TRIAGE-GS: Towards Reducing Inefficiencies Affecting Genetics Encounters Through Genome Sequencing

Official title

TRIAGE-GS: A Randomized Controlled Trial of a Genomics-first Approach to Rare Disease Diagnosis

Overview

Individually rare genetic diseases are collectively common, and affect many Canadian families. Making the right diagnosis is both important and challenging. Healthcare providers and families often remain in the dark for too long, limited by the scope and speed of current genetic testing. The goal of this clinical trial is to learn if performing genome sequencing (a comprehensive genetic test) as soon as a rare genetic disease is suspected is more effective than usual care, where a person waits to see a genetics specialist and then typically gets offered more targeted testing. Researchers will compare a "genome-sequencing first" approach to the standard-of-care in individuals who were referred to the Genetics Clinic at either SickKids or CHEO and recently had their referral accepted by the clinic. The main questions this clinical trial aims to answer are: 1. Are there more and faster diagnoses with a "genome sequencing first" approach compared to standard-of-care? 2. What do patients, families, and healthcare providers think about a "genome sequencing first" approach compared to standard-of-care? 3. What is the financial impact of a "genome sequencing first" approach compared to standard-of-care on the healthcare system? Participants will be asked to: * Let us review their medical records. * Complete up to 5 questionnaires over the course of the study. * Give a blood sample for clinical genome sequencing (if in the genome sequencing first group). This study aims to provide the robust evidence needed to improve care pathways for rare disease diagnosis in Canada. The findings also promise to help translate new genetic technologies into the clinic. Earlier diagnosis is a key first step towards personalized care, targeted treatments, and better outcomes.

Detailed description

This is a multi-centre, prospective, interventional, open randomized controlled trial that compares patient outcomes generated by clinical whole genome sequencing (GS) initiated at time of referral triage (i.e., prior to evaluation with a medical geneticist) to standard-of-care, where genetic testing is ordered post-evaluation. 200 individuals referred to SickKids or CHEO for suspected undiagnosed rare disease (RD) will be enrolled, along with their biological parents when possible. The purpose of this study is to examine the safety, utility, and feasibility of a "genomics first" diagnostic pathway for RD. The investigators hypothesize that a GS-first pathway will have non-inferior diagnostic yield and lead to a shorter duration of time to RD diagnosis, fewer diagnostics-focused clinic visits, and improved stakeholder satisfaction.

Interventions

• Genetic Genome sequencing pre-geneticist evaluation
  The intervention is receiving immediate clinical routine GS, prior to evaluation by a medical geneticist. Pre-test counselling will be done by a research genetic counsellor. Results of GS will be returned during the participant's first visit to Genetics Clinic by their clinical team. Subsequent clinical care (including any other clinically indicated genetic testing or workup) will be arranged by the medical geneticist in clinic.

Primary outcome measures

• Determine the time-to-event (diagnosis or no active follow-up) of a GS-first (pre-geneticist evaluation) outpatient care model for rare disease compared to standard of care. [Time frame: From date of randomization until the date of the disclosure of diagnosis/plan, up to 18 months.]
• Compare clinical utility of GS-first to standard of care from the perspectives of care teams. [Time frame: 0-2 weeks after the first results disclosure to the participant/family.]
• Compare personal utility of GS-first to standard-of-care from the perspectives of patients, families, and care teams. [Time frame: 0-2 weeks after the first results disclosure to the participant/family.]
• Assess cost-effectiveness as the incremental cost per additional case detected for GS-first compared to standard-of-care from a healthcare system payer perspective. [Time frame: Overall during the study period (up to 18 months).]

Secondary outcome measures (10)

• Primary diagnostic yield [Time frame: Overall during the study period (up to 18 months), and within a 6-month time interval from the date of randomization.]
• Proportion of participants with dual diagnoses [Time frame: Overall during the study period (up to 18 months).]
• Proportion of participants with partial genetic diagnoses [Time frame: Overall during the study period (up to 18 months).]
• Proportion of participants with potential genetic diagnoses [Time frame: Overall during the study period (up to 18 months).]
• Proportion of participants with variants of uncertain significance deemed non-contributory by the clinician [Time frame: Overall during the study period (up to 18 months).]
• Proportion of participants with secondary/incidental findings [Time frame: Overall during the study period (up to 18 months).]
• Number of new informative HPO terms coded after evaluation by a geneticist (compared with data extracted from collateral records at the time of the referral) [Time frame: Overall during the study period (up to 18 months).]
• Differences in amount of time/effort required for reporting genome sequencing [Time frame: Overall during the study period (up to 18 months).]
• Number of diagnoses missed by GS in the intervention arm that were later made after geneticist evaluation [Time frame: Overall during the study period (up to 18 months).]
• Incremental cost per unit improvement in C-GUIDE score [Time frame: Overall during the study period (up to 18 months).]

Eligibility criteria

Inclusion criteria

• Referral accepted to the Genetics Clinic at SickKids or CHEO within 7 days of screening for study eligibility.
• Referral is for a patient that is ≤18 years old.
• Reason for referral is a suspected but as-yet-undiagnosed RD
• A genetic aetiology is a possible explanation for the phenotype such that genetic testing is likely to be offered in Genetics Clinic, as determined by the research team.

Exclusion criteria

• Patient has a known or suspected clinical diagnosis using established criteria of a genetic condition with low locus heterogeneity (e.g., HHT, fCCM, NF1, TSC, others)
• Referral considered "Urgent" using established site criteria.
• Genome-wide sequencing (exome sequencing or GS) or a comprehensive panel that encompasses all genes relevant for the reported phenotype previously completed on a clinical or research basis.
• Patient or family member previously assessed by a medical geneticist within the last 2 years for the same phenotype(s).
• Patient lacks Ontario Health Insurance Plan (OHIP) or comparable coverage (as this will limit options for standard genetic testing).
• Referral is solely to facilitate familial variant testing or for genetic counselling.
• A family member is already enrolled in the study and was referred for the same indication.
• Patient/family does not provide informed consent to participate within 2 weeks of being approached.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Diagnostic

Study locations

Canada · 2 centers

• Children's Hospital of Eastern Ontario — Ottawa
• The Hospital for Sick Children — Toronto

Publications

• Stanley KJ, Chisholm C, Gillespie MK, Caluseriu O, Del Signore N, Elango S, Hartley T, Hewson S, Kim RH, McSheffrey G, Mendoza-Londono R, Sawyer SL, Somerville M, Venkataramanan V, White-Brown A, Telesca S, Shickh S, Marshall CR, Ungar WJ, Hayeems RZ, Bhawra J, Boycott KM, Costain G. TRIAGE-GS: protocol for a randomised controlled trial of a genomics-first approach to rare disease diagnosis for pa PMID 40784761

Identifiers

NCT: NCT06935019 · CTO5061

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗