NICUSeq: A Trial to Evaluate the Clinical Utility of Human Whole Genome Sequencing (WGS) Compared to Standard of Care in Acute Care Neonates and Infants

Study Overview
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Brief Summary
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Prospective, multi-site, study to evaluate the clinical utility of cWGS in a proband. One group will receive cWGS and a clinical report approximately 15 days after blood samples are received, while the other group will continue to receive standard of care until Day 60. The standard of care group will receive cWGS and a clinical report at Day 60 as part of secondary and tertiary analyses. Both groups will be followed for a total of 90 days.

Detailed Description
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This is a prospective, multi-site, randomized study to evaluate the clinical utility of cWGS in each proband. Throughout this study, each proband will receive SOC testing as determined by the site clinical team. Upon enrollment in the study, each proband will be randomly assigned to the 15 day cWGS group or the SOC group. SOC is defined as the management of the proband's care under the same or similar conditions as if the proband was not enrolled in this study. A blood sample from each enrolled proband will be collected and shipped to the Illumina Clinical Services Laboratory (ICSL), which is Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited. ICSL will conduct cWGS testing with the TruGenome Undiagnosed Disease Test (TruGenome Test). The TruGenome Test cWGS results will be provided to the Principal Investigator (PI) or designee who will evaluate each proband test outcome based on the aggregate medical information, informed by the cWGS or SOC results.

Official Title
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NICUSeq: A Prospective Trial to Evaluate the Clinical Utility of Human Whole Genome Sequencing (WGS) Compared to Standard of Care in Acute Care Neonates and Infants

Conditions
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Rare Diseases

Intervention / Treatment
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* Other: clinical whole genome sequencing (cWGS)


Participation Criteria
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Eligibility Criteria
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Proband Inclusion Criteria Current admission in a Neonatal Intensive Care Unit/Intensive Care Unit at a participating clinical site at the time of enrollment from day of life 0 to 120 days A suspected genetic etiology of disease, based on objective clinical findings or other phenotypic defects for which a genetic test would be considered Must be able to have 1 - 1.25 ml tube of whole blood drawn for testing One parent of the proband must be able to provide written informed consent At least one biological parent must agree to participate and provide at least 4 ml of whole blood for testing Exclusion Criteria: Proband Exclusion Criteria Known non-genetic cause(s) of disease, disorder, or phenotypic defect The phenotype is fully explained by complications of prematurity Trisomy 13, 18 or 21 or Turner Syndrome is the likely diagnosis; such a proband will be eligible if a diagnostic karyotype is normal Blood transfusion within 48 hours (each proband will be re-eligible 48 hours after the most recent transfusion) The PI decides that the study is not in the best interest of the proband (for example, the neonate or infant is at a high risk of severe morbidity or mortality within the next 7 days and these risks could be mitigated by alternative testing). Subsequent eligibility for enrollment of each proband is at the discretion of the site PI.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 120 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-cohort, time delay study receiving Clinical Whole Genome Sequencing (cWGS) at either 15 days or 60 days in an acutely ill newborn population
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 15 day cWGS and Standard of Care<br>Enrolled cohorts receive the results of the clinical whole genome sequencing (cWGS) after 15 days of the sample receipt while still undergoing standard of care (SOC). | Other: clinical whole genome sequencing (cWGS)<br>* Clinical Whole Genome Sequencing (cWGS) consists of the sequencing, analysis and interpretation of subjects samples and a return of the result to the ordering physician.<br>|
| No Intervention: Standard of Care<br>Enrolled cohorts receive the results of the clinical whole genome sequencing (cWGS) after 60 days of the sample receipt while still undergoing standard of care (SOC). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A difference in Change of Management between the 15 day cWGS and standard of care groups | Change of Management is a binary (yes or no) based on assignments made by the PI or designee at each site using the following domains: Condition specific management Condition specific supportive interventions Palliative care/End of Life Care A change in any of these domains will be considered a change of management. | Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic Yield | Diagnostic yield (# positive diagnoses/ total # of each proband expressed as a percentage) | 90 Days | 
| Diagnostic Accuracy | Diagnostic accuracy (percent positive agreement between test outcome classified by the medical monitor and the site PI or designee) % diagnoses returned before discharge or death | 90 Days | 
| Genetic Results Returned | % diagnoses returned before discharge or death | 90 Days | 
| Costs | Pre-test costs of hospital care | 90 Days | 
| Average Time to Diagnosis | Average time (in days) to diagnose between cWGS and SOC based on the comparison of the (a) cWGS results and the (b) current clinical diagnoses | 90 Days | 
| The amount of imaging tests ordered as assessed by counting the number of tests per cohort. | Clinical services utilization includes the number of imaging tests ordered. | 90 Days | 
| cWGS satisfaction questionnaire will be given to clinicians and families at the conclusion of the study. | The questionnaire is a likard scale questionnaire developed by the study team to assess satisfaction levels from the perspective of the clinician and also the parent. | 90 Days | 
| Assessment of Clinical Utility by using a questionnaire | A questionnaire developed by the study team will assess the Clinical Utility of the cWGS test | 90 Days | 
| Change in Care Setting from the ICU environment | Changes in care level setting from the ICU environment will be compared between the 15 day cWGS group and the SOC group. | 90 Days | 
| Time to diagnosis | Time to diagnosis (in days of life) | 90 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICU, Intensive Care Unit