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

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.

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