<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/NCT03829176</url>
  </required_header>
  <id_info>
    <org_study_id>2017P001832</org_study_id>
    <nct_id>NCT03829176</nct_id>
  </id_info>
  <brief_title>Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder</brief_title>
  <official_title>Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Broad Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Laboratory for Molecular Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study &quot;Investigating the Feasibility and Implementation of Whole Genome Sequencing in&#xD;
      Patients With Suspected Genetic Disorder&quot; is a research study that aims to explore the use of&#xD;
      whole genome sequencing as a potential first line genetic test for patients for which a&#xD;
      genetic diagnosis is suspected. This is an internally funded research study.&#xD;
&#xD;
      The investigators will enroll 500 participants who are being seen in one of the various&#xD;
      genetics clinics within the Partners HealthCare system for a suspected genetic disorder for&#xD;
      which standard-of-care genetic testing is ordered. At the time of their standard-of-care&#xD;
      genetic testing, an extra blood sample will be collected, and genome sequencing may be&#xD;
      performed. Within 3-4 months, patients learn if they received genome sequencing or not, and&#xD;
      any results are returned and explained. Investigators are also studying the experiences of&#xD;
      both participants and their providers to better understand how to implement genome sequencing&#xD;
      into clinical care.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goal of this research protocol is to conduct a randomized clinical trial to assess the&#xD;
      benefits and risks of incorporating whole genome sequencing (WGS) as a first line diagnostic&#xD;
      test in various genetic and sub-specialty clinics within a large, tertiary medical center.&#xD;
&#xD;
      The investigators will enroll 500 participants within the Partners HealthCare system (e.g.&#xD;
      Massachusetts General Hospital, Massachusetts Eye and Ear, etc.). The study will be enrolling&#xD;
      from multiple genetics and sub-specialty clinics, including but not limited to: cardiology,&#xD;
      GI cancer genetics, medical genetics, ataxia, endocrine genetics. Participants are eligible&#xD;
      if their provider orders genetic testing for diagnosis of symptoms suspicious for a genetic&#xD;
      disorder. Participants must not have had a genetic workup in the past.&#xD;
&#xD;
      At the time of enrollment, a small blood sample will be obtained at the time of the&#xD;
      participant's blood draw for standard-of-care testing. All participants will be subject to&#xD;
      1:1 randomization, in which 250 will receive a WGS report, and 250 will be randomized to the&#xD;
      arm that receives standard of care testing only. Any WGS report that is generated will be&#xD;
      incorporated into the patient's electronic medical record.&#xD;
&#xD;
      For pediatric patients, the study team will attempt to collect blood samples from both&#xD;
      biological parents when possible for trio analysis (WGS performed on the proband and both&#xD;
      biological parents). The purpose of trio analysis is primarily for the purpose of&#xD;
      interpreting the proband/child's results. For non-pediatric patients, saliva samples may be&#xD;
      requested from living parents for confirmation purposes. No genetic testing reports will be&#xD;
      generated for parents. The exception to this is if a parent of a pediatric patient (part of&#xD;
      trio) opts to receive results from the ACMG 59 list.&#xD;
&#xD;
      The participants are blinded to the arm in which they are assigned until 3-4 months from the&#xD;
      time of consent. At that time, a study genetic counselor will call the participant to&#xD;
      disclose the randomization assignment. If the participant was randomized to receive a WGS&#xD;
      report, a plan will be made to review the WGS either by phone, video conferencing, or in&#xD;
      person. After reviewing the results, the research team will write a letter to the participant&#xD;
      summarizing the results and any relevant medical management recommendations. This letter will&#xD;
      also include a copy of their WGS report.&#xD;
&#xD;
      All participants (or their parents) will be surveyed at three points during their enrollment:&#xD;
      baseline (at time of consent), immediately post-disclosure, and 6 months post-disclosure. The&#xD;
      medical providers who offered the standard of care testing will also be surveyed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2018</start_date>
  <completion_date type="Actual">October 1, 2020</completion_date>
  <primary_completion_date type="Actual">October 1, 2020</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>
    <masking_description>Participant, care provider, and study genetic counselor will be blinded to the arm in which the participant was assigned until 3-4 months post-enrollment when the laboratory notifies if a WGS report is generated or not.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Diagnostic capabilities: standard-of-care vs whole genome sequencing diagnostic yield</measure>
    <time_frame>From date of consent until the date of first documented report, assessed up to 12 months</time_frame>
    <description>Assess and compare the overall yields for primary and secondary/incidental findings</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Diagnostic capabilities: standard-of-care vs whole genome sequencing time to reach diagnosis</measure>
    <time_frame>From date of consent until the date of first positive report, assessed up to 12 months</time_frame>
    <description>Assess and compare the time that is required to reach a diagnosis by both standard-of-care genetic testing and whole genome sequencing</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Resources Needed to Implement WGS at an Academic Medical Center</measure>
    <time_frame>Baseline to End of Study, up to 2 years</time_frame>
    <description>Assess by recording resources needed to implement WGS at an Academic Medical Center by documenting resources needed for engagement, execution, reporting, and evaluation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Participant characteristics</measure>
    <time_frame>Baseline</time_frame>
    <description>Age, sociodemographics, personal and family history</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in perceived utility of genomic results</measure>
    <time_frame>Baseline, post-disclosure (approximately 3-4 months after enrollment), 6 months post-disclosure</time_frame>
    <description>Assessed in participant (or parent) surveys via questions assessing: reasons for decline, motivations for enrollment, change in expectations, confidence, concerns, preferences for information sharing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physician confidence and attitudes about genomic sequencing</measure>
    <time_frame>Baseline</time_frame>
    <description>Assessed in physician surveys</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">200</enrollment>
  <condition>Hereditary Disease</condition>
  <condition>Genetic Predisposition to Disease</condition>
  <arm_group>
    <arm_group_label>Standard-of-Care</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants who are randomized to not have whole genome sequencing performed on their sample. These participants will have standard-of-care genetic testing only (ordered by their clinical provider) and will not receive genetic results as part of this study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Whole Genome Sequencing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants who are randomized to have their genome sequenced and receive a whole genome sequencing report. Results disclosure sessions will include a discussion of the whole genome sequencing report, how the results compare to their standard-of-care genetic testing report, and any potential relevant recommendations. Participants in this arm will receive a copy of their whole genome sequencing report accompanied by a summary letter written by a study genetic counselor.</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Whole Genome Sequencing</intervention_name>
    <description>Participants in this arm will have their sample analyzed by whole genome sequencing (WGS), and a report will be included in their medical record. Analysis will be phenotype-driven (gene list will be curated based on primary indication for testing and other available medical history information), and may include genes on ACMG 59 list if participant elects for these results. This report will include pathogenic, likely pathogenic, and suspicious VUS results identified in the genes analyzed.</description>
    <arm_group_label>Whole Genome Sequencing</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participants of any gender over the age of 3 months.&#xD;
&#xD;
          2. Participants (ages 7+) must be proficient in English. If the participant is under the&#xD;
             age of 7 or is over the age of 7 and non-verbal, these criteria apply to their parent&#xD;
             who is providing consent.&#xD;
&#xD;
          3. Participant is being evaluated clinically at an Partners HealthCare genetics clinic,&#xD;
             and not had a prior genetic work up for their referral indication.&#xD;
&#xD;
          4. Have a suspected genetic disorder in which the genetic cause is unknown, as confirmed&#xD;
             by review of the subject's medical records.&#xD;
&#xD;
          5. Genetic testing has been ordered for the participant by their clinical genetics&#xD;
             provider as part of a diagnostic workup.&#xD;
&#xD;
          6. Willing and able to provide a blood sample. The amount of blood drawn from a patient&#xD;
             will be 2 teaspoons or less.&#xD;
&#xD;
          7. Ability to provide informed consent or assent to participate in this protocol.&#xD;
             Children who have not attained the legal age of consent must provide assent (those who&#xD;
             do not have the capacity to assent must not object to taking part), along with&#xD;
             permission from the child's parent(s) or guardian. Adults who are unable to consent&#xD;
             must be able to provide assent or must not object to taking part, along with&#xD;
             permission from their legal authorized representative (LAR).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participants who live outside of the United States.&#xD;
&#xD;
          2. Non-English-speaking participants.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sekar Kathiresan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>November 2020</verification_date>
  <study_first_submitted>October 30, 2018</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>November 17, 2020</last_update_submitted>
  <last_update_submitted_qc>November 17, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Sekar Kathiresan</investigator_full_name>
    <investigator_title>Director of the Center for Genomic Medicine</investigator_title>
  </responsible_party>
  <keyword>Whole Genome Sequencing</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Genetic Diseases, Inborn</mesh_term>
    <mesh_term>Genetic Predisposition to Disease</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/NCT03829176
org study id: 2017P001832
nct id: NCT03829176
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
The study "Investigating the Feasibility and Implementation of Whole Genome Sequencing in
      Patients With Suspected Genetic Disorder" is a research study that aims to explore the use of
      whole genome sequencing as a potential first line genetic test for patients for which a
      genetic diagnosis is suspected. This is an internally funded research study.

      The investigators will enroll 500 participants who are being seen in one of the various
      genetics clinics within the Partners HealthCare system for a suspected genetic disorder for
      which standard-of-care genetic testing is ordered. At the time of their standard-of-care
      genetic testing, an extra blood sample will be collected, and genome sequencing may be
      performed. Within 3-4 months, patients learn if they received genome sequencing or not, and
      any results are returned and explained. Investigators are also studying the experiences of
      both participants and their providers to better understand how to implement genome sequencing
      into clinical care.
The goal of this research protocol is to conduct a randomized clinical trial to assess the
      benefits and risks of incorporating whole genome sequencing (WGS) as a first line diagnostic
      test in various genetic and sub-specialty clinics within a large, tertiary medical center.

      The investigators will enroll 500 participants within the Partners HealthCare system (e.g.
      Massachusetts General Hospital, Massachusetts Eye and Ear, etc.). The study will be enrolling
      from multiple genetics and sub-specialty clinics, including but not limited to: cardiology,
      GI cancer genetics, medical genetics, ataxia, endocrine genetics. Participants are eligible
      if their provider orders genetic testing for diagnosis of symptoms suspicious for a genetic
      disorder. Participants must not have had a genetic workup in the past.

      At the time of enrollment, a small blood sample will be obtained at the time of the
      participant's blood draw for standard-of-care testing. All participants will be subject to
      1:1 randomization, in which 250 will receive a WGS report, and 250 will be randomized to the
      arm that receives standard of care testing only. Any WGS report that is generated will be
      incorporated into the patient's electronic medical record.

      For pediatric patients, the study team will attempt to collect blood samples from both
      biological parents when possible for trio analysis (WGS performed on the proband and both
      biological parents). The purpose of trio analysis is primarily for the purpose of
      interpreting the proband/child's results. For non-pediatric patients, saliva samples may be
      requested from living parents for confirmation purposes. No genetic testing reports will be
      generated for parents. The exception to this is if a parent of a pediatric patient (part of
      trio) opts to receive results from the ACMG 59 list.

      The participants are blinded to the arm in which they are assigned until 3-4 months from the
      time of consent. At that time, a study genetic counselor will call the participant to
      disclose the randomization assignment. If the participant was randomized to receive a WGS
      report, a plan will be made to review the WGS either by phone, video conferencing, or in
      person. After reviewing the results, the research team will write a letter to the participant
      summarizing the results and any relevant medical management recommendations. This letter will
      also include a copy of their WGS report.

      All participants (or their parents) will be surveyed at three points during their enrollment:
      baseline (at time of consent), immediately post-disclosure, and 6 months post-disclosure. The
      medical providers who offered the standard of care testing will also be surveyed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Double (Participant, Care Provider)
masking description: Participant, care provider, and study genetic counselor will be blinded to the arm in which the participant was assigned until 3-4 months post-enrollment when the laboratory notifies if a WGS report is generated or not.
measure: Diagnostic capabilities: standard-of-care vs whole genome sequencing diagnostic yield
time frame: From date of consent until the date of first documented report, assessed up to 12 months
description: Assess and compare the overall yields for primary and secondary/incidental findings
measure: Diagnostic capabilities: standard-of-care vs whole genome sequencing time to reach diagnosis
time frame: From date of consent until the date of first positive report, assessed up to 12 months
description: Assess and compare the time that is required to reach a diagnosis by both standard-of-care genetic testing and whole genome sequencing
measure: Resources Needed to Implement WGS at an Academic Medical Center
time frame: Baseline to End of Study, up to 2 years
description: Assess by recording resources needed to implement WGS at an Academic Medical Center by documenting resources needed for engagement, execution, reporting, and evaluation.
measure: Participant characteristics
time frame: Baseline
description: Age, sociodemographics, personal and family history
measure: Change in perceived utility of genomic results
time frame: Baseline, post-disclosure (approximately 3-4 months after enrollment), 6 months post-disclosure
description: Assessed in participant (or parent) surveys via questions assessing: reasons for decline, motivations for enrollment, change in expectations, confidence, concerns, preferences for information sharing
measure: Physician confidence and attitudes about genomic sequencing
time frame: Baseline
description: Assessed in physician surveys
arm group label: Standard-of-Care
arm group type: No Intervention
description: Participants who are randomized to not have whole genome sequencing performed on their sample. These participants will have standard-of-care genetic testing only (ordered by their clinical provider) and will not receive genetic results as part of this study.
arm group label: Whole Genome Sequencing
arm group type: Experimental
description: Participants who are randomized to have their genome sequenced and receive a whole genome sequencing report. Results disclosure sessions will include a discussion of the whole genome sequencing report, how the results compare to their standard-of-care genetic testing report, and any potential relevant recommendations. Participants in this arm will receive a copy of their whole genome sequencing report accompanied by a summary letter written by a study genetic counselor.
intervention type: Genetic
intervention name: Whole Genome Sequencing
description: Participants in this arm will have their sample analyzed by whole genome sequencing (WGS), and a report will be included in their medical record. Analysis will be phenotype-driven (gene list will be curated based on primary indication for testing and other available medical history information), and may include genes on ACMG 59 list if participant elects for these results. This report will include pathogenic, likely pathogenic, and suspicious VUS results identified in the genes analyzed.
arm group label: Whole Genome Sequencing
criteria: 
gender: All
minimum age: 3 Months
maximum age: N/A
healthy volunteers: No
last name: Sekar Kathiresan, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
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responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Sekar Kathiresan
investigator title: Director of the Center for Genomic Medicine
mesh term: Genetic Diseases, Inborn
mesh term: Genetic Predisposition to Disease