<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/NCT03291743</url>
  </required_header>
  <id_info>
    <org_study_id>RTDB-2201</org_study_id>
    <nct_id>NCT03291743</nct_id>
  </id_info>
  <brief_title>The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives</brief_title>
  <official_title>The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Carilion Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Carilion Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pursuing very early diagnosis is standard of care for several diseases including colon&#xD;
      cancer, diabetes and liver disease where an early and aggressive diagnostic and therapeutic&#xD;
      approach has been shown to change their natural history. Crohn's disease [CD] still lags&#xD;
      since commonly at presentation CD has already run a long course, often responding poorly to&#xD;
      therapy or requiring surgery. This innovative project proposes a minimally invasive strategy&#xD;
      - capsule endoscopy-based screening of first degree relatives [FDR's] of CD patients - to&#xD;
      develop tools to diagnose CD at or near its biologic onset.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Crohn's Disease (CD) is a form of inflammatory bowel disease (IBD) that affects the&#xD;
      gastrointestinal tract. CD is a chronic, remitting, and relapsing disease that is rarely&#xD;
      diagnosed at or near its biological onset. In routine clinical practice, CD diagnosed at the&#xD;
      pre-clinical stage is largely by chance during routine screening procedures. Current evidence&#xD;
      suggests these earlier diagnoses lead to better treatment outcomes and may even offer clues&#xD;
      to better understand the disease's etiology and pathogenesis. Consequently, diagnosing CD at&#xD;
      an early stage may offer several advantages including better response to medical treatment;&#xD;
      possible avoidance of long term complications and surgery; and long term cost savings.&#xD;
&#xD;
      In the last several years it has become apparent that Crohn's Disease tends to evolve over&#xD;
      time from an inflammatory disease to a fibrosing one due to the repeated healing and repair&#xD;
      cycles. The fibrosing found in CD is similar to that of other diseases that affect organs&#xD;
      like the liver and pancreas. Extensive fibrosis (build-up of excessive scar tissue) does not&#xD;
      respond to drug therapy and must be treated with surgery; therefore, surgical intervention&#xD;
      (e.g., intestinal resection) is a treatment modality common to CD patients largely due to&#xD;
      this indication. Ideally, Crohn's Disease should be diagnosed before this irreversible damage&#xD;
      takes place and while the disease is still responsive to medical therapy; however, the&#xD;
      disease only comes to medical attention in the presence of symptoms most often associated&#xD;
      with severe bowel damage such as obstructions and strictures. Even still, the presence of&#xD;
      these symptoms does not always lead to prompt diagnosis. Additionally, this evidence&#xD;
      indicates that CD has already run a long course before it becomes symptomatic and further&#xD;
      supports the need for earlier diagnosis.&#xD;
&#xD;
      An efficient screening strategy for Crohn's Disease has yet to be identified. To date,&#xD;
      colonoscopy is considered the gold-standard as there are no noninvasive tests that can&#xD;
      conclusively screen for disease. Screening the general population has been shown to be&#xD;
      inefficient due to the overall risk of developing the disease so it is crucial to determine&#xD;
      the populations at the greatest risk. Crohn's Disease has proven to have a strong genetic&#xD;
      component. Referral center studies published in the last several years have shown that 5-15%&#xD;
      of patients with CD have a family history of the disease; therefore, family members of CD&#xD;
      patients may constitute an ideal population for screening. Familial studies have focused&#xD;
      mostly on first-degree relatives [FDR] and have found that this group is at a higher risk for&#xD;
      developing the disease than the general population. In addition, a landmark study published&#xD;
      in 2003 showed that &gt;40% of asymptomatic first-degree relatives of CD patients [CD-FDR] had&#xD;
      elevated fecal calprotectin-an intestinal inflammation marker that closely reflects disease&#xD;
      activity in CD patients-with values between those of healthy controls and FDR's with&#xD;
      diagnosed disease. Additional abnormalities such as, Anti-Saccharomyces Cerevisae Antibodies&#xD;
      [ASCA] positivity and elevated inflammatory markers-have also been reported in asymptomatic&#xD;
      first-degree relatives at a greater proportion than the known risk of developing the disease.&#xD;
&#xD;
      Recently, at another institution, the investigators conducted an ileocolonoscopy-based&#xD;
      screening study in 38 first-degree relatives of patients with Crohn's Disease. Identified&#xD;
      first-degree relatives were carefully excluded in the presence of digestive symptoms or a&#xD;
      medical history that contained possible causes of intestinal inflammation. The healthy&#xD;
      control group consisted of 10 age and sex-matched individuals who were scheduled for a&#xD;
      colonoscopy due to unrelated reasons (e.g., colon cancer screening or rectal bleeding) and&#xD;
      whose results were found to be normal. In both groups, tissue, blood, and stool samples were&#xD;
      collected. Median values for fecal calprotectin (FC) and histology were significantly greater&#xD;
      in first-degree relatives when compared to the healthy controls. Additionally, colonoscopy&#xD;
      identified three different phenotypes within the first-degree relative population: 1) normal,&#xD;
      or superimposable to controls; 2) minor lesions (aphthae or small superficial erosions), and&#xD;
      3) typical features of Crohn's Disease. These findings were confirmed with histological&#xD;
      scoring that resulted in three highly separated clusters.&#xD;
&#xD;
      That preliminary research supports the idea that screening within this high-risk population&#xD;
      allows for earlier diagnosis. Validating these results on a larger scale and with less&#xD;
      invasive methods may lead to the development of a screening strategy that can be implemented&#xD;
      as part of routine clinical practice. Additionally, more research is needed to further&#xD;
      characterize the novel phenotype identified as it may hold crucial clues to the pathogenesis&#xD;
      of the disease.&#xD;
&#xD;
      This study seeks to detect asymptomatic, first-degree relatives of patients with established&#xD;
      Crohn's Disease in hopes of catching the disease at or near its biologic onset (pre-clinical&#xD;
      stage). Screening will be done using the PillCam™ COLON 2 capsule endoscopy system. Capsule&#xD;
      findings will be reviewed by Dr. Sorrentino and Dr. Nguyen at the central site. These&#xD;
      findings will then be verified using proven ileocolonoscopy methods. Blood, stool, and tissue&#xD;
      specimens will be collected for research-related testing and to be stored for further&#xD;
      research. Healthy-controls will be enrolled for comparison purposes. The goal of this study&#xD;
      is to validate the preliminary data from our pilot study using a multi-center approach.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Death of Principal Investigator&#xD;
  </why_stopped>
  <start_date type="Actual">February 10, 2017</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">September 30, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Prevalence of Crohn's Disease in First Degree Relatives by capsule endoscopy screening</measure>
    <time_frame>coincident at screening</time_frame>
    <description>This study will screen asymptomatic, first-degree relatives of patients with established Crohn's Disease to detect the disease at or near its biologic onset.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation of capsule endoscopy with ileocolonoscopy; characterization of disease state</measure>
    <time_frame>coincident at screening</time_frame>
    <description>Evaluate the accuracy of capsule endoscopy (CE) in screening for pre-clinical Crohn's Disease by verifying CE findings with ileocolonoscopy.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">38</enrollment>
  <condition>Crohn Disease</condition>
  <condition>Genetic Predisposition</condition>
  <condition>IBD</condition>
  <arm_group>
    <arm_group_label>First Degree Relative</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A total of 112 high risk first-degree relatives will be enrolled in total. Patients with Crohn's Disease will be given information about the study when in clinic for routine care to share with their first degree relatives (FDR). Screening will be done using capsule endoscopy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This study will also enroll 35 healthy controls who will be age and sex matched to the first degree relative (FDR) population. Enrollment will begin after 20-25 FDR's have passed screening and will continue at this interval until all controls have been enrolled. Controls will be initially screened by colonoscopy. If enrolled they will undergo capsule endoscopy as well</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Capsule endoscopy</intervention_name>
    <description>PillCam(TM) CROHN'S CAPSULE</description>
    <arm_group_label>First Degree Relative</arm_group_label>
    <arm_group_label>Healthy Controls</arm_group_label>
    <other_name>PillCam(TM)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female who are 18-65 years of age&#xD;
&#xD;
          -  FDR: Has a first degree relative (mother, father, offspring, or full sibling) who has&#xD;
             been diagnosed with Crohn's Disease Healthy Controls: Normal colonoscopy and histology&#xD;
             (if applicable) results, and no family history of inflammatory bowel disease (Crohn's&#xD;
             Disease and Ulcerative Colitis)&#xD;
&#xD;
          -  Willingness to comply with protocol requirements, timelines, and procedures&#xD;
&#xD;
          -  Must be able and willing to provide written consent; medical, surgical, and medication&#xD;
             history; current and concomitant medication use; and any other documents deemed&#xD;
             relevant by the investigator.&#xD;
&#xD;
          -  A negative pregnancy test for all female subjects of childbearing potential at the&#xD;
             time of consent. Subject must also agree to follow medically approved birth control&#xD;
             measures while enrolled&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Suspected or confirmed diagnosis of inflammatory bowel disease or any other&#xD;
             gastrointestinal disease or condition&#xD;
&#xD;
          -  Known medical history of clinically significant cardiovascular, hematologic,&#xD;
             orthopedic, rheumatologic, muscular, neurologic (e.g. dementia, seizure disorder,&#xD;
             traumatic brain injury), endocrine, ophthalmologic, infectious (e.g. human&#xD;
             immunodeficiency virus, tuberculosis, hepatitis), immunologic, renal, pulmonary (e.g.&#xD;
             COPD), dermatologic, reproductive, or psychiatric disorders, conditions, or diseases&#xD;
             that would present unacceptable risk to study subjects, compromise the acquisition or&#xD;
             interpretation of study data, or otherwise interfere with the study subject's&#xD;
             participation&#xD;
&#xD;
          -  A systolic blood pressure reading ≥ 180 mmHg and/or a diastolic blood pressure reading&#xD;
             of ≥ 110 mmHg at screening&#xD;
&#xD;
          -  An oral temperature reading of 100.5º F or greater&#xD;
&#xD;
          -  Meets any of the following criteria:&#xD;
&#xD;
               -  Use of systemic non-steroidal anti-inflammatory medication (including low-dose&#xD;
                  aspirin) within 14 days prior to consent&#xD;
&#xD;
               -  History of oral corticosteroid use within 30 days prior to consent&#xD;
&#xD;
               -  Use of IV corticosteroids within 14 days prior to consent&#xD;
&#xD;
               -  Treatment with IV anti-infectives within 30 days prior to consent&#xD;
&#xD;
               -  Treatment with oral anti-infectives within 14 days prior to consent&#xD;
&#xD;
          -  Previous or current history of malignancy (including fully excised cutaneous basal&#xD;
             cell carcinoma and squamous cell carcinoma)&#xD;
&#xD;
          -  History of stem cell or fecal transplant&#xD;
&#xD;
          -  History of clinically significant alcoholism or substance abuse in the last 12 months,&#xD;
             as defined in the DSM-IV&#xD;
&#xD;
          -  Currently has an implanted electrical device (e.g., pacemaker)&#xD;
&#xD;
          -  Screening lab results were found to be exclusionary based on the following&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dario R Sorrentino, MD, FRACP</last_name>
    <role>Principal Investigator</role>
    <affiliation>Carilion Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Carilion Clinic</name>
      <address>
        <city>Roanoke</city>
        <state>Virginia</state>
        <zip>24013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>December 2022</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>December 9, 2022</last_update_submitted>
  <last_update_submitted_qc>December 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Crohn's</keyword>
  <keyword>Capsule endoscopy</keyword>
  <keyword>IBD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Crohn Disease</mesh_term>
    <mesh_term>Genetic Predisposition to Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03291743
org study id: RTDB-2201
nct id: NCT03291743
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
Pursuing very early diagnosis is standard of care for several diseases including colon
      cancer, diabetes and liver disease where an early and aggressive diagnostic and therapeutic
      approach has been shown to change their natural history. Crohn's disease [CD] still lags
      since commonly at presentation CD has already run a long course, often responding poorly to
      therapy or requiring surgery. This innovative project proposes a minimally invasive strategy
      - capsule endoscopy-based screening of first degree relatives [FDR's] of CD patients - to
      develop tools to diagnose CD at or near its biologic onset.
Crohn's Disease (CD) is a form of inflammatory bowel disease (IBD) that affects the
      gastrointestinal tract. CD is a chronic, remitting, and relapsing disease that is rarely
      diagnosed at or near its biological onset. In routine clinical practice, CD diagnosed at the
      pre-clinical stage is largely by chance during routine screening procedures. Current evidence
      suggests these earlier diagnoses lead to better treatment outcomes and may even offer clues
      to better understand the disease's etiology and pathogenesis. Consequently, diagnosing CD at
      an early stage may offer several advantages including better response to medical treatment;
      possible avoidance of long term complications and surgery; and long term cost savings.

      In the last several years it has become apparent that Crohn's Disease tends to evolve over
      time from an inflammatory disease to a fibrosing one due to the repeated healing and repair
      cycles. The fibrosing found in CD is similar to that of other diseases that affect organs
      like the liver and pancreas. Extensive fibrosis (build-up of excessive scar tissue) does not
      respond to drug therapy and must be treated with surgery; therefore, surgical intervention
      (e.g., intestinal resection) is a treatment modality common to CD patients largely due to
      this indication. Ideally, Crohn's Disease should be diagnosed before this irreversible damage
      takes place and while the disease is still responsive to medical therapy; however, the
      disease only comes to medical attention in the presence of symptoms most often associated
      with severe bowel damage such as obstructions and strictures. Even still, the presence of
      these symptoms does not always lead to prompt diagnosis. Additionally, this evidence
      indicates that CD has already run a long course before it becomes symptomatic and further
      supports the need for earlier diagnosis.

      An efficient screening strategy for Crohn's Disease has yet to be identified. To date,
      colonoscopy is considered the gold-standard as there are no noninvasive tests that can
      conclusively screen for disease. Screening the general population has been shown to be
      inefficient due to the overall risk of developing the disease so it is crucial to determine
      the populations at the greatest risk. Crohn's Disease has proven to have a strong genetic
      component. Referral center studies published in the last several years have shown that 5-15%
      of patients with CD have a family history of the disease; therefore, family members of CD
      patients may constitute an ideal population for screening. Familial studies have focused
      mostly on first-degree relatives [FDR] and have found that this group is at a higher risk for
      developing the disease than the general population. In addition, a landmark study published
      in 2003 showed that >40% of asymptomatic first-degree relatives of CD patients [CD-FDR] had
      elevated fecal calprotectin-an intestinal inflammation marker that closely reflects disease
      activity in CD patients-with values between those of healthy controls and FDR's with
      diagnosed disease. Additional abnormalities such as, Anti-Saccharomyces Cerevisae Antibodies
      [ASCA] positivity and elevated inflammatory markers-have also been reported in asymptomatic
      first-degree relatives at a greater proportion than the known risk of developing the disease.

      Recently, at another institution, the investigators conducted an ileocolonoscopy-based
      screening study in 38 first-degree relatives of patients with Crohn's Disease. Identified
      first-degree relatives were carefully excluded in the presence of digestive symptoms or a
      medical history that contained possible causes of intestinal inflammation. The healthy
      control group consisted of 10 age and sex-matched individuals who were scheduled for a
      colonoscopy due to unrelated reasons (e.g., colon cancer screening or rectal bleeding) and
      whose results were found to be normal. In both groups, tissue, blood, and stool samples were
      collected. Median values for fecal calprotectin (FC) and histology were significantly greater
      in first-degree relatives when compared to the healthy controls. Additionally, colonoscopy
      identified three different phenotypes within the first-degree relative population: 1) normal,
      or superimposable to controls; 2) minor lesions (aphthae or small superficial erosions), and
      3) typical features of Crohn's Disease. These findings were confirmed with histological
      scoring that resulted in three highly separated clusters.

      That preliminary research supports the idea that screening within this high-risk population
      allows for earlier diagnosis. Validating these results on a larger scale and with less
      invasive methods may lead to the development of a screening strategy that can be implemented
      as part of routine clinical practice. Additionally, more research is needed to further
      characterize the novel phenotype identified as it may hold crucial clues to the pathogenesis
      of the disease.

      This study seeks to detect asymptomatic, first-degree relatives of patients with established
      Crohn's Disease in hopes of catching the disease at or near its biologic onset (pre-clinical
      stage). Screening will be done using the PillCam™ COLON 2 capsule endoscopy system. Capsule
      findings will be reviewed by Dr. Sorrentino and Dr. Nguyen at the central site. These
      findings will then be verified using proven ileocolonoscopy methods. Blood, stool, and tissue
      specimens will be collected for research-related testing and to be stored for further
      research. Healthy-controls will be enrolled for comparison purposes. The goal of this study
      is to validate the preliminary data from our pilot study using a multi-center approach.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Prevalence of Crohn's Disease in First Degree Relatives by capsule endoscopy screening
time frame: coincident at screening
description: This study will screen asymptomatic, first-degree relatives of patients with established Crohn's Disease to detect the disease at or near its biologic onset.
measure: Correlation of capsule endoscopy with ileocolonoscopy; characterization of disease state
time frame: coincident at screening
description: Evaluate the accuracy of capsule endoscopy (CE) in screening for pre-clinical Crohn's Disease by verifying CE findings with ileocolonoscopy.
arm group label: First Degree Relative
arm group type: Experimental
description: A total of 112 high risk first-degree relatives will be enrolled in total. Patients with Crohn's Disease will be given information about the study when in clinic for routine care to share with their first degree relatives (FDR). Screening will be done using capsule endoscopy.
arm group label: Healthy Controls
arm group type: Active Comparator
description: This study will also enroll 35 healthy controls who will be age and sex matched to the first degree relative (FDR) population. Enrollment will begin after 20-25 FDR's have passed screening and will continue at this interval until all controls have been enrolled. Controls will be initially screened by colonoscopy. If enrolled they will undergo capsule endoscopy as well
intervention type: Device
intervention name: Capsule endoscopy
description: PillCam(TM) CROHN'S CAPSULE
arm group label: First Degree Relative
arm group label: Healthy Controls
other name: PillCam(TM)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dario R Sorrentino, MD, FRACP
role: Principal Investigator
affiliation: Carilion Clinic
facility: 
country: United States
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responsible party type: Sponsor
mesh term: Crohn Disease
mesh term: Genetic Predisposition to Disease
sharing ipd: No