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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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IBD, Crohn Disease, Genetic Predisposition

Intervention / Treatment
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* Device: Capsule endoscopy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Degree Relative<br>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. | Device: Capsule endoscopy<br>* PillCam(TM) CROHN'S CAPSULE<br>* Other names: PillCam(TM);|
| Active Comparator: Healthy Controls<br>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 | Device: Capsule endoscopy<br>* PillCam(TM) CROHN'S CAPSULE<br>* Other names: PillCam(TM);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Crohn's Disease in First Degree Relatives by capsule endoscopy 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. | coincident at screening | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of capsule endoscopy with ileocolonoscopy; characterization of disease state | Evaluate the accuracy of capsule endoscopy (CE) in screening for pre-clinical Crohn's Disease by verifying CE findings with ileocolonoscopy. | coincident at screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's, Capsule endoscopy, IBD