Clinical trial NCT03211039: Perinatal Precision Medicine
Official title: Prenatal Precision Medicine (NSIGHT2): A Randomized, Blinded, Prospective Study of the Clinical Utility of Rapid Genomic Sequencing for Infants in the Acute-care Setting
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Genetic Diseases
Genetic Syndrome
Mendelian Disorders
Keywords: Neonate
Genomic Medicine
Rapid Precision Medicine
Rapid Whole Genome Sequencing
Diagnosis
Infant
Intensive care unit
clinical trial
Rapid Whole Exome Sequencing
Single locus disease
Ultra-rapid whole genome sequencing
Clinical Utility
Lead sponsor: Rady Pediatric Genomics & Systems Medicine Institute
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Human Genome Research Institute (NHGRI)
First posted: 2017-07-07
Enrollment: 213
Sex: ALL
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The initial symptom-driven analysis will be conducted on the patient's (NICU infants) sample only (singleton analysis). Patients will be randomized to receive either whole genome sequencing or whole exome sequencing. If a diagnosis is not found promptly (within 24 hours) via singleton analysis, sequential analysis of the family (or any combination of parents and/or other family members) will be analyzed using the same technology that the patient was randomized to receive.

The study includes parental and physician questionnaires to understand perceptions regarding testing. There is no randomization of parents or physicians nor a requirement to respond to the questionnaires for the patient (NICU infant) to participate in the study.

Enrollment: 213 patients (NICU infants)
Primary purpose: DIAGNOSTIC

Brief summary: This study will seek to determine if rapid genomic sequencing improves outcomes for acutely ill infants. The investigator will enroll up to 1,000 acutely ill infants in a prospective, randomized, blinded study to either rapid Whole Genome Sequencing (WGS) or rapid Whole Exome Sequencing (WES, which is 2% of the genome and \~4-fold less expensive). 213 infants were actually enrolled. Outcomes will be measured both by objective clinical measures and family perceptions (patient/family centered outcomes). Primary analysis of WGS or WES will be in infants alone. Secondary analysis, in infants who do not receive a diagnosis, will be of families - ideally trios (mother, father, and affected infant), which is \~2-fold more expensive. Trios will be analyzed within the same randomization arm (WGS or WES). This study is designed to quantify which acutely ill infants benefit from rapid genomic sequencing, by how much they benefit, how they benefit, which rapid genomic sequencing method is superior, and the cost effectiveness of such testing.

Detailed description: Acutely ill infant inpatients who have an undiagnosed illness, and their families, will be eligible to participate in the study. The investigators will enroll up to 1,000 infants. Locally, the study population will be recruited from Rady Children's Hospital (RCH) inpatient population, primarily the neonatal intensive care unit (NICU), pediatric intensive care unit (PICU), and cardiovascular intensive care unit (CVICU), with a smaller population presenting to other hospital in-patient services. Recruitment will be targeted at the RCH main campus, but it may include referrals from satellite locations in the RCH network (particularly the RCH NICU network throughout San Diego County). All patients will continue to receive routine care as clinically indicated, including the state newborn screen and other genetic testing as determined by their treating providers. Half of the affected study participants will be randomized to receive rapid whole genome sequencing (WGS) and the other half will receive rapid whole exome sequencing (WES). Each arm will initially be analyzed using the patient's (proband's) sample only. If a proband-only analysis fails to yield a diagnosis, genomic data from the biological family members (typically parents), when available, will be used to supplement analysis (trio analysis). Occasionally, a second affected sibling may be available for family analysis. Not infrequently, the father is not available for study. Similarly, the investigators anticipate the need for targeted genetic analysis of biological parents, and possibly other family members, to confirm diagnostic results and/or provide additional information regarding inheritance.

The investigators anticipate that in rare cases a newborn may be so ill that the team lacks equipoise that the child can wait for the estimated ten day turnaround time of our send-out exome testing. In these rare cases, the PI, or his delegate, will decide if the child is not eligible for randomization. These children will remain in the research study throughout the entirety of the study, but will receive in-house ultra-rapid whole genome sequencing by the Rady Children's Institute for Genomic Medicine (RCIGM, also called RadyPGSMI) laboratory in lieu of either a rapid genome or rapid exome (both anticipated to be 10 day turn-arounds).

Enrollment will be sought within the first 96 hours following admission to RCH or an RCH network ICU or within 96 hours of meeting criteria for the study if the infant was not previously eligible. Patients and their family members who consent to participate will have their blood drawn and will be randomized to receive either rapid WGS or rapid WES. The initial symptom-driven analysis will be conducted on the patient's sample only (singleton analysis). If a diagnosis is not found promptly (within 24 hours) via a singleton analysis, the family (or any combination of parents and/or other family members) will be analyzed using the same technology that the patient was randomized to receive. Pathogenic and likely pathogenic variants (as determined by American College of Medical Genetics (ACMG) guidelines) that relate in part or in whole to the patient's current phenotype will be clinically confirmed and reported into the patients' medical record. Although the intention of the study is to return symptom-driven results to the medical record, the clinical report for confirmation of symptom-driven findings may include negative findings of testing. In the event that our analysis incidentally finds a pathogenic variant for which a treatment or intervention exists to improve morbidity and/or mortality, families may choose not to receive this additional information.

Eligibility criteria: Inclusion Criteria:

Individual in whom one of the following criteria is met:

1. Acutely ill inpatient of less than 4 months of age and within 96 hours of admission.
2. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of an abnormal response to standard therapy for an underlying condition.
3. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of clinical feature or laboratory test value suggestive of a genetic condition.
4. Biological relative of an infant enrolled in this study.

Exclusion Criteria:

Inpatients of greater than 4 months of age, or who do not meet any of the inclusion criteria, or with:

1. Neonatal infection or sepsis with normal response to therapy
2. Isolated prematurity
3. Isolated unconjugated hyperbilirubinemia
4. Hypoxic Ischemic Encephalopathy with clear precipitating event
5. Previously confirmed genetic diagnosis that explains their clinical condition (i.e. have a positive genetic test)
6. Isolated Transient Neonatal Tachypnea
7. Permission is unable to be obtained by a legal guardian or court-appointed representative within 96 hours of becoming eligible for enrollment.
8. Non-viable neonates - newborns less than 28 days of life with a modified code status (only full code patients may be enrolled).

Primary outcomes:
measure: Subject's Main Provider's Perceived Clinical Utility of Genomic Sequencing
timeFrame: Within one week of the return of results
measure: Test Results Led to Change in Patient Management
timeFrame: Within 1 week of return of results
measure: Test Led to Changes in Management That Altered Patient Outcome
timeFrame: 1 year
Secondary outcomes:
measure: Diagnostic Proportion for Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES)
timeFrame: Within approximately 30 days of enrollment
measure: Result Within 7 Days of Sample Receipt
timeFrame: Within 7 days of sample receipt
measure: Parental Perceived Usefulness of Test
timeFrame: Within one week of the return of results and approximately one year after enrollment
measure: Parental Perception of Test Benefit for Their Infant
timeFrame: Within one week of the return of results and approximately one year after enrollment
measure: Parental Decisional Regret With Sequencing
timeFrame: Within one week of the return of results and approximately one year after enrollment
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Rady Children's Institute for Genomic Medicine (RCIGM)
state: California
Study officials:
affiliation: Rady Pediatric Genomics & Systems Medicine Institute
name: Stephen F Kingsmore, MD, DSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Milko LV, Chen F, Chan K, Brower AM, Agrawal PB, Beggs AH, Berg JS, Brenner SE, Holm IA, Koenig BA, Parad RB, Powell CM, Kingsmore SF. FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation. NPJ Genom Med. 2019 Dec 10;4:32. doi: 10.1038/s41525-019-0105-8. eCollection 2019.
citation: Kingsmore SF, Nofsinger R, Ellsworth K. Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review. NPJ Genom Med. 2024 Feb 27;9(1):17. doi: 10.1038/s41525-024-00404-0.
citation: Chan K, Hu Z, Bush LW, Cope H, Holm IA, Kingsmore SF, Wilhelm K, Scharfe C, Brower A. NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders. Int J Neonatal Screen. 2023 Oct 30;9(4):63. doi: 10.3390/ijns9040063.
citation: Owen MJ, Lefebvre S, Hansen C, Kunard CM, Dimmock DP, Smith LD, Scharer G, Mardach R, Willis MJ, Feigenbaum A, Niemi AK, Ding Y, Van Der Kraan L, Ellsworth K, Guidugli L, Lajoie BR, McPhail TK, Mehtalia SS, Chau KK, Kwon YH, Zhu Z, Batalov S, Chowdhury S, Rego S, Perry J, Speziale M, Nespeca M, Wright MS, Reese MG, De La Vega FM, Azure J, Frise E, Rigby CS, White S, Hobbs CA, Gilmer S, Knight G, Oriol A, Lenberg J, Nahas SA, Perofsky K, Kim K, Carroll J, Coufal NG, Sanford E, Wigby K, Weir J, Thomson VS, Fraser L, Lazare SS, Shin YH, Grunenwald H, Lee R, Jones D, Tran D, Gross A, Daigle P, Case A, Lue M, Richardson JA, Reynders J, Defay T, Hall KP, Veeraraghavan N, Kingsmore SF. An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases. Nat Commun. 2022 Jul 26;13(1):4057. doi: 10.1038/s41467-022-31446-6.
citation: Kingsmore SF, Cole FS. The Role of Genome Sequencing in Neonatal Intensive Care Units. Annu Rev Genomics Hum Genet. 2022 Aug 31;23:427-448. doi: 10.1146/annurev-genom-120921-103442. Epub 2022 Jun 8.
citation: Dimmock DP, Clark MM, Gaughran M, Cakici JA, Caylor SA, Clarke C, Feddock M, Chowdhury S, Salz L, Cheung C, Bird LM, Hobbs C, Wigby K, Farnaes L, Bloss CS, Kingsmore SF; RCIGM Investigators. An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm. Am J Hum Genet. 2020 Nov 5;107(5):942-952. doi: 10.1016/j.ajhg.2020.10.003.
citation: Cakici JA, Dimmock DP, Caylor SA, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS. A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants. Am J Hum Genet. 2020 Nov 5;107(5):953-962. doi: 10.1016/j.ajhg.2020.10.004.
citation: Kingsmore SF, Cakici JA, Clark MM, Gaughran M, Feddock M, Batalov S, Bainbridge MN, Carroll J, Caylor SA, Clarke C, Ding Y, Ellsworth K, Farnaes L, Hildreth A, Hobbs C, James K, Kint CI, Lenberg J, Nahas S, Prince L, Reyes I, Salz L, Sanford E, Schols P, Sweeney N, Tokita M, Veeraraghavan N, Watkins K, Wigby K, Wong T, Chowdhury S, Wright MS, Dimmock D; RCIGM Investigators. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. doi: 10.1016/j.ajhg.2019.08.009. Epub 2019 Sep 26.
citation: Cakici JA, Dimmock D, Caylor S, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS. Assessing Diversity in Newborn Genomic Sequencing Research Recruitment: Race/Ethnicity and Primary Spoken Language Variation in Eligibility, Enrollment, and Reasons for Declining. Clin Ther. 2023 Aug;45(8):736-744. doi: 10.1016/j.clinthera.2023.06.014. Epub 2023 Jul 8.
citation: Owen MJ, Batalov S, Ellsworth KA, Wright M, Breeding S, Hugh K, Kingsmore SF, Ding Y. Rapid Whole Genome Sequencing for Diagnosis of Single Locus Genetic Diseases in Critically Ill Children. Methods Mol Biol. 2023;2621:217-239. doi: 10.1007/978-1-0716-2950-5_12.
citation: Laurenzano SE, McFall C, Nguyen L, Savla D, Coufal NG, Wright MS, Tokita M, Dimmock D, Kingsmore SF, Newfield RS. Neonatal diabetes mellitus due to a novel variant in the INS gene. Cold Spring Harb Mol Case Stud. 2019 Aug 1;5(4):a004085. doi: 10.1101/mcs.a004085. Print 2019 Aug.