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The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03291743
Recruitment Status : Recruiting
First Posted : September 25, 2017
Last Update Posted : October 9, 2019
Information provided by (Responsible Party):
Dario Sorrentino, Carilion Clinic

Tracking Information
First Submitted Date  ICMJE September 19, 2017
First Posted Date  ICMJE September 25, 2017
Last Update Posted Date October 9, 2019
Actual Study Start Date  ICMJE February 10, 2017
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
Prevalence of Crohn's Disease in First Degree Relatives by capsule endoscopy screening [ Time Frame: coincident at screening ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2017)
Correlation of capsule endoscopy with ileocolonoscopy; characterization of disease state [ Time Frame: coincident at screening ]
Evaluate the accuracy of capsule endoscopy (CE) in screening for pre-clinical Crohn's Disease by verifying CE findings with ileocolonoscopy.
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 The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives
Official Title  ICMJE The Biologic Onset of Crohn's Disease: A Screening Study in First Degree Relatives
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Crohn Disease
  • Genetic Predisposition
  • IBD
Intervention  ICMJE Device: Capsule endoscopy
Other Name: PillCam(TM)
Study Arms  ICMJE
  • Experimental: First Degree Relative
    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.
    Intervention: Device: Capsule endoscopy
  • Active Comparator: Healthy Controls
    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: Device: Capsule endoscopy
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 30, 2021
Estimated Primary Completion Date May 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female who are 18-65 years of age
  • FDR: Has a first degree relative (mother, father, offspring, or full sibling) who has been diagnosed with Crohn's Disease Healthy Controls: Normal colonoscopy and histology (if applicable) results, and no family history of inflammatory bowel disease (Crohn's Disease and Ulcerative Colitis)
  • Willingness to comply with protocol requirements, timelines, and procedures
  • Must be able and willing to provide written consent; medical, surgical, and medication history; current and concomitant medication use; and any other documents deemed relevant by the investigator.
  • A negative pregnancy test for all female subjects of childbearing potential at the time of consent. Subject must also agree to follow medically approved birth control measures while enrolled

Exclusion Criteria:

  • Suspected or confirmed diagnosis of inflammatory bowel disease or any other gastrointestinal disease or condition
  • Known medical history of clinically significant cardiovascular, hematologic, orthopedic, rheumatologic, muscular, neurologic (e.g. dementia, seizure disorder, traumatic brain injury), endocrine, ophthalmologic, infectious (e.g. human immunodeficiency virus, tuberculosis, hepatitis), immunologic, renal, pulmonary (e.g. COPD), dermatologic, reproductive, or psychiatric disorders, conditions, or diseases that would present unacceptable risk to study subjects, compromise the acquisition or interpretation of study data, or otherwise interfere with the study subject's participation
  • A systolic blood pressure reading ≥ 180 mmHg and/or a diastolic blood pressure reading of ≥ 110 mmHg at screening
  • An oral temperature reading of 100.5º F or greater
  • Meets any of the following criteria:

    • Use of systemic non-steroidal anti-inflammatory medication (including low-dose aspirin) within 14 days prior to consent
    • History of oral corticosteroid use within 30 days prior to consent
    • Use of IV corticosteroids within 14 days prior to consent
    • Treatment with IV anti-infectives within 30 days prior to consent
    • Treatment with oral anti-infectives within 14 days prior to consent
  • Previous or current history of malignancy (including fully excised cutaneous basal cell carcinoma and squamous cell carcinoma)
  • History of stem cell or fecal transplant
  • History of clinically significant alcoholism or substance abuse in the last 12 months, as defined in the DSM-IV
  • Currently has an implanted electrical device (e.g., pacemaker)
  • Screening lab results were found to be exclusionary based on the following
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Dario R Sorrentino, MD, FRACP 540-224-5170
Contact: Vu Q Nguyen, MD 540-206-9226
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03291743
Other Study ID Numbers  ICMJE RTDB-2201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Dario Sorrentino, Carilion Clinic
Study Sponsor  ICMJE Dario Sorrentino
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Dario R Sorrentino, MD, FRACP Carilion Clinic
PRS Account Carilion Clinic
Verification Date October 2019

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