Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001222831
Ethics application status
Approved
Date submitted
27/05/2021
Date registered
13/09/2021
Date last updated
13/09/2021
Date data sharing statement initially provided
13/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of Pharmacogenetic Testing on Cost Effectiveness in Mental Illness
Scientific title
Remission rates and cost-effectiveness of Pharmaco-genetic testing and academic detailing in adults with depression and psychosis in a public mental health service
Secondary ID [1] 304069 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PMP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major depressive disorder (MDD) 321719 0
Schizophrenia, 321721 0
schizoaffective disorder 322855 0
bipolar disorder 322856 0
Condition category
Condition code
Mental Health 319461 319461 0 0
Depression
Mental Health 319463 319463 0 0
Schizophrenia
Mental Health 320434 320434 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pharmacogenetic testing: At baseline participants will provide a saliva sample for DNA testing. Genetic testing of each participant's DNA for the drug-metabolising enzymes CYP2D6 and CYP2C19 will be analysed to predict if the individual is a slow, normal or ultra rapid metaboliser of commonly prescribed antidepressants and antipsychotic medications. A panel of experts, psychiatrists and pharmacologists (CI/AIs) will provide a set of treatment recommendations to the treating psychiatrist at 6 weeks after testing. These recommendations could include no change, increase or decrease in dose, or change to alternative medications. Changes to prescribing and adherence to the prescription will be monitored from the hospital, and mental health service medication records and Medicare PBS data. No specific action will be applied to the intervention group to encourage adoption of the recommendations by the doctor and participant or to increase adherence by the participant as the aim is to see if the recommendations alone are acted upon and if so whether they make any difference to clinical and quality of life outcomes.
In the qualitative sub-study in the last 6 months of the trial intervention participants, their doctors/psychiatrists, case workers and carers will be asked a series of semi-structured questions taking 20-40 minutes. We will purposefully select the first willing 10 intervention patients varied in gender, age, age at diagnosis and living situation, 3 carers and 10 project and health staff to identify inhibitors and promotors within the health system, affecting uptake of genetic testing and of the prescribing recommendations. Themes will be: related to outcomes ie benefits or otherwise of the testing, and process observations ie the recruitment, ease of understanding of the purpose of testing, the testing itself, receipt of recommendations, clarity of recommendations, barriers and enablers to the process, recommendations for improvement of the process.
Intervention code [1] 320396 0
Diagnosis / Prognosis
Intervention code [2] 320399 0
Treatment: Drugs
Comparator / control treatment
Control treatment will be provision of medication recommendations to the treating psychiatrist based on existing evidence-based guidelines (ie without reference to the participant's genetic results) using the Royal Australian and New Zealand Clinical Practice Guidelines for Mood Disorders and for Schizophrenia and Related Disorders
Control group
Active

Outcomes
Primary outcome [1] 327341 0
Remission as determined by a cut off <10 on the PHQ9 if depression is the primary diagnosis
Timepoint [1] 327341 0
baseline, 6, 12 (primary endpoint) and 18 months post baseline
Primary outcome [2] 327360 0
Remission as determined by the 8 items of the PANSS each item should be less than or equal to 3 for a period of 6 months, if the diagnosis is psychosis ie Schizophrenia Spectrum Disorders (SSD)
Timepoint [2] 327360 0
baseline, 6, 12 (primary endpoint) and 18 months post baseline
Secondary outcome [1] 394647 0
Readmission rates comparison between intervention and controls as indicated by emergency department and hospital in-patient admissions as assessed by data linkage to patient medical records,
Timepoint [1] 394647 0
baseline, 6, 12 and 18 months post baseline.
Secondary outcome [2] 398572 0
cost-effectiveness: cost of implementing the intervention ; direct costs associated with health care resource utilisation (genetic tests, clinical staff costs) over the study period. The EQ-5D will be used at baseline, 6, 12 and 18 months to estimate utility values. Utility values derived from the EQ-5D instrument will be used to estimate Quality-Adjusted Life- Years (QALYs) gains for each patient and estimate incremental QALYs.
Timepoint [2] 398572 0
baseline, 6, 12 and 18 months post-baseline
Secondary outcome [3] 398577 0
Utility values derived from the EQ-5D instrument will be used to estimate Quality-Adjusted Life- Years (QALYs)
Timepoint [3] 398577 0
baseline, 6, 12 and 18 months post baseline
Secondary outcome [4] 398578 0
Medicare and state Health data will be used to estimate direct costs associated with health care resource utilisation including pharmaceuticals, out of hospital services (e.g., doctor visits) and hospital services (including in patient and ED presentations)
Timepoint [4] 398578 0
baseline, 6, 12 and 18 months post baseline - ie using all available data up to 18 months from baseline
Secondary outcome [5] 398579 0
PHQ-9 to measure depression,
Timepoint [5] 398579 0
baseline, 6, 12 and 18 months post baseline
Secondary outcome [6] 398581 0
Qualitative semi-structured interviews of a subset of participants, carers and study personnel will be interviewed, with the following assessed:
- perceived benefit of genetic information
- perceived barriers or difficulties with the Precision Medicine Pathway process
- suggested improvements
Timepoint [6] 398581 0
10 intervention participants (purposeful selection of 5 psychosis, 5 depression, gender and age balanced), 3 carers and 10 project and clinical staff will be interviewed in the last 6 months of the trial

Eligibility
Key inclusion criteria
Adults with a diagnosis of treatment resistant MDD or SSD, both with or without comorbid disorders confirmed by the MINI interview and are taking prescribed psychotropic medications. Treatment resistance is defined as have trialed 2 or more medications with inadequate treatment response for a minimum of 4 months as determined by the patient and psychiatrist and for those with MDD, PHQ-9 >= 10 and for SDD, each item with a score > 3 on PANSS.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Intellectual or cognitive or language difficulty that prohibits an understanding or participation in the program, active psychosis, severe distress or suicidality, or substance intoxication.

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)
Randomisation will be determined after baseline assessment is completed and will not be a clinical decision as to which arm of the trial the person enters. Allocation will be concealed by phone contact to a centralised off site person who will access the computer-generated lists derived from concealed permutated blocks.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be blocked to increase the likelihood of scheduled group sizes, using a standard permutated block algorithm in which block sizes will be randomly chosen to protect concealment. Block randomisation within strata will be used to ensure equal proportions of MDD and SSD.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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
Ultra-rapid and slow metabolisers (extreme metabolisers, EM) will be randomly allocated to 1 of 2 study arms, whereas normal metabolisers (NMs) will be randomized to 1 of 2 study arms or to exclusion in a 1:1:3 sequence. To compute the required sample size for primary outcome of remission at 12 months confirmed by the Mini International Neuropsychiatric Interview, we specify the values 0.10 and 0.35 as the control and intervention-group proportions. Based on a binomial two-tailed test, type I error rate of 5% and power of 80%, we calculate the number of EMs needed in each arm to be 43. Assuming a prevalence of 10% of EMs, both study groups will aim to include 43 EMs and 155 NMs, while a total of 465 NMs will be randomly excluded to elevate the proportion of EMs from 10% to 22%. To account for 20% attrition we will need to recruit a total sample of 1032 patients. Missing information will be treated using established statistical protocols.

Data analyses will use an intention- to- treat approach to provide a valid comparison of treatment strategies. Where necessary, analyses will also use ‘as treated’ and ‘per
protocol’ to estimate the effect of treatment. Reporting of trial findings will adhere to CONSORT guidelines for pragmatic trials. Primary outcome analysis of remission (versus non-remission) will test proportions between control and PMP groups at 12 months and 18 months.

The gene sequences will be bioinformatically analysed for functional variants. The bioinformatic technique of note is haplotype phasing to determine which variants are grouped on the maternally and paternally inherited genes. The health outcomes, costs and questionnaire will be modelled by the statistician and health economist. Covariates such as health, economic, genotype, gender and intervention status will be adjusted for.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2021
Actual
Date of last participant enrolment
Anticipated
30/03/2023
Actual
Date of last data collection
Anticipated
30/09/2024
Actual
Sample size
Target
1032
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 19215 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 19216 0
Noarlunga Health Service - Noarlunga Centre
Recruitment postcode(s) [1] 33787 0
5042 - Bedford Park
Recruitment postcode(s) [2] 33788 0
5168 - Noarlunga Centre
Recruitment postcode(s) [3] 33789 0
5043 - Marion

Funding & Sponsors
Funding source category [1] 308453 0
University
Name [1] 308453 0
Flinders University
Country [1] 308453 0
Australia
Primary sponsor type
University
Name
Flinders University of South Australia
Address
Sturt Rd
Bedford Park
SA 5042
Country
Australia
Secondary sponsor category [1] 310165 0
Hospital
Name [1] 310165 0
Southern Adelaide Local Health Network
Address [1] 310165 0
Flinders Medical Centre
Flinders Drive
Bedford Park
SA 5042
Country [1] 310165 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308408 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 308408 0
Flinders Medical Centre
Ward 6C, Room 6A219
Flinders Drive, Bedford Park SA 5042
Ethics committee country [1] 308408 0
Australia
Date submitted for ethics approval [1] 308408 0
23/04/2021
Approval date [1] 308408 0
07/05/2021
Ethics approval number [1] 308408 0

Summary
Brief summary
Approximately 25% of all medicine is broken down by liver enzymes called CYP2D6 and CYP2C19. In many people these enzymes work more slowly than normal causing particular medicines to accumulate in the body at concentrations higher than intended. In some people these enzymes work too quickly, clearing some medicines before they can work.
This type of testing is called precision medicine. Recommendations based on a genetic test may suggest an increase or decrease in medication or that a medicine not be used and that an alternative be prescribed. Numerous genetic studies have shown that a significant number of prescribed medicines are ineffective or cause negative side effects. This study aims to improve the genetic methods used to guide and inform medicine prescriptions. Precision prescriptions may reduce side-effects and increase symptom relief for many individuals.

In the main research project, the randomised controlled trial (phase 2) of the Precision Medicine Pathway, we are testing whether genetic testing which determines how well the liver processes medication when given to the participant and their psychiatrist, actually influences any changes in prescribing and in so doing reduces psychiatric symptoms, improves the severity of the illness and quality of life. Understanding a person’s genes may be able to explain why some people respond to a treatment, while others do not, or why some people experience a side effect and others do not.

In this second part of the research project we would like to talk to some of the participants, their carers and the research and clinical mental health staff involved in the project to learn whether the genetic information was beneficial or not, and whether there were any barriers or difficulties being involved in the process of the Precision Medicine Pathway including saliva collection, filling in questionnaires, and receiving the information from the genetic testing. We would also be interested in whether any improvements could be made in any of these processes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110610 0
Prof Malcolm Battersby
Address 110610 0
College of Medicine and Public Health
Flinders University, Flinders Medical Centre
Bedford Park, SA, 5042
Country 110610 0
Australia
Phone 110610 0
+61 08 8404 2314
Fax 110610 0
Email 110610 0
[email protected]
Contact person for public queries
Name 110611 0
Prof Malcolm Battersby
Address 110611 0
College of Medicine and Public Health
Flinders University, Flinders Medical Centre
Bedford Park, SA, 5042
Country 110611 0
Australia
Phone 110611 0
+61 08 8404 2314
Fax 110611 0
Email 110611 0
[email protected]
Contact person for scientific queries
Name 110612 0
Prof Malcolm Battersby
Address 110612 0
College of Medicine and Public Health
Flinders University, Flinders Medical Centre
Bedford Park, SA, 5042
Country 110612 0
Australia
Phone 110612 0
+61 08 8404 2314
Fax 110612 0
Email 110612 0
[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?
de-identified Phamacogenetic data and quantitative questionnaire data and prescribing recommendations
When will data be available (start and end dates)?
15.1.22 - 31.12.26 or 5 years following primary publication
Available to whom?
researchers and clinicians - psychiatrists who provide a methodologically sound proposal, case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
comparison of genetic testing methods for CYP2D6 and CYO2C19 for antidepressant and antipsychotic medications
How or where can data be obtained?
email to trial geneticist and co-investigator [email protected]


What supporting documents are/will be available?




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.