- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03211039
Perinatal Precision Medicine (NSIGHT2)
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 Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
California
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San Diego, California, United States, 92123
- Rady Children's Institute for Genomic Medicine (RCIGM)
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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.
Exclusion Criteria:
Inpatients of greater than 4 months of age, or who do not meet any of the inclusion criteria, or with:
- 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).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Whole Genome Sequencing
Genetic test that looks at all coding and non-coding areas of the genome
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Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.
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Other: Whole Exome Sequencing
Genetic test that looks at all coding areas of the genome
|
Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Subject's Main Provider's Perceived Clinical Utility of Genomic Sequencing
Time Frame: Within one week of the return of results
|
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.
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Within one week of the return of results
|
Test Results Led to Change in Patient Management
Time Frame: Within 1 week of return of results
|
Test results led to Change in clinical management (select all that apply):
|
Within 1 week of return of results
|
Test Led to Changes in Management That Altered Patient Outcome
Time Frame: 1 year
|
Primary physician perception of change in outcome
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Diagnostic Proportion for Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES)
Time Frame: Within approximately 30 days of enrollment
|
WGS and WES are two clinical diagnostic test modalities.
Results of testing were placed in the electronic medical record.
Results either provided a molecular diagnosis that explained the patient's condition or did not.
The diagnostic proportion is the number of patients who received a molecular diagnosis by the test modality divided by the total number of patients who were tested by that modality.
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Within approximately 30 days of enrollment
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Result Within 7 Days of Sample Receipt
Time Frame: Within 7 days of sample receipt
|
Time to result.
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Within 7 days of sample receipt
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Parental Perceived Usefulness of Test
Time Frame: Within one week of the return of results and approximately one year after enrollment
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Parental perception that test was useful
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Within one week of the return of results and approximately one year after enrollment
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Parental Perception of Test Benefit for Their Infant
Time Frame: Within one week of the return of results and approximately one year after enrollment
|
Parental perception that the test benefitted their infant
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Within one week of the return of results and approximately one year after enrollment
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Parental Decisional Regret With Sequencing
Time Frame: Within one week of the return of results and approximately one year after enrollment
|
Markers of harm in genetic diagnosis as evidenced by Brehaut's Decisional Regret scale.
Scale 0-100.
Higher scores indicate higher regret.
|
Within one week of the return of results and approximately one year after enrollment
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Stephen F Kingsmore, MD, DSc, Rady Pediatric Genomics & Systems Medicine Institute
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 161983
- U19HD077693 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
Study Data/Documents
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Individual Participant Data Set
Information identifier: 37114
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Summary level phenotype data
Information identifier: 37114
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Subject Sample Telemetry Report (SSTR) for Subject and Sample IDs, consents, summary counts, processing status, and molecular and sequence sample uses
Information identifier: 37114
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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