. Blood samples are routinely taken by medical staff on site. If the participant is agreeable to providing a stool sample this can be self-administered during the admission process.
Group 2: Includes 25 chronic clozapine use participants.
These participants routinely have their blood tests conducted by a commercial provider at a community site. These participants will be requested, at a single timepoint, for their additional autophagy study blood sample on the day of their routine appointment with their psychiatrist. The questionnaires BPRS, PANSS and GAF will be administered at these same time points by the psychiatrist or registrar without requiring time or effort by the participant. If they agree to provide a stool sample they will be able to provide this on the day of their appointment also, or at home. This group is a cross-sectional group; there will be no follow-up appointments or observations as data will only be collected at the timepoint of enrolment.
For both groups, the participants that will be recruited will have a formal diagnosis of schizophrenia or schizoaffective disorder, and will be recruited from the Southern Adelaide Local Health Network Mental Health Service. The normal routine care for all patients commencing clozapine treatment begins with weekly clinical evaluations and blood collection for the first 18 weeks to monitor the health of the patient in response to clozapine. Following these 18 weeks, the patient is then routinely assessed at 4-weekly intervals, including clinical evaluations and blood tests.
Metabolic profiling, or evaluations of the interface between the gut microbiome and host physiology, will evaluate clinical differences of how clozapine is altering the host’s systemic metabolism by possible changes to the gut microbiome. Differences will be determined by observing weight and Body Mass Index change obtained from existing clinical data records in SA Health, along with recording the Bristol stool chart in patients treated with clozapine. We will also be integrating the routine Clozapine Management Clinical Guideline provided by SA Health that will provide an opportunity to analyse an existing suite of participant measures that includes c-reactive protein, blood glucose, blood pressure, and clozapine serum levels. This will determine if drug treatment is causing any host metabolic side effects. These measures are collected weekly from the routine blood collection and analysis during the individual's treatment with clozapine, and will be provided for this study from commencement of treatment up until 12 months post-enrolment.
Blood and stool samples will be used to measure clozapine serum levels, changes in autophagic flux, microbiome, and inflammatory profiles. These longitudinal changes will be compared against baseline for the group of participants treated with clozapine, and compared against the cross-sectional samples collected from the patients treated with clozapine for more than 12 months. This will help determine the mechanism of action that may be contributing to both short- and long-term clinical and metabolic effects of clozapine.
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Intervention code [1]
323842
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Not applicable
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Comparator / control treatment
Comparisons will be made between Group 1 (receiving clozapine up to 6 months) and Group 2 (chronically receiving clozapine for at least 12 months) to observe the long-term effects of clozapine.
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Control group
Active
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Outcomes
Primary outcome [1]
331519
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Changes in LC3II over time with clozapine treatment measured in blood samples, determined using the equation LC3II = LC3II+CQ – LC3II-CQ, will be the primary outcome of effect on autophagic flux.
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Assessment method [1]
331519
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Timepoint [1]
331519
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine (primary timepoint); 24 weeks after commencing clozapine. Group 2: Baseline (at enrolment)
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Secondary outcome [1]
410167
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Change in microbiome composition from clozapine treatment as measured by metagenomic sequencing of stool samples.
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Assessment method [1]
410167
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Timepoint [1]
410167
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Secondary outcome [2]
410166
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Change in microbiome composition from clozapine treatment as measured by the Bristol Stool Scale questionnaire.
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Assessment method [2]
410166
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Timepoint [2]
410166
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Secondary outcome [3]
411075
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Assess if drug treatment is having a clinical effect as measured by the formal psychiatric tool Global assessment of functioning (GAF), that will evaluate and compare symptoms over time against baseline recordings in response to antipsychotic treatment.
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Assessment method [3]
411075
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Timepoint [3]
411075
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Secondary outcome [4]
410165
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Assess if drug treatment is having a clinical effect as measured by the formal psychiatric tool positive and negative symptoms of schizophrenia (PANSS) that will evaluate and compare symptoms over time against baseline recordings in response to antipsychotic treatment.
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Assessment method [4]
410165
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Timepoint [4]
410165
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Secondary outcome [5]
410168
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Change in immune response due to clozapine treatment as measured by inflammatory marker screening of blood samples.
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Assessment method [5]
410168
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Timepoint [5]
410168
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Secondary outcome [6]
411074
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Assess if drug treatment is having a clinical effect as measured by the formal psychiatric tool Brief Psychiatric rating scale (BPRS) that will evaluate and compare symptoms over time against baseline recordings in response to antipsychotic treatment.
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Assessment method [6]
411074
0
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Timepoint [6]
411074
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Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
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Eligibility
Key inclusion criteria
Aged 18-70 years, primary clinical diagnosis using Diagnostic and Statistical Manual of Mental Disorders - 5th ed. criteria of schizophrenia or schizoaffective disorder who are currently taking clozapine for at least 12 months or are treatment-resistant and have agreed to commence a trial of clozapine. Treatment resistance in psychosis is defined as a failure to respond to an adequate trial of at least two antipsychotic medications.
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Minimum age
18
Years
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Maximum age
70
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Primary diagnosis of substance abuse, non-schizophrenia related neuropsychiatric disorder (dementia, Parkinson’s disease, Huntington’s disease), inability either through cognitive impairment, distress, suicidality, or inadequate English skills to understand or participate in the study. (As this is a pilot with no dedicated funding, use of a translator will not be possible for those with non-English speaking backgrounds).
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Study design
Purpose
Natural history
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Duration
Longitudinal
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Selection
Defined population
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Timing
Both
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Statistical methods / analysis
This is a pilot study, and since it is the first time autophagic flux will be measured in a vulnerable human cohort, a proper power calculation is technically not possible. However, based on prior experiments conducted when developing the method used in this study, we can estimate the inter-individual variability and an expected change. In an experiment conducted on 57 individuals, with stable atherosclerosis (n=38, mean autophagic flux=0.4252, SD=0.3849) or with severe unstable atherosclerosis (n=19, mean autophagic flux=0.1239, SD=0.1239), we observed a decrease in autophagic flux of -0.2862 between groups. This provides a calculated effect size of 1. In this pilot study, with an alpha risk of 0.05 and n=25 participants per group, we calculate (using G*Power) that we would obtain a power of 0.93 (by t- test) should the change between groups be similar to the one observed in our atherosclerosis study.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
31/05/2024
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Actual
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Date of last participant enrolment
Anticipated
30/06/2024
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Actual
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Date of last data collection
Anticipated
31/12/2024
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Actual
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Sample size
Target
50
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
22461
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Flinders Medical Centre - Bedford Park
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Recruitment postcode(s) [1]
37695
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5042 - Bedford Park
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Funding & Sponsors
Funding source category [1]
311210
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University
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Name [1]
311210
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Flinders University of South Australia
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Address [1]
311210
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Sturt Rd, Bedford Park SA 5042
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Country [1]
311210
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Australia
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Primary sponsor type
University
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Name
Flinders University of South Australia
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Address
Sturt Rd, Bedford Park SA 5042
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Country
Australia
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Secondary sponsor category [1]
312580
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Other Collaborative groups
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Name [1]
312580
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South Australian Health and Medical Research Institute
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Address [1]
312580
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SAHMRI, North Terrace, Adelaide SA 5000 Australia PO Box 11060, Adelaide SA 5001
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Country [1]
312580
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Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
310739
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Southern Adelaide Clinical Human Research Ethics Committee
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Ethics committee address [1]
310739
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Flinders Medical Centre, Level 6, Ward 6C, Room 6A219 Flinders Drive, Bedford Park, SA 5042 Southern Adelaide Local Health Network
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Ethics committee country [1]
310739
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Australia
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Date submitted for ethics approval [1]
310739
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04/03/2022
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Approval date [1]
310739
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10/05/2022
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Ethics approval number [1]
310739
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2022/HRE00043
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Summary
Brief summary
Clozapine is an antipsychotic drug given to people with psychosis (schizophrenia and schizoaffective disorder) that in addition to reducing psychotic symptoms can also prevent certain cancers and age-related diseases, but can also cause weight changes. How clozapine causes these effects is unknown. Evidence suggests that disruptions in autophagy, a natural process of repair that occurs inside all cells of the body and slows the ageing process, could contribute to the development of those side effects. For this reason, this research project is aiming to see if clozapine changes a person’s autophagy. This study is the first of its kind, and the results of this pilot study could lead to a better understanding of the currently unknown mechanisms of clozapine’s actions to better assist those being treated with clozapine, and also to help inform the clinical applications of clozapine in additional settings.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
118698
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Prof Tarun Bastiampillai
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Address
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SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
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Country
118698
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Australia
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Phone
118698
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+61 08 84042320
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Fax
118698
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Email
118698
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[email protected]
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Contact person for public queries
Name
118699
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Tarun Bastiampillai
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Address
118699
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SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
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Country
118699
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Australia
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Phone
118699
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+61 08 84042320
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Fax
118699
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Email
118699
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[email protected]
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Contact person for scientific queries
Name
118700
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Tarun Bastiampillai
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Address
118700
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SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
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Country
118700
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Australia
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Phone
118700
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+61 08 84042320
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Fax
118700
0
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Email
118700
0
[email protected]
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Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
•
Case-by-case basis at the discretion of the Primary Sponsor.
Conditions for requesting access:
•
-
What individual participant data might be shared?
•
Individual participant data underlying published results, after de-identification.
What types of analyses could be done with individual participant data?
•
For purposes linked to the aims in the approved proposal, and for meta-analyses.
When can requests for individual participant data be made (start and end dates)?
From:
Immediately following publication, no end date.
To:
-
Where can requests to access individual participant data be made, or data be obtained directly?
•
Access subject to approvals by the Principal Investigator (
[email protected]
).
Are there extra considerations when requesting access to individual participant data?
No
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
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