Prospective Observational Study to Validate a Novel PRO Tool and Imaging Index Items in Stricturing Crohn*s Disease

The development of a stricture in patients with Crohn*s disease (CD) marks an
important event that portends an increased risk of disease complications and
surgery. Up to 11% of patients with CD present with a stricture at diagnosis,
and in long-term follow up, up to one-third of patients will progress to a
stricturing phenotype. The mechanisms by which fibrotic predominant strictures
develop in CD are complex. An excessive repair response to transmural
inflammation causes a reduction in luminal diameter that is dependent on both
the pleiotropic actions of inflammatory mediators and the interplay of
profibrotic genetic, cellular, and microbiota-related factors. A variety of
endoscopic scoring indices are sensitive to mucosal changes in CD, but
stricture assessment can be potentially challenging for several reasons. Of
note, an endoscopy cannot visualize the transmural nature of stricturing
disease, the luminal length of many strictures, penetrating complications in
the peri-enteric mesentery, upstream bowel dilation and obstruction, or
proximally located strictures and inflammation. In the case of multiple
strictures, an inability to pass the endoscope through the first stricture will
preclude assessment of all bowel segments. Cross-sectional imaging,
particularly with computed tomography enterography (CTE) and magnetic resonance
enterography (MRE), has therefore emerged as an accurate method for assessing
stricturing CD and its obstructing and penetrating complications. Both
modalities have demonstrated high sensitivity (> 85%) and specificity (> 90%)
for identifying CD strictures and provide useful adjunctive information that
can alter clinical management in a substantial proportion of patients. Recent
consensus recommendations from the CONSTRICT study group define criteria for a
stricture on CTE or MRE as: luminal narrowing, wall thickening, and prestenotic
dilation. However, this definition has not been formally validated. Health
status as reported directly from the patient without interpretation of anyone
else, commonly referred to as a patient-reported outcome (PRO), are an
essential component for patient care. Although several PRO instruments have
been developed in the inflammatory bowel disease (IBD) therapeutic area, there
is currently no validated PRO measure for stricturing CD. Therefore, it is
hypothesized that development of rigorous clinical definitions and outcome
tools for stricturing CD will allow testing of antifibrotic therapies in
patients with these complications.

The objectives of this study are to:
1. Perform quantitative testing of a novel stricture patient-reported
outcome (PRO) tool, including validation and assessment of responsiveness.
2. Assess responsiveness of the MRI-based stricture radiology index (SRI)
items.

Approximately 165 patients with stricturing Crohn*s disease (CD) will be
enrolled across multiple sites in North America and/or Europe to participate in
a 24-week data collection study.

Subjects will undergo 2 imaging assessments during the study, a CTE or MRE scan
at baseline and at 24 weeks (end of study [EOS]), performed as part of routine
clinical SOC CTE or MRE or performed as a study CTE or MRE in the event that an
SOC imaging assessment is not available, followed by best medical therapy. The
baseline CTE or MRE must be completed within +/-4 weeks of consent. An SOC
contrast-enhanced
abdominopelvic CT performed within ±4 weeks of informed consent may be
collected as the baseline imaging assessment if a stricture meeting the
eligibility criteria is captured.

Pseudonymized CTE or MRE scans will be assessed by expert central readers using
the Mayo Clinic Biomedical Imaging Resource (BIR) workstation central reading
platform for eligibility assessment.

Subjects will receive SOC medical therapies with proven efficacy for management
of CD at the discretion of their treating physician as part of routine care.
The course of best medical therapy will typically depend on the therapies the
subject is taking at the time of obstruction and the degree of inflammation in
the stricture as assessed on baseline CTE or MRE. If the baseline imaging is
performed prior to consent, there must be no change to subject treatment for CD
between the time of imaging assessment and informed consent.

For analysis, subjects will be classified into 1of 2 groups:
1. Subjects who receive standard medical therapy and endoscopic balloon
dilation (EBD)
2. Subjects who receive standard medical therapy.

Subjects will complete electronic patient-reported outcome (ePRO) assessments
throughout the study using their own electronic devices.
• From Weeks 1 to 4, subjects will complete the Patient CDAI (Crohn*s Disease
Activity Index) Diary and STARPRO daily; the PGI-S (Patient Global Impression
-Severity) will be completed at Screening/Baseline (day of informed consent)
and on Day7 of every weekly period from Weeks 1 to 4.
• At Weeks 12 and 24 (EOS) only, subjects will complete the Patient CDAI Diary
and STARPRO, once daily for 7 days; the PGI-S will be completed on Day 7 at
Week 12 and Week 24 (EOS) only.
• The SIQ-CD (Symptoms and Impacts Questionnaire for CD) will be completed once
daily for 7 days at Weeks 1, 12, and 24/EOS.
• In addition to the above schedule, from Weeks 12 to 24/EOS, subjects will
complete a *Patient Daily Symptom Check-In* (one question, once daily) asking
if their symptoms have changed. If symptoms have changed, patients will be
required to complete the STARPRO and Patient CDAI Diary daily for 7 days; the
PGI-S will also be completed on the 1stday of symptom change and once again on
the 7th day following a change in symptoms.

The current observational study is considered to be of minimal risk to
participating subjects. Subjects will be treated for their stricturing CD as
per routine clinical care. Study-specific assessments are noninvasive (e.g.,
patient-reported data collection via questionnaires or at-home testing) or in
line with routine clinical care. Three study blood samples will be collected
and stored at baseline, week 12 (if in-person visit) and week 24 .
The direct benefit to subjects includes receiving standard of care (SOC) and
medical follow-up for this condition in a tertiary care IBD-specialized center.
There is the potential to benefit future patients with stricturing CD with
successful validation of outcome measures. Regulatory-accepted outcome measures
for assessment of stricturing CD may enable development and approval of
effective drugs.