<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02225522</url>
  </required_header>
  <id_info>
    <org_study_id>HD13-010</org_study_id>
    <nct_id>NCT02225522</nct_id>
  </id_info>
  <brief_title>Genomic Sequencing in Acutely Ill Neonates</brief_title>
  <acronym>NSIGHT</acronym>
  <official_title>Prospective Randomized Trial of the Clinical Utility of Rapid Next Generation Sequencing in Acutely Ill Neonates</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Mercy Hospital Kansas City</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Mercy Hospital Kansas City</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare the effectiveness of rapid next generation sequencing&#xD;
      (NGS, such as whole genome sequencing1) with current practice to provide diagnostic or&#xD;
      prognostic information or treatment guidance in acutely ill neonates and infants,&#xD;
      particularly with respect to clinical care, cost and outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized, blinded, prospective study examining the comparative effectiveness -&#xD;
      both clinical and cost effectiveness - of rapid NGS (StatSeq), compared to standard of care,&#xD;
      including an expanded newborn screen, in acutely ill neonates and infants with potential&#xD;
      genetic diseases. Acutely ill neonates and infants who have an undiagnosed illness, and their&#xD;
      families, will be eligible to participate in the study. The investigators will enroll&#xD;
      approximately 1,000 neonates and infants at a single study site. The study population will be&#xD;
      recruited from Children's Mercy Hospital inpatient population, primarily the intensive care&#xD;
      nursery (ICN, also known as the NICU), with a smaller subpopulation presenting to other&#xD;
      hospital services, such as the pediatric intensive care unit (PICU). All affected study&#xD;
      participants will receive an expanded newborn screen (NBS). Newborn screening is biochemical&#xD;
      testing of a heel-prick blood spot that is federally mandated to be performed on all US live&#xD;
      births. 67 diseases are tested for by NBS in MO, most of which are genetic diseases. The&#xD;
      expanded NBS proposed herein is the clinically available StepOne Newborn Screen® from Perkin&#xD;
      Elmer, and will be performed in addition to standard State of MO screening on all enrolled&#xD;
      infants in both arms. Half of the affected study participants will be randomized to receive&#xD;
      StatSeq in addition to standard testing for their acute illness and expanded NBS.&#xD;
      Additionally, all willing clinical providers will be enrolled and their perceptions on&#xD;
      clinical outcomes will be measured.&#xD;
&#xD;
      All subjects will have blood drawn for nucleic acid (DNA and RNA) isolation and the expanded&#xD;
      NBS at the time of enrollment in the study. All blood sample volumes will adhere to the CMH&#xD;
      policy on maximum blood in pediatric patients. If the volume allowed for in this policy&#xD;
      exceeds 5ml, 5 ml will be the maximum collected at enrollment. Buccal smears, heel-prick&#xD;
      blood spots, additional blood, urine and tissue samples may be collected, if available as&#xD;
      sample retains from other studies, and stored in the Center for Pediatric Genomic Medicine&#xD;
      (CPGM) per their approved IRB protocol (IRB Study #11120514). The latter samples will not&#xD;
      involve invasive sampling. Nucleic acids will be isolated and prepared for NGS with standard&#xD;
      protocols at the CPGM (Center for Pediatric Genomic Medicine). Familial samples (for example,&#xD;
      mother, father, affected or unaffected siblings) will also be obtained, and nucleic acids&#xD;
      will also be sequenced per the Genome Center Biorepository protocol, as indicated, to assist&#xD;
      in diagnosis of the acute medical condition in the newborn. All sequencing data will be&#xD;
      stored in the Genome Center Biorepository (IRB Study #11120514).&#xD;
&#xD;
      A minimum of two expert Center data analysts will be responsible for analyzing the DNA&#xD;
      variants following NGS. One of the analysts will then compile a report to be presented to the&#xD;
      Molecular Pathology Laboratory Director or Assistant Director. In the case of positive study&#xD;
      findings that may be diagnostic, the Molecular Pathology Laboratory Director or Assistant&#xD;
      Director will perform confirmatory clinical diagnostic testing and, if confirmed, a standard&#xD;
      clinical diagnostic report will be placed in the patient's medical record. In the case of&#xD;
      acutely material (actionable) positive study findings, the results will be verbally conveyed&#xD;
      to the primary clinical team directly prior to confirmatory testing. A generic research note&#xD;
      will be placed in the patient's medical record that indicates that a verbal, provisional&#xD;
      report was issued (Appendix A). Verbal, provisional reporting of results before confirmatory&#xD;
      testing will only be performed in cases where the delay in reporting necessary for&#xD;
      confirmation was likely to result in significant harm to the patient. Confirmatory testing&#xD;
      will be performed promptly in all cases, including those in which in which a verbal report&#xD;
      has been given. A case conference format may be utilized for return of results if the&#xD;
      complexity of the diagnosis or potential treatment for that diagnosis warrants detailed&#xD;
      discussion. If no potentially pathogenic variants are identified, a verbal report will be&#xD;
      provided to the clinical care physician of record to communicate that there were no causative&#xD;
      findings, and a generic research note will be placed in the medical record that states that&#xD;
      nondiagnostic research grade NGS was performed (Appendix B). No negative diagnostic written&#xD;
      report of results will be placed in the patient's chart in this instance, as there is no&#xD;
      available clinical grade testing to confirm negative results for all genes tested. Follow up&#xD;
      with the patient's family will be guided by the clinical care team. All study participants&#xD;
      and their clinicians will be notified of randomization assignment at/by day 10 after&#xD;
      randomization. This information will help alleviate anxiety on the part of the family, and&#xD;
      also provides a mechanism for patient crossover into the rapid NGS arm if the patient is&#xD;
      clinically deteriorating, and at the clinical care team's request. Rarely, those participants&#xD;
      and clinicians will be notified sooner if they were randomized to the rapid NGS group and a&#xD;
      diagnosis is made in less than 10 days. Both molecular diagnoses made and time to diagnosis&#xD;
      will be recorded as primary outcomes.&#xD;
&#xD;
      All positive results from the Perkin Elmer StepOne expanded NBS (received by all enrolled&#xD;
      infants and NOT a study variable) will be returned to the Genome Center personnel. Based on&#xD;
      these results, confirmatory testing through Perkin Elmer will be performed if this condition&#xD;
      was not identified on the standard State NBS screen for each infant. These provisional&#xD;
      results will be verbally communicated with the primary clinician team and additional samples&#xD;
      requested, if necessary, for confirmation. Upon confirmation, the results will be entered in&#xD;
      the patient's medical record.&#xD;
&#xD;
      Each time a study participant is enrolled, the primary clinical providers will be asked to&#xD;
      fill out a survey prior to StatSeq testing and after return of results. We will also review&#xD;
      the patient's medical record and collect clinical variables including laboratory testing,&#xD;
      radiology results, medications and other treatments received to further analyze the effect&#xD;
      rapid NGS has on clinical care. We plan to follow up with families annually up to 5 years&#xD;
      post enrollment and record clinical outcomes related to this study.&#xD;
&#xD;
      This study will be integrated with two other study protocols, one being the CMH Genomic&#xD;
      Medicine Repository (IRB 11120514) and the other Genomes in newborns (#13120442) that studies&#xD;
      the ethical and legal implications of rapid NGS in this population. Data records will be&#xD;
      requested from both studies. The participants must agree to enroll in the Genome Center&#xD;
      Biorepository. The Genomes in newborns study will be optional.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Molecular Diagnosis Made</measure>
    <time_frame>28 days</time_frame>
    <description>If randomized to the Rapid Genome Sequencing group, did the testing result in a molecular diagnosis for the patient with three weeks of receipt of the DNA in the lab.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to Molecular Diagnosis</measure>
    <time_frame>28 days</time_frame>
    <description>How many days from enrollment were required in our to achieve a molecular diagnosis in the infant</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Clinical Management</measure>
    <time_frame>28 days</time_frame>
    <description>If randomized to the Rapid Genome Sequencing group and a molecular diagnosis achieved, did it provide a change in clinical management as determined by a survey of primary care team attending via a survey</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Consults</measure>
    <time_frame>28 days</time_frame>
    <description>Total number of consultations including follow up required during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost Effectiveness</measure>
    <time_frame>28 days</time_frame>
    <description>Determination of utilization of healthcare resources in hospital charges in both arms</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Length of Stay</measure>
    <time_frame>After 12 months</time_frame>
    <description>Length of stay in days to discharge.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Deaths</measure>
    <time_frame>After 12 months</time_frame>
    <description>Number of deaths in each group</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">65</enrollment>
  <condition>Diseases/Diagnoses</condition>
  <condition>Genetic Disease</condition>
  <arm_group>
    <arm_group_label>Standard Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients in this arm receive standard genetic evaluation without the addition of next generation sequencing for the diagnosis of their presumed genetic condition</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rapid whole genome sequencing (StatSeq)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this arm will receive standard of care genetic evaluation and next generation sequencing of their genome to achieve rapid diagnosis of genetic conditions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Rapid whole genome sequencing (StatSeq)</intervention_name>
    <description>Patients in this arm will received standard genetic testing, the Perkins Elmer StepOne expanded newborn screen and the rapid whole genome sequencing (StatSeq). the receipt of the StatSeq testing is the different factor between arms. the standard genetic testing includes any testing that is clinically available to the attending physician that would normally be ordered for the patient if not enrolled in this study.</description>
    <arm_group_label>Rapid whole genome sequencing (StatSeq)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: One of the following criteria required.&#xD;
&#xD;
          -  Clinical genetic testing or a genetic consult is ordered&#xD;
&#xD;
          -  Subject has one major structural anomaly or three or more minor anomalies&#xD;
&#xD;
          -  Abnormal laboratory testing suggestive of a genetic disease&#xD;
&#xD;
          -  Abnormal response to standard therapy for a major underlying condition&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previously confirmed genetic diagnosis that explains the clinical condition&#xD;
&#xD;
          -  Has features pathognomonic for a large chromosomal aberration (Trisomy 13, 18, 21 or&#xD;
             other)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>4 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen Kingsmore, MB BAO ChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rady Children's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Steve Leeder, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Mercy Hospital and Clinics</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Laurel K Willig, MD</last_name>
    <role>Study Director</role>
    <affiliation>Children's Mercy Hospital and Clinics</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Joshua E Petrikin, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Mercy Hospital Kansas City</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Mercy Hospital</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2016</verification_date>
  <study_first_submitted>August 13, 2014</study_first_submitted>
  <study_first_submitted_qc>August 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 26, 2014</study_first_posted>
  <last_update_submitted>June 22, 2017</last_update_submitted>
  <last_update_submitted_qc>June 22, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Intensive Care Units, Neonatal</keyword>
  <keyword>Infant, Newborn</keyword>
  <keyword>Genetic Diseases, Inborn</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Genetic Diseases, Inborn</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02225522
org study id: HD13-010
nct id: NCT02225522
lead sponsor: 
has dmc: Yes
The purpose of this study is to compare the effectiveness of rapid next generation sequencing
      (NGS, such as whole genome sequencing1) with current practice to provide diagnostic or
      prognostic information or treatment guidance in acutely ill neonates and infants,
      particularly with respect to clinical care, cost and outcomes.
This is a randomized, blinded, prospective study examining the comparative effectiveness -
      both clinical and cost effectiveness - of rapid NGS (StatSeq), compared to standard of care,
      including an expanded newborn screen, in acutely ill neonates and infants with potential
      genetic diseases. Acutely ill neonates and infants who have an undiagnosed illness, and their
      families, will be eligible to participate in the study. The investigators will enroll
      approximately 1,000 neonates and infants at a single study site. The study population will be
      recruited from Children's Mercy Hospital inpatient population, primarily the intensive care
      nursery (ICN, also known as the NICU), with a smaller subpopulation presenting to other
      hospital services, such as the pediatric intensive care unit (PICU). All affected study
      participants will receive an expanded newborn screen (NBS). Newborn screening is biochemical
      testing of a heel-prick blood spot that is federally mandated to be performed on all US live
      births. 67 diseases are tested for by NBS in MO, most of which are genetic diseases. The
      expanded NBS proposed herein is the clinically available StepOne Newborn Screen® from Perkin
      Elmer, and will be performed in addition to standard State of MO screening on all enrolled
      infants in both arms. Half of the affected study participants will be randomized to receive
      StatSeq in addition to standard testing for their acute illness and expanded NBS.
      Additionally, all willing clinical providers will be enrolled and their perceptions on
      clinical outcomes will be measured.

      All subjects will have blood drawn for nucleic acid (DNA and RNA) isolation and the expanded
      NBS at the time of enrollment in the study. All blood sample volumes will adhere to the CMH
      policy on maximum blood in pediatric patients. If the volume allowed for in this policy
      exceeds 5ml, 5 ml will be the maximum collected at enrollment. Buccal smears, heel-prick
      blood spots, additional blood, urine and tissue samples may be collected, if available as
      sample retains from other studies, and stored in the Center for Pediatric Genomic Medicine
      (CPGM) per their approved IRB protocol (IRB Study #11120514). The latter samples will not
      involve invasive sampling. Nucleic acids will be isolated and prepared for NGS with standard
      protocols at the CPGM (Center for Pediatric Genomic Medicine). Familial samples (for example,
      mother, father, affected or unaffected siblings) will also be obtained, and nucleic acids
      will also be sequenced per the Genome Center Biorepository protocol, as indicated, to assist
      in diagnosis of the acute medical condition in the newborn. All sequencing data will be
      stored in the Genome Center Biorepository (IRB Study #11120514).

      A minimum of two expert Center data analysts will be responsible for analyzing the DNA
      variants following NGS. One of the analysts will then compile a report to be presented to the
      Molecular Pathology Laboratory Director or Assistant Director. In the case of positive study
      findings that may be diagnostic, the Molecular Pathology Laboratory Director or Assistant
      Director will perform confirmatory clinical diagnostic testing and, if confirmed, a standard
      clinical diagnostic report will be placed in the patient's medical record. In the case of
      acutely material (actionable) positive study findings, the results will be verbally conveyed
      to the primary clinical team directly prior to confirmatory testing. A generic research note
      will be placed in the patient's medical record that indicates that a verbal, provisional
      report was issued (Appendix A). Verbal, provisional reporting of results before confirmatory
      testing will only be performed in cases where the delay in reporting necessary for
      confirmation was likely to result in significant harm to the patient. Confirmatory testing
      will be performed promptly in all cases, including those in which in which a verbal report
      has been given. A case conference format may be utilized for return of results if the
      complexity of the diagnosis or potential treatment for that diagnosis warrants detailed
      discussion. If no potentially pathogenic variants are identified, a verbal report will be
      provided to the clinical care physician of record to communicate that there were no causative
      findings, and a generic research note will be placed in the medical record that states that
      nondiagnostic research grade NGS was performed (Appendix B). No negative diagnostic written
      report of results will be placed in the patient's chart in this instance, as there is no
      available clinical grade testing to confirm negative results for all genes tested. Follow up
      with the patient's family will be guided by the clinical care team. All study participants
      and their clinicians will be notified of randomization assignment at/by day 10 after
      randomization. This information will help alleviate anxiety on the part of the family, and
      also provides a mechanism for patient crossover into the rapid NGS arm if the patient is
      clinically deteriorating, and at the clinical care team's request. Rarely, those participants
      and clinicians will be notified sooner if they were randomized to the rapid NGS group and a
      diagnosis is made in less than 10 days. Both molecular diagnoses made and time to diagnosis
      will be recorded as primary outcomes.

      All positive results from the Perkin Elmer StepOne expanded NBS (received by all enrolled
      infants and NOT a study variable) will be returned to the Genome Center personnel. Based on
      these results, confirmatory testing through Perkin Elmer will be performed if this condition
      was not identified on the standard State NBS screen for each infant. These provisional
      results will be verbally communicated with the primary clinician team and additional samples
      requested, if necessary, for confirmation. Upon confirmation, the results will be entered in
      the patient's medical record.

      Each time a study participant is enrolled, the primary clinical providers will be asked to
      fill out a survey prior to StatSeq testing and after return of results. We will also review
      the patient's medical record and collect clinical variables including laboratory testing,
      radiology results, medications and other treatments received to further analyze the effect
      rapid NGS has on clinical care. We plan to follow up with families annually up to 5 years
      post enrollment and record clinical outcomes related to this study.

      This study will be integrated with two other study protocols, one being the CMH Genomic
      Medicine Repository (IRB 11120514) and the other Genomes in newborns (#13120442) that studies
      the ethical and legal implications of rapid NGS in this population. Data records will be
      requested from both studies. The participants must agree to enroll in the Genome Center
      Biorepository. The Genomes in newborns study will be optional.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Double (Participant, Care Provider)
measure: Molecular Diagnosis Made
time frame: 28 days
description: If randomized to the Rapid Genome Sequencing group, did the testing result in a molecular diagnosis for the patient with three weeks of receipt of the DNA in the lab.
measure: Time to Molecular Diagnosis
time frame: 28 days
description: How many days from enrollment were required in our to achieve a molecular diagnosis in the infant
measure: Change in Clinical Management
time frame: 28 days
description: If randomized to the Rapid Genome Sequencing group and a molecular diagnosis achieved, did it provide a change in clinical management as determined by a survey of primary care team attending via a survey
measure: Number of Consults
time frame: 28 days
description: Total number of consultations including follow up required during hospitalization
measure: Cost Effectiveness
time frame: 28 days
description: Determination of utilization of healthcare resources in hospital charges in both arms
measure: Length of Stay
time frame: After 12 months
description: Length of stay in days to discharge.
measure: Number of Deaths
time frame: After 12 months
description: Number of deaths in each group
arm group label: Standard Care
arm group type: No Intervention
description: Patients in this arm receive standard genetic evaluation without the addition of next generation sequencing for the diagnosis of their presumed genetic condition
arm group label: Rapid whole genome sequencing (StatSeq)
arm group type: Experimental
description: Patients in this arm will receive standard of care genetic evaluation and next generation sequencing of their genome to achieve rapid diagnosis of genetic conditions.
intervention type: Other
intervention name: Rapid whole genome sequencing (StatSeq)
description: Patients in this arm will received standard genetic testing, the Perkins Elmer StepOne expanded newborn screen and the rapid whole genome sequencing (StatSeq). the receipt of the StatSeq testing is the different factor between arms. the standard genetic testing includes any testing that is clinically available to the attending physician that would normally be ordered for the patient if not enrolled in this study.
arm group label: Rapid whole genome sequencing (StatSeq)
criteria: 
gender: All
minimum age: N/A
maximum age: 4 Months
healthy volunteers: No
last name: Stephen Kingsmore, MB BAO ChB
role: Principal Investigator
affiliation: Rady Children's Hospital
last name: Steve Leeder, PhD
role: Principal Investigator
affiliation: Children's Mercy Hospital and Clinics
last name: Laurel K Willig, MD
role: Study Director
affiliation: Children's Mercy Hospital and Clinics
last name: Joshua E Petrikin, MD
role: Principal Investigator
affiliation: Children's Mercy Hospital Kansas City
facility: 
country: United States
responsible party type: Sponsor
mesh term: Genetic Diseases, Inborn