Perinatal Precision Medicine

NCT03211039 | Active Not Recruiting Results FDA Device

• 2 other identifiers: 161983U19HD077693
• Study Type: interventional
• Target: 213
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (3)

• Subject's Main Provider's Perceived Clinical Utility of Genomic Sequencing

  Perceived utility/benefit of sequencing based on "Clinician Assessment" questionnaire completed by patient's providers. Question: Was the test clinically useful? Response was measured on a 5-point Likert scale (very useful=5, useful=4, neutral=3, not very useful=2, not useful at all=1.

  Within one week of the return of results

• Test Results Led to Change in Patient Management

  Test results led to Change in clinical management (select all that apply): * Surgical intervention added * Surgical intervention removed * Surgical intervention changed * Medication added * Medication removed * Medication changed * Diet changed * New specialty service sought * Prior specialty service no longer required * New imaging sought * Prior imaging cancelled * New test ordered * Prior testing cancelled * Screening for additional comorbidities added * Screening for additional comorbidities removed * Palliative care initiated * Palliative care withdrawn * Other: (text box for written description)

  Within 1 week of return of results

• Test Led to Changes in Management That Altered Patient Outcome

  Primary physician perception of change in outcome

  1 year

Secondary Outcomes (5)

• Diagnostic Proportion for Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES)

  Within approximately 30 days of enrollment

• Result Within 7 Days of Sample Receipt

  Within 7 days of sample receipt

• Parental Perceived Usefulness of Test

  Within one week of the return of results and approximately one year after enrollment

• Parental Perception of Test Benefit for Their Infant

  Within one week of the return of results and approximately one year after enrollment

• Parental Decisional Regret With Sequencing

  Within one week of the return of results and approximately one year after enrollment

Study Arms (2)

Whole Genome Sequencing

OTHER

Genetic test that looks at all coding and non-coding areas of the genome

Genetic: Genomic sequencing and molecular diagnostic results, if any.

Whole Exome Sequencing

OTHER

Genetic test that looks at all coding areas of the genome

Genetic: Genomic sequencing and molecular diagnostic results, if any.

Interventions

Genomic sequencing and molecular diagnostic results, if any. GENETIC

Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.

Whole Exome Sequencing; Whole Genome Sequencing

Eligibility Criteria

• Age: Up to 4 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Individual in whom one of the following criteria is met:
• Acutely ill inpatient of less than 4 months of age and within 96 hours of admission.
• 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.
• 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.
• Biological relative of an infant enrolled in this study.

You may not qualify if:

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

Sponsors & Collaborators

• Rady Pediatric Genomics & Systems Medicine Institute: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Human Genome Research Institute (NHGRI): collaborator

Study Sites (1)

Rady Children's Institute for Genomic Medicine (RCIGM)

San Diego, California, 92123, United States

Location

Related Publications (11)

• 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.

  PMID: 31839987 BACKGROUND

• 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.

  PMID: 38413639 BACKGROUND

• 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.

  PMID: 37987476 BACKGROUND

• 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.

  PMID: 35882841 BACKGROUND

• 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.

  PMID: 35676073 BACKGROUND

• 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.

  PMID: 33157007 RESULT

• 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.

  PMID: 33157008 RESULT

• 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.

  PMID: 31564432 RESULT

• 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.

  PMID: 37429778 RESULT

• 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.

  PMID: 37041447 RESULT

• 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.

  PMID: 31196892 DERIVED

MeSH Terms

Conditions

Genetic Diseases, Inborn; Disease

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Stephen F. Kingsmore
• Organization: Rady Children's Institute for Genomic Medicine

skingsmore@rchsd.org

816 854 0882

Study Officials

• Stephen F Kingsmore, MD, DSc

  Rady Pediatric Genomics & Systems Medicine Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Patients (NICU infants) and their parents, the patient's providers, and the enrollment staff will be blinded to the randomization arm they receive.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: President and CEO

Model Details: 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)

Study Record Dates

• First Submitted: May 24, 2017
• First Posted: July 7, 2017
• Study Start: June 29, 2017
• Primary Completion: October 9, 2018
• Study Completion: July 30, 2024
• Last Updated: March 1, 2024
• Results First Posted: February 27, 2023

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Following publication of results; Indefinitely
• Access Criteria: Researchers must register at NBSTRN and request access to this dataset via the LPDR.

Locations

US (1)