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Trial registered on ANZCTR


Registration number
ACTRN12621000009819
Ethics application status
Approved
Date submitted
28/10/2020
Date registered
8/01/2021
Date last updated
2/05/2024
Date data sharing statement initially provided
8/01/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Polygenic Risk Modification on breast cancer risk management and prevention: The PRiMo Trial
Scientific title
Effect of Polygenic Risk Modification on breast cancer risk management and prevention in unaffected women from genetically predisposed families: The PRiMo Trial
Secondary ID [1] 302482 0
Funding Body: NBCF (National Breast Cancer Foundation); Grant code: IIRS-20-068
Universal Trial Number (UTN)
U1111-1258-7456
Trial acronym
PRiMo
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer Risk Assessment 319186 0
Ovarian Cancer Risk Assessment 319887 0
Condition category
Condition code
Cancer 317155 317155 0 0
Breast
Human Genetics and Inherited Disorders 317156 317156 0 0
Other human genetics and inherited disorders
Cancer 317290 317290 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a 'personalised' breast and ovarian cancer risk assessment that includes the modifying effects of common genomic variation (the Polygenic Risk Score (PRS)).

The trial will be offered to unaffected women referred to a participating specialist service (Familial Cancer Clinic) in Australia for predictive testing for a pathogenic variant in a high or moderate risk breast (+/- ovarian) cancer-associated gene (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C or RAD51D) previously detected in a genetic relative ('single gene' testing).

A cohort of unaffected women who have previously tested positive for a moderate risk breast cancer gene (PALB2, CHEK2, ATM, RAD51C, or RAD51D) will also be recruited to the study.

The trial will compare the current standard of care with a personalised assessment of the risk of breast and ovarian cancer that includes 'single gene' testing, family history, personal risk factors and research genomic testing (PRS).

For participants assigned to the intervention arm an integrated risk assessment will be completed by the study team. The assessment will involve combining basic risk factor information provided by the participant (age, ethnicity, lifestyle risk factors and the family history of cancer) with the result of the predictive gene test from the clinical laboratory and a polygenic risk score calculated by the study team using the genotyping results from the research testing.

The PRS will be calculated from an individual's genotyping results as the sum of the log odds associated with previously validated risk allele and a report generated by the central study team using standard methods, including the 'Polygen' tool developed at the Parkville Familial Cancer Centre.

All components will be combined to produce a highly personalised risk assessment using the CanRisk tool and the output summarised in a custom report that includes the primary genetic information and a risk summary that describes personalised 5 and 10 year risks for breast and ovarian cancer.

The results of the Personalised Risk Assessment and the resulting risk management advice will be provided to the participant by their genetics specialist team in a 60 minute face-to-face (in-person or telehealth) appointment.
Risk management advice for each participant will be determined by the managing genetics specialist team and the study team will not be directly involved in their care or provide medical advice to study participants. However, information will be provided to the managing genetics specialist team to ensure a standard approach is used when applying the existing national guidelines for the management of hereditary risk of breast and ovarian cancer (eviQ guidelines, CCNSW) to the personalised risk assessment.
Intervention code [1] 318685 0
Prevention
Comparator / control treatment
The comparator is the current model of care which is for a genetics specialist team to provide a risk assessment and risk management advice based on the results of 'single gene' testing and residual family history, in line with the national eviQ guidelines.

The study will not supply additional risk information but the managing genetics team will be free to use any other risk information (e.g, lifestyle risk factors) that they would normally incorporate into a risk assessment.

Participants randomised to 'standard care' will have the option of crossing over to receive a PRS modified risk assessment at 1 year.
Control group
Active

Outcomes
Primary outcome [1] 325236 0
Changes in risk management behaviour - a composite outcome including rates of screening episodes, risk management intentions, and uptake of risk reducing measures, collected using study-specific questionnaires.
Timepoint [1] 325236 0
Pre-result, post-result, and annually post-result disclosure for 3 years.
Primary outcome [2] 325238 0
Prospective breast cancer incidence rates distributed across the risk categories (high, moderate, low) collected using study-specific questionnaires and matched to state-based cancer registries or medical records.
Timepoint [2] 325238 0
Annually post-result disclosure for 3 years (intervention or standard care).
Primary outcome [3] 325844 0
Prospective ovarian cancer incidence rates distributed across the risk categories (high, moderate, low) collected using study-specific questionnaires and matched to state-based cancer registries or medical records.
Timepoint [3] 325844 0
Annually post-result disclosure for 3 years (intervention or standard care).
Secondary outcome [1] 387299 0
Quality of life assessed using validated AQoL 8D instrument.Longitudianl quality of life scores from AQoL 8D will be used in the cost effectiveness analysis of PRS Risk Modified assessments along with the cost of care and the primary study outcomes
Timepoint [1] 387299 0
Pre-result; post-result; 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [2] 389308 0
Cancer Risk Perception assessed using a validated numerical measure collected through study-specific questionnaires and semi-structured qualitative interviews (on a subset of participants).
Timepoint [2] 389308 0
Pre-result, post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [3] 389309 0
Measure worry about risk of developing cancer and the impact of worry on daily functioning among individuals at risk for hereditary cancer using validated Cancer Worry Scale (CWS).
Timepoint [3] 389309 0
Pre-result, post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [4] 389310 0
Measure impact of genetic counselling services using validated GOS (Genetic Outcome Scale)
Timepoint [4] 389310 0
Pre-result, post-result disclosure
Secondary outcome [5] 389322 0
Measure the psychosocial impact of returning genomic findings to participants in research and clinical practice using validated instrument FACToR (Feelings about genomic testing results)
Timepoint [5] 389322 0
Post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [6] 389323 0
Measure psychological adaptation to genetic information across four domains:Non-intrusiveness,support,self-worth and self-efficacy using validated instrument PAGIS (Psychological adaptation to genetic information scale)
Timepoint [6] 389323 0
Post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [7] 389324 0
Assess positive outcomes reported by people who have experienced traumatic events using validated instrument PGI-SF (Posttraumatic Growth Index-Short Form)
Timepoint [7] 389324 0
Post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [8] 389325 0
Measure common threatening life experiences such as serious illness and financial issues using validated instrument LTE (List of Threatening Experiences)
Timepoint [8] 389325 0
Post-result, 6 months post-result, annually post-result disclosure for 3 years.
Secondary outcome [9] 389327 0
Experience of receiving personalised risk information- including motivation for genetic testing, expectations of information arising from genetic testing and understanding of information arising from genetic testing, impact of their results and changes over time, dis/advantages of participation. Evaluation by semi-structured qualitative interviews
Timepoint [9] 389327 0
4-6 weeks post-result, 12 months post-result disclosure
Secondary outcome [10] 428265 0
Evaluation of patient experiences through focus groups in addition to the planned qualitative interviews. The semi-structured focus group will cover; (i)experience of receiving and/or considering receiving their PRS,including differences, advantages and/or value, satisfaction and function. (ii) Perspectives on acceptability, appropriateness, feasibility and other outcomes reflecting readiness for clinical implementation. (iii) Perspectives on barriers and enablers of future clinical implementation and the strategies (including actions, behaviours, tools and resources) needed to facilitate this.
Timepoint [10] 428265 0
12 months post-result disclosure
Secondary outcome [11] 434668 0
Personal Utility of Genomic Results (PrU). A validated scale measuring the perceived non-clinical benefits of genomic testing. Assesses patient-perceived and reported nonclinical benefits (such as self-knowledge and practical benefits that improve coping).
Timepoint [11] 434668 0
Secondary outcome [12] 434669 0
Personal Utility of Genomic Results (PrU). A validated scale measuring the perceived non-clinical benefits of genomic testing. Assesses patient-perceived and reported nonclinical benefits (such as self-knowledge and practical benefits that improve coping).
Timepoint [12] 434669 0
4-6 weeks post-result, 6-months, 12-months post-result disclosure

Eligibility
Key inclusion criteria
Prospective Enrolment:
(1) Undergoing a predictive test for a likely pathogenic (Class 4) or pathogenic (Class 5) familial mutation in a gene associated with increased risk of breast cancer - BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D at a participating Familial Cancer Clinic.

Retrospective Enrolment:
(1) Have previously completed germline testing and been found to harbour a likely pathogenic (Class 4) or pathogenic (Class 5) variant in a breast/ovarian cancer associated ‘moderate risk’ gene: PALB2, CHEK2, ATM, RAD51C, RAD51D at a participating Familial Cancer Clinic.

Prospective and Retrospective enrolment
(2) Female, unaffected by invasive or in-situ breast cancer or epithelial ovarian cancer
(3) Aged 18 years or above and < 80 years
(4) Have access to the internet and a computer, tablet or smart phone and a basic level of familiarity with digital platforms.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) Unable to read and understand patient study information, including an English language patient information and consent form
(2) Have previously undertaken genomic testing that included polygenic risk information for breast or ovarian cancer
(3) Undergoing current treatment for a cancer diagnosis.
(4) No DNA sample at a participating diagnostic laboratory
(5) Known at time of enrolment to have or be at risk for a significant risk-factor for breast or ovarian cancer that is not captured in the PRiMo risk assessment. For example, a diagnosis of Li-Fraumeni syndrome or predictive testing for a variant with an atypical risk in a known gene (hypomorphs).

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment is carried out using central randomization by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation is simple block randomization table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
The study design will allow participants in the standard care arm to crossover following completion of the survey at 1 year post-result appointment.

The study design also includes a retrospective enrolment of a cohort of unaffected women who have previously tested positive for a moderate risk breast cancer gene will also be recruited to the study. All women in this group will be offered the genomic testing and a composite risk assessment. as for the intervention arm of the prospective cohort. The women who consent to receive the intervention will act as their own control.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical Analysis:
1. Demographic and other cohort features will be examined by descriptive statistics and include tests for heterogeneity between study sites and laboratories.
2. Analyses of main outcomes:
i) Risk Management Intentions: The proportion of participants in either arm reporting the intention to engage with each risk management option will compared (chi squared test) overall and subdivided by gene and risk category status.
ii) Risk Management uptake: Simple proportions will be examined as above. Rates (screening episodes, risk reducing measures, cancer events) will be analysed by Cox regression and associations between variables and outcomes analysed by regression modelling.
iii) Accuracy and Calibration of Risk assessment. Accuracy will be measured using the continuous risk measures (Lifetime and 5- or 10-year risk) and comparing the area under the receiver operating curve (AUROC) and the Matthews Correlation Coefficient (MCC). Calibration will be measured by dividing the risk into the clinical categories or intervals (e.g. the deciles) of the continuous risk measures and estimating the goodness of fit.
3. Internal consistency of the psychosocial tools will be measured by Cronbach’s alpha coefficient. The impact of variables, including the PRS, on psychosocial outcomes will be analysed in a linear mixed model incorporating data on other stressful life events and accounting for clustering as above. Mean values for the tools will be compared between intervention and control groups using the Kruskal-Wallis H test.
Narrative data from the structured interviews will be analysed using response frequencies and qualitative content analysis.
4. Simulated outcomes for a lifetime horizon and a cost effectiveness analysis will be performed using a validated custom micro-simulation model, MiBrOvCare.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2021
Actual
23/06/2021
Date of last participant enrolment
Anticipated
31/03/2025
Actual
Date of last data collection
Anticipated
31/12/2027
Actual
Sample size
Target
2400
Accrual to date
894
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 17639 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 17642 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 17643 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 17644 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [5] 17645 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [6] 17646 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 17647 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [8] 17648 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [9] 17649 0
Prince of Wales Hospital - Randwick
Recruitment hospital [10] 17650 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [11] 17651 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [12] 17652 0
Westmead Hospital - Westmead
Recruitment hospital [13] 17654 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 31385 0
3000 - Melbourne
Recruitment postcode(s) [2] 31395 0
3084 - Heidelberg
Recruitment postcode(s) [3] 31412 0
3168 - Clayton
Recruitment postcode(s) [4] 31419 0
3144 - Malvern
Recruitment postcode(s) [5] 31421 0
4029 - Herston
Recruitment postcode(s) [6] 31422 0
7000 - Hobart
Recruitment postcode(s) [7] 31423 0
6008 - Subiaco
Recruitment postcode(s) [8] 31424 0
5000 - Adelaide
Recruitment postcode(s) [9] 31425 0
2031 - Randwick
Recruitment postcode(s) [10] 31426 0
2050 - Camperdown
Recruitment postcode(s) [11] 31427 0
2065 - St Leonards
Recruitment postcode(s) [12] 31428 0
2145 - Westmead
Recruitment postcode(s) [13] 31430 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 306821 0
Charities/Societies/Foundations
Name [1] 306821 0
National Breast Cancer Foundation
Country [1] 306821 0
Australia
Funding source category [2] 312408 0
Charities/Societies/Foundations
Name [2] 312408 0
Love Your Sister Foundation
Country [2] 312408 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
Office of Cancer Research
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne, Victoria
3000 Australia
Country
Australia
Secondary sponsor category [1] 307387 0
None
Name [1] 307387 0
Address [1] 307387 0
Country [1] 307387 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306984 0
Peter MacCallum Cancer Centre
Ethics committee address [1] 306984 0
Ethics committee country [1] 306984 0
Australia
Date submitted for ethics approval [1] 306984 0
14/09/2020
Approval date [1] 306984 0
30/11/2020
Ethics approval number [1] 306984 0
HREC/64060/PMCC

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105654 0
Prof Paul James
Address 105654 0
Parkville Familial Cancer Centre
305 Grattan Street
Melbourne VIC 3000. Australia
Peter MacCallum Cancer Centre
Country 105654 0
Australia
Phone 105654 0
+61 03 8559 5322
Fax 105654 0
Email 105654 0
[email protected]
Contact person for public queries
Name 105655 0
Simone McInerny
Address 105655 0
Parkville Familial Cancer Centre
305 Grattan Street
Melbourne VIC 3000. Australia
Peter MacCallum Cancer Centre
Country 105655 0
Australia
Phone 105655 0
+61 038559 6190
Fax 105655 0
Email 105655 0
[email protected]
Contact person for scientific queries
Name 105656 0
Paul James
Address 105656 0
Parkville Familial Cancer Centre
305 Grattan Street
Melbourne VIC 3000. Australia
Peter MacCallum Cancer Centre
Country 105656 0
Australia
Phone 105656 0
+61 03 8559 5322
Fax 105656 0
Email 105656 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 individual participant data collected during the trial, except for data provided by Services Australia, from participants that gave permission for their data to be used for related future research projects will be available to researchers whose proposed use of the data has been approved by a HREC and the PRiMo steering committee. Study documents such as the study protocol and PICF will also be available.
When will data be available (start and end dates)?
Data will be available beginning 3 months after publication and ending with the retention period when study data is destroyed.
Available to whom?
De-identified individual participant data collected during the trial, except for data provided by Services Australia, from participants that gave permission for their data to be used for related future research projects will be available to researchers whose proposed use of the data has been approved by a HREC and the PRiMo steering committee. Study documents such as the study protocol and PICF will also be available.
Available for what types of analyses?
De-identified individual participant data collected during the trial, except for data provided by Services Australia, from participants that gave permission for their data to be used for related future research projects will be available to researchers whose proposed use of the data has been approved by a HREC and the PRiMo steering committee. Study documents such as the study protocol and PICF will also be available.
How or where can data be obtained?
Data Access request can be emailed to the PRiMo Study Team at [email protected].
PRiMo Trial Steering Committee are the Data Custodians and hold responsibility for the release of participant data from the PRiMo Trial.


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
SourceTitleYear of PublicationDOI
EmbasePersonalising genetic counselling (POETIC) trial: Protocol for a hybrid type II effectiveness-implementation randomised clinical trial of a patient screening tool to improve patient empowerment after cancer genetic counselling.2023https://dx.doi.org/10.1186/s13063-023-07723-0
N.B. These documents automatically identified may not have been verified by the study sponsor.