Clinical trial NCT04157595: Mackenzie's Mission: The Australian Reproductive Carrier Screening Project
Official title: Mackenzie's Mission: The Australian Reproductive Carrier Screening Project
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: X-Linked Genetic Diseases
Autosomal Recessive Disorder
Keywords: reproductive genetics
carrier screening
rare disease
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
Collaborators: name: Australian Government Department of Health and Ageing
name: The University of New South Wales
name: The University of Western Australia
name: Harry Perkins Institute of Medical Research
name: University of Sydney
name: Macquarie University, Australia
name: Griffith University
name: Victorian Clinical Genetics Services
name: NSW Health Pathology
name: PathWest Laboratory Medicine WA
name: King Edward Memorial Hospital
name: Royal Brisbane and Women's Hospital
name: Women's and Children's Hospital, Australia
name: Sydney Children's Hospitals Network
name: Royal Hobart Hospital
First posted: 2019-11-08
Enrollment: 18302
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: This study will investigate reproductive genetic carrier screening (RGCS) in 10,000 couples across Australia. Carrier screening for approximately 1300 genes associated with severe, childhood-onset, X-linked and autosomal recessive conditions will be performed on each member of the couple. A combined result will be issued indicating whether the couple has a 'low' or 'increased' risk of having a child with a genetic condition. It is anticipated that 1-2% of couples will be at an increased risk of having an affected child.

The study will evaluate all aspects of the RGCS program to assess the feasibility and acceptability of a publicly-funded population-wide RGCS program, including:

* education of recruiting healthcare providers
* education of participating couples
* implementation and uptake of RGCS
* frequency of increased-risk couples and their reproductive decisions
* psychosocial impacts
* ethical issues
* health economic implications
* health implementation research

Detailed description: PROTOCOL SYNOPSIS

Couples will be invited to take part in the study by their healthcare provider (HCP). The couple will enrol via an online portal, complete an education module, provide consent and complete a questionnaire. Those who consent to carrier screening will be sent mouth swab kits with samples returned by mail.The carrier screening performed will be done via accredited testing laboratories in partnership with clinical genetics services. Genetic counselling will be available to study participants throughout the process. Couples at increased risk will be offered a genetic counselling consultation and offered support to access reproductive options (i.e. prenatal diagnosis, preimplantation genetic diagnosis (PGD) which will be funded by the study for one cycle of IVF with PGD). All participants will be asked to complete an initial survey at study enrolment and invited to complete optional surveys at the time of screening, after return of screening results, and approximately 13 to 19 months after results. Subsets of participants will also be invited to take part in interviews.

GENE LIST FOR CARRIER SCREENING

The approximately 1300 genes tested in the Mackenzie's Mission carrier screening panel meet the following criteria:

1. The associated condition is one where an 'average' couple would take steps to prevent the birth of a child with that condition.

   - This includes conditions with significant negative impact on quality of life for the child, the condition being lethal in childhood, and a significant impact on the family.
2. AND/OR: There is a potential benefit for knowing about the condition to inform management in the neonatal period. This criterion was particularly important if the condition was either not included on a newborn screening panel, and/or intervention would be required prior to results from newborn screening being known.
3. AND there is strong evidence for mutations in the gene being causative of the condition in question, with enough variants reported to allow confidence in informing couples of their chance of having a child with the condition in question.

Eligibility criteria: In order to take part in the study, couples need to have visited a recruiting HCP who will assess them for eligibility based on the criteria below:

INCLUSION CRITERIA

* Planning to become pregnant or in early pregnancy (less than 10 weeks gestation at enrolment and less than 11 weeks gestation at sample receipt by the laboratory)
* Both members of the couple available to participate in the study and available to provide a sample for testing at the same time.
* If the couples are using an egg/sperm donor/s, the donor/s need to be available to provide a DNA sample for testing and consent to having carrier screening.

NB: If both members of the couple are known carriers of the same autosomal recessive condition, or the female is a known carrier of an X-linked recessive condition, they will still be eligible to have RGCS through the study, but will only be considered an 'increased-risk' couple for the purposes of this study if they are identified through the study testing to be carriers of pathogenic variants in a different gene.

EXCLUSION CRITERIA

Participating couples meeting any of the following requirements will be excluded from this study:

* Pregnant and greater than 10 weeks gestation at enrolment.
* Only one member of the couple agrees to participate in the study.
* One or both members of the couple are less than 18 years old.
* Both members of the couple are not available to be tested at the same time.
* The couple are using an egg/sperm donor/s and the donor/s are not available for testing or the couple are using an anonymous donor.
* One member of the couple has already been screened as part of the study.

Primary outcomes:
measure: Screening Uptake (Quantitative)
timeFrame: At offer of screening
measure: Frequency of Increased-Risk Couples
timeFrame: At reporting of results (~Weeks 5-6 since enrolment)
measure: Reproductive Choices made by Increased-Risk Couples
timeFrame: Reproductive choices made by couples will be tracked from the date an increased-risk result is received until study closure on 31 December 2022. A subset of couples will be interviewed ~19 months after receiving an increased-risk result.
measure: Cohort Characteristics of those who decline and those who accept RGCS
timeFrame: Couples who decline screening;at offer or at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.
measure: Predictors of Uptake - Decliners
timeFrame: Couples who decline screening; at offer or enrolment (Day 0); optional
measure: Predictors of Uptake - Decliners
timeFrame: At decision not to provide samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Predictors of Uptake - Acceptors
timeFrame: Couples who accept screening; at offer or enrolment (Day 0); compulsory.
measure: Predictors of Uptake - Acceptors
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
Secondary outcomes:
measure: Participant Experience - Attitudes/Perceptions
timeFrame: Couples who decline screening;at offer or at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.
measure: Participant Experience - State-Anxiety - pre-screening
timeFrame: Couples who decline screening; at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.
measure: Participant Experience - State-Anxiety - pre-screening II
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - State-Anxiety - post-result
timeFrame: Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional
measure: Participant Experience - State-Anxiety - long-term follow-up
timeFrame: Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional
measure: Participant Experience - Trait-Anxiety - pre-screening
timeFrame: Couples who decline screening; at enrolment (Day 0); optional. Couples who accept screening; at enrolment (Day 0); compulsory.
measure: Participant Experience - Trait-Anxiety - pre-screening II
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Trait-Anxiety - post-result
timeFrame: Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional
measure: Participant Experience - Trait-Anxiety - long-term follow-up
timeFrame: Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional
measure: Health Economic Impact - Assessment of Quality of Life - pre-screening
timeFrame: Couples who decline testing, at enrolment (Day 0); optional. Couples who accept testing, at enrolment (Day 0); compulsory
measure: Health Economic Impact - Assessment of Quality of Life - post-result
timeFrame: Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional
measure: Health Economic Impact - Assessment of Quality of Life - long-term follow-up
timeFrame: Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional
measure: Health Economic Impact - Participants' willingness to pay
timeFrame: Couples who decline screening, at enrolment (Day 0); optional. Couples who accept screening, at enrolment (Day 0); compulsory
measure: Participant Experience - Health Literacy
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Evaluation of Educational and Decision-Aid Materials
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Decisional Conflict
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Deliberation
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Decision-Making Approach
timeFrame: At provision of samples for screening, anticipated to be within ten days of enrolment (Days 2-10); optional
measure: Participant Experience - Genomics Outcome Scale (GOS-6)
timeFrame: Increased-risk couples, before and after genetic counselling session (~Weeks 5-6 since enrolment)
measure: Participant Experience - Decisional Regret - post-result
timeFrame: Low-risk and increased-risk couples; post-result (~Weeks 17-18 since enrolment); optional
measure: Participant Experience - Decisional Regret - long-term follow-up
timeFrame: Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional
measure: Participant Experience - Qualitative Interviews
timeFrame: Low-risk couples; long-term follow-up (~13 months since enrolment); optional. Increased-risk couples; long-term follow-up (~19 months since enrolment); optional
Other outcomes:
measure: Ethical Issues - Assessment of ethical aspects of publicly funded preconception screening
timeFrame: Throughout study; 3 years
measure: Implementation Outcomes - Barriers & Enablers to Implementation
timeFrame: Study investigators; at committee meetings for the duration of the study (3 years); Jan 2019 - Dec 2022
measure: Implementation Outcomes - Anticipated vs Actual Outcomes
timeFrame: Study investigators; 1 month before the study begins recruitment
measure: Implementation Outcomes - Patient Safety Behaviour Questionnaire
timeFrame: HCPs; at HCP conferences or professional meetings; for the duration of the study (3 years).
measure: Implementation Outcomes - Uptake by HCPs
timeFrame: HCPs; at invitation to become a recruiting HCP; for the duration of the study (3 years)
measure: Implementation Outcomes - Factors influencing Recruitment by HCPs - post-education
timeFrame: Recruiting HCPs; 3 months after education
measure: Implementation Outcomes - Factors influencing Recruitment by HCPs - post-recruitment
timeFrame: Recruiting HCPs; 6 weeks after recruitment of first participant
measure: Implementation Outcomes - HCP Experience - post-implementation
timeFrame: Recruiting HCPs; 3 months after end of recruitment
measure: Health Economic Impact - Costs per increased-risk couple identified
timeFrame: 3 months after enrolment
measure: Health Economic Impact - Costs per affected pregnancy identified
timeFrame: 6 months after enrolment
measure: Health Economic Impact - Costs per affected birth averted
timeFrame: Throughout study; 3 years
measure: Health Economic Impact - Costs of the carrier screening program
timeFrame: Throughout study; 3 years
Locations:
city: Forster
country: Australia
facility: Forster Community Health Service
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Hunter Genetics
state: New South Wales
city: Sydney
country: Australia
facility: Royal Hospital for Women
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Children's Hospital, Randwick
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Sydney
country: Australia
facility: The Children's Hospital at Westmead
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Tamworth
country: Australia
facility: Tamworth Communith Health Services
state: New South Wales
city: Taree
country: Australia
facility: Taree Community Health Service
state: New South Wales
city: Wagga Wagga
country: Australia
facility: Wagga Wagga Base Hospital
state: New South Wales
city: Darwin
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Cairns
country: Australia
facility: Cairns Hospital
state: Queensland
city: Mareeba
country: Australia
facility: Mareeba Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Melbourne
country: Australia
facility: Victorian Clinical Genetics Services
state: Victoria
city: Melbourne
country: Australia
facility: Northern Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Mercy Hospital for Women
state: Victoria
city: Warragul
country: Australia
facility: West Gippsland Heath Service (Warragul Hospital)
state: Victoria
city: Joondalup
country: Australia
facility: Joondalup Health Campus
state: Western Australia
city: Perth
country: Australia
facility: King Edward Memorial Hospital
state: Western Australia
Study officials:
affiliation: Murdoch Children's Research Institute/Victorian Clinical Genetics Services
name: Martin Delatycki
role: PRINCIPAL_INVESTIGATOR
affiliation: Sydney Children's Hospital Network/NSW Health Pathology/UNSW
name: Edwin Kirk
role: PRINCIPAL_INVESTIGATOR
affiliation: University of WA/Harry Perkins Institute/PathWest Laboratory Medicine
name: Nigel Laing
role: PRINCIPAL_INVESTIGATOR
References: