Administrative information
Title {1} | The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care |
Trial registration {2a and 2b} | ANZCTR: ACTRN12621000181808 |
Protocol version {3} | PRESIDE protocol V1.2 July 2022 |
Funding {4} | The Medical Research Future Fund (MRFF, ID MRF1200060) |
Author details {5a} | Sibel Saya1,2, Patty Chondros1, Anastasia Abela1,2, Cathrine Mihalopolous3, Mary Lou Chatterton3, Jane Gunn1, Timothy F Chen4, Thomas M Polasek5,6, Elise Dettmann1, Rachel Brooks1,2, Michelle King1,2, Luke Spencer1,2, Pavithran Alphonse1,2, Shakira Milton1,2, Georgia Ramsay1,2, Zoe Siviour1,2, Jamie Liew1,2, Philip Ly1,2, Matthew Thoenig1,2, Raushaan Seychell1,2, Floriana La Rocca1,2, Luke B Hesson7.8.9, Nydia Mejias10, Terri Sivertsen7, Melanie Anne Galea7, Chad Bousman11, Jon Emery1,2
1. Department of General Practice and Primary Care, Melbourne Medical School, University of Melbourne, Melbourne, Australia 2. Centre for Cancer Research, University of Melbourne, Melbourne, Australia 3. Monash University Health Economics Group, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia 4. Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia 5. Certara, Princeton, NJ, USA 6. Centre for Medicine Use and Safety, Monash University, Melbourne, Australia 7. Genetics Department, Douglass Hanly Moir Pathology, Sonic Healthcare, Sydney, NSW, Australia 8. School of Clinical Medicine, Faculty of Medicine, UNSW Sydney, Randwick, NSW, Australia 9. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia 10. Translational Software, WA, USA 11. Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada |
Name and contact information for the trial sponsor {5b} | Clinical Trials Governance The University of Melbourne Contact (Trial CI): jon.emery@unimelb.edu.au |
Role of sponsor {5c} | The sponsor does not have input or ultimate authority in the study design; collection, management, analysis and interpretation of the data; writing of the report; and the decision to submit the report for publication |
Introduction
Background and rationale {6a}
Prevalence of depression worldwide and in Australia
Treatment of major depressive disorder
Pharmacogenomic-informed prescribing of antidepressants
Objectives {7}
Primary objective
Secondary objectives
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Change in depressive symptoms at 4, 8 and 26 weeks
-
Depressive symptom remission at 12 weeks
-
Depressive symptom response at 12 weeks
-
Side effect frequency at 4, 8, 12 and 26 weeks
-
Medication adherence at 4, 8, 12 and 26 weeks
-
Quality of life at 4, 8, 12 and 26 weeks
-
Number of antidepressant medication changes within 26 weeks
-
Cost-effectiveness within 26 weeks
Trial design {8}
Methods: participants, interventions and outcomes
Study setting {9}
Eligibility criteria {10}
Eligibility criteria for general practice clinics
Inclusion criteria for participants
Exclusion criteria for participants
Who will take informed consent? {26a}
General practitioner informed consent
Patient informed consent for trial participation
Patient informed consent for release of administrative health service use and prescribing data (optional)
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Determination of PGx genotype and phenotype
Incorporation of interaction with concomitant medications into PGx phenotype
Determination of algorithm of actionable recommendations
Selection of medications for inclusion in the antidepressant prescribing report
Return of report to GPs
CYP2C19 phenotype | CYP2D6 phenotype |
Citalopram [SSRI]
CYP2C19
|
Desvenlafaxine [SNRI]
|
Duloxetine [SNRI]
|
Escitalopram [SSRI]
CYP2C19
|
Fluoxetine [SSRI]
|
Fluvoxamine [SSRI]
CYP2D6
|
Mirtazapine [others]
|
Paroxetine [SSRI]
CYP2D6
|
Sertraline [SSRI]
CYP2C19
|
Venlafaxine [SNRI]
CYP2D6
|
---|---|---|---|---|---|---|---|---|---|---|---|
Intermediate, normal or null | Intermediate | 20 mg mane | 50 mg mane | 60 mg mane | 10 mg mane | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | 20 mg mane | 50 mg mane | Not recommended |
Poor | Intermediate |
10 mg mane
| 50 mg mane | 60 mg mane |
5 mg mane
| 20 mg mane | 50 mg nocte | 30 mg nocte | 20 mg mane |
25 mg mane
| Not recommended |
Rapid or ultrarapid | Intermediate | Not recommended | 50 mg mane | 60 mg mane | Not recommended | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | 20 mg mane | 50 mg mane | Not recommended |
Intermediate, normal or null | Normal | 20 mg mane | 50 mg mane | 60 mg mane | 10 mg mane | 20 mg mane | 50 mg nocte | 30 mg nocte | 20 mg mane | 50 mg mane | 75 mg mane |
Poor | Normal |
10 mg mane
| 50 mg mane | 60 mg mane |
5 mg mane
| 20 mg mane | 50 mg nocte | 15 mg nocte increase to | 20 mg mane |
25 mg mane
| 75 mg mane |
Rapid or ultrarapid | Normal | Not recommended | 50 mg mane | 60 mg mane | Not recommended | 20 mg mane | 50 mg nocte | 30 mg nocte | 20 mg mane | 50 mg mane | 75 mg mane |
Intermediate, normal or null | Null | 20 mg mane | 50 mg mane | 60 mg mane | 10 mg mane | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | 20 mg mane | 50 mg mane | 75 mg mane |
Poor | Null |
10 mg mane
| 50 mg mane | 60 mg mane |
5 mg mane
| 20 mg mane | 50 mg nocte | 30 mg nocte | 20 mg mane |
25 mg mane
| 75 mg mane |
Rapid or ultrarapid | Null | Not recommended | 50 mg mane | 60 mg mane | Not recommended | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | 20 mg mane | 50 mg mane | 75 mg mane |
Intermediate, normal or null | Poor | 20 mg mane | 50 mg mane | 60 mg mane | 10 mg mane | 20 mg mane |
25 mg nocte
| 30 mg nocte |
10 mg mane
| 50 mg mane | Not recommended |
Poor | Poor |
10 mg mane
| 50 mg mane | 60 mg mane |
5 mg mane
| 20 mg mane |
25 mg nocte
| 15 mg nocte increase to |
10 mg mane
|
25 mg mane
| Not recommended |
Rapid or ultrarapid | Poor | Not recommended | 50 mg mane | 60 mg mane | Not recommended | 20 mg mane |
25 mg nocte
| 30 mg nocte |
10 mg mane
| 50 mg mane | Not recommended |
Intermediate, normal or null | Ultrarapid | 20 mg mane | 50 mg mane | 60 mg mane | 10 mg mane | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | Not recommended | 50 mg mane |
75 mg CR mane increase to 225 mg
|
Poor | Ultrarapid |
10 mg mane
| 50 mg mane | 60 mg mane |
5 mg mane
| 20 mg mane | 50 mg nocte | 30 mg nocte | Not recommended |
25 mg mane
|
75 mg CR mane increase to 225 mg
|
Rapid or ultrarapid | Ultrarapid | Not recommended | 50 mg mane | 60 mg mane | Not recommended | 20 mg mane | 50 mg nocte | 15 mg nocte increase to | Not recommended | 50 mg mane |
75 mg CR mane increase to 225 mg
|
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome measures
Secondary outcomes measures
Participant timeline {13}
Trial period
| |||||||
---|---|---|---|---|---|---|---|
Enrolment
|
Allocation to intervention
|
Post-allocation
| |||||
Time point | 0 weeks | 2–3 weeks | 4 weeks | 8 weeks | 12 weeks | 26 weeks | Post-26 weeks |
Enrolment | X | ||||||
Eligibility screen
| X | ||||||
Informed consent
| X | ||||||
DNA collection
| X | ||||||
Allocation to intervention
| X | ||||||
Interventions | |||||||
Antidepressant prescribing report
| X | ||||||
Full clinical PGx report
| X | ||||||
Assessments | |||||||
Demographics
| X | ||||||
PHQ-9
| X | X | X | X | X | ||
FISBER
| X | X | X | X | X | ||
AQoL-4D
| X | X | X | ||||
MARS-5
| X | X | X | X | X | ||
COVID-19 QoL and Mental Health Impact Scale
| X | ||||||
Resource use questionnaire
| X | X | X | ||||
GP record audit
| X | ||||||
MBS and PBS data
| X |
Sample size {14}
Recruitment {15}
Identification of potential participants
Participant recruitment and consent
Ineligible patients and patients who do not wish to participate in the trial
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
On trial
On completion of the trial
Data collection and management
Plans for assessment and collection of outcomes {18a}
Questionnaire measures
Administrative health service use data collection
Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data collection
GP record audit
Process evaluation
Plans to promote participant retention and complete follow-up {18b}
GP and participant withdrawal
Data management {19}
Confidentiality {27}
-
Minimal sensitive and health information is collected on participants. The data collected is limited to that required to address the primary and secondary objectives.
-
Participant identifiers are stored securely with restricted access using REDCap’s permission control functionality. Where possible, participant data is identified through the use of a unique participant study ID assigned to the participant (“re-identifiable”). The study coordinator is responsible for the management of REDCap’s permission control functionality and restricting access to participant identifiers to those who a directly involved in participant follow-up.
-
The trial statistician conducting the analyses will be provided with anonymised data using a unique participant trial ID.
-
All DNA sample specimens and associated forms are transported to the testing laboratory through Melbourne Pathology (Sonic Healthcare), using a courier. Upon receipt by Melbourne Pathology, a unique identifier (episode ID) is allocated to each sample. This episode ID, along with the participant trial ID, then accompanies all data through the genotyping and phenotyping process, including return to researchers at UoM. These two unique identifiers then allow for reidentification of the data by UoM researchers, without the need to send personal identifiers.
-
All data is managed according to UoM’s Research Data Management Policy and Research Code of Conduct, including security protocols such as two-factor authentication and storage on secure servers.