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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.
Scientific title
Effects of clozapine on autophagy in people with treatment-resistant psychosis.
Secondary ID [1] 306897 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psychosis 325998 0
Schizophrenia 325997 0
Autophagy 326002 0
Condition category
Condition code
Mental Health 323309 323309 0 0
Schizophrenia
Mental Health 323954 323954 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
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.
Intervention code [1] 323842 0
Not applicable
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.
Control group
Active

Outcomes
Primary outcome [1] 331519 0
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.
Timepoint [1] 331519 0
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)
Secondary outcome [1] 410167 0
Change in microbiome composition from clozapine treatment as measured by metagenomic sequencing of stool samples.
Timepoint [1] 410167 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
Secondary outcome [2] 410166 0
Change in microbiome composition from clozapine treatment as measured by the Bristol Stool Scale questionnaire.
Timepoint [2] 410166 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
Secondary outcome [3] 411075 0
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.
Timepoint [3] 411075 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
Secondary outcome [4] 410165 0
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.
Timepoint [4] 410165 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
Secondary outcome [5] 410168 0
Change in immune response due to clozapine treatment as measured by inflammatory marker screening of blood samples.
Timepoint [5] 410168 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.
Secondary outcome [6] 411074 0
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.
Timepoint [6] 411074 0
Group 1: Baseline (at enrolment); 2 weeks after commencing clozapine; 12 weeks after commencing clozapine; 24 weeks after commencing clozapine. Group 2: At enrolment.

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.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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).

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Both
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/05/2024
Actual
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 22461 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 37695 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 311210 0
University
Name [1] 311210 0
Flinders University of South Australia
Country [1] 311210 0
Australia
Primary sponsor type
University
Name
Flinders University of South Australia
Country
Australia
Secondary sponsor category [1] 312580 0
Other Collaborative groups
Name [1] 312580 0
South Australian Health and Medical Research Institute
Country [1] 312580 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310739 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 310739 0
Ethics committee country [1] 310739 0
Australia
Date submitted for ethics approval [1] 310739 0
04/03/2022
Approval date [1] 310739 0
10/05/2022
Ethics approval number [1] 310739 0
2022/HRE00043

Summary
Brief summary
Trial website
Public notes

Contacts
Principal investigator
Name 118698 0
Prof Tarun Bastiampillai
Address 118698 0
SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
Country 118698 0
Australia
Phone 118698 0
+61 08 84042320
Fax 118698 0
Email 118698 0
tarun.bastiampillai@flinders.edu.au
Contact person for public queries
Name 118699 0
Tarun Bastiampillai
Address 118699 0
SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
Country 118699 0
Australia
Phone 118699 0
+61 08 84042320
Fax 118699 0
Email 118699 0
tarun.bastiampillai@flinders.edu.au
Contact person for scientific queries
Name 118700 0
Tarun Bastiampillai
Address 118700 0
SALHN Division of Mental Health Services, Margaret Tobin Centre, Flinders Medical Centre, Bedford Pk, S.A, 5042
Country 118700 0
Australia
Phone 118700 0
+61 08 84042320
Fax 118700 0
Email 118700 0
tarun.bastiampillai@flinders.edu.au

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 (tarun.bastiampillai@flinders.edu.au).

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.