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Perinatal Precision Medicine (NSIGHT2)

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ClinicalTrials.gov Identifier: NCT03211039
Recruitment Status : Active, not recruiting
First Posted : July 7, 2017
Last Update Posted : May 29, 2019
Sponsor:
Information provided by (Responsible Party):
Stephen F. Kingsmore, Rady Pediatric Genomics & Systems Medicine Institute

Tracking Information
First Submitted Date  ICMJE May 24, 2017
First Posted Date  ICMJE July 7, 2017
Last Update Posted Date May 29, 2019
Actual Study Start Date  ICMJE June 29, 2017
Estimated Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2017)
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" scale completed by patient's providers.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03211039 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2017)
  • Diagnostic rates between WGS and WES [ Time Frame: Within approximately 30 days of enrollment ]
    Diagnostic rate of genome and exome based on rate of clinically confirmed diagnoses posted in medical record.
  • Comparing diagnostic rates between singleton and trio analysis [ Time Frame: Within approximately 30 days of enrollment ]
    Marginal increase in diagnostic yield above singleton analysis based on the number of clinically confirmed diagnoses posted in medical record following singleton and trio levels of analysis in cases when both biological parents are available.
  • Parental perceived benefits or harm of testing [ Time Frame: Within one week of the return of results and approximately one year after enrollment ]
    Perceived utility/benefits of sequencing based on Holm survey as assessed by parents/legal guardian of patient.
  • Parental satisfaction with sequencing [ Time Frame: Within one week of the return of results and approximately one year after enrollment ]
    Parental satisfaction with decision to pursue sequencing based on Brennan survey
  • 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.
  • Association of parental surveys with parent's demographics [ Time Frame: Within one week of the return of results and approximately one year after enrollment ]
    Associations between parental opinions to clinical utility survey, satisfaction with sequencing survey, and decisional regret survey and the parent's highest level of education, primary language spoken at home, and their trust in the heath care system.
  • Parental availability for trio analysis [ Time Frame: Within three days of patient enrollment ]
    Number of subjects in which both parents are available for trio analysis.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Perinatal Precision Medicine
Official Title  ICMJE Prenatal Precision Medicine (NSIGHT2): A Randomized, Blinded, Prospective Study of the Clinical Utility of Rapid Genomic Sequencing for Infants in the Acute-care Setting
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). 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 RCIGM 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 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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The initial symptom-driven analysis will be conducted on the patient's 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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Patients and their families, the patient's providers, and the enrollment staff will be blinded to the randomization arm they receive.
Primary Purpose: Diagnostic
Condition  ICMJE
  • Genetic Diseases
  • Genetic Syndrome
Intervention  ICMJE Genetic: Genomic sequencing and molecular diagnostic results, if any.
Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.
Study Arms  ICMJE
  • Whole Genome Sequencing
    Genetic test that looks at all coding and non-coding areas of the genome
    Intervention: Genetic: Genomic sequencing and molecular diagnostic results, if any.
  • Whole Exome Sequencing
    Genetic test that looks at all coding areas of the genome
    Intervention: Genetic: Genomic sequencing and molecular diagnostic results, if any.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 5, 2017)
1000
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 30, 2019
Estimated Primary Completion Date August 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 4 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03211039
Other Study ID Numbers  ICMJE 161983
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Samples and data may be shared confidentially with collaborators, such as commercial laboratories or technology companies. All data and sample sharing will be strictly confidential. No identifying information will be shared.
Responsible Party Stephen F. Kingsmore, Rady Pediatric Genomics & Systems Medicine Institute
Study Sponsor  ICMJE Rady Pediatric Genomics & Systems Medicine Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stephen Kingsmore, MD, DSc Rady Pediatric Genomics & Systems Medicine Institute
PRS Account Rady Pediatric Genomics & Systems Medicine Institute
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP