Assessment of Patient-reported Symptoms and Endoscopic, Histologic, and Biomarker Outcomes in Patients With Acute Pouchitis Treated with Antibiotics

Disease activity in patients with pouchitis can be assessed through any
combination of clinical symptoms, endoscopy, or histopathology. Currently, 5
pouchitis disease activity indices exist: the Heidelberg Pouchitis Activity
Score (HPAS) and Pouchitis Disease Activity Index (PDAI), which consist of
clinical, endoscopic, and histologic items; the Japanese Diagnostic Criteria
for Pouchitis (JDCP), consisting of clinical and endoscopic items; the St.
Mark*s Criteria, consisting of endoscopic and histologic items; and the
Endoscopic Pouch Activity Index (EPAI), which is an endoscopy-specific index.
Two modifications of the PDAI also exist: the modified PDA (mPDAI), consisting
of PDAI clinical and endoscopic items and the Objective Pouchitis Score (OPS),
consisting of PDAI endoscopic and histologic items. Pouchitis indices were
primarily developed as tools to aid clinicians in diagnosing pouchitis and were
not intended for use as evaluative indices in clinical trials, although the
PDAI and mPDAI have both been used for assessing the effectiveness of some
therapies. Unfortunately, these indices were not developed using modern
clinimetric methods and have never been fully validated and thus their value as
robust evaluative indices for drug registration trials is unknown.

Using Research and Development/University of California, Los Angeles
(RAND/UCLA) appropriateness methodology, experts deemed 2 endoscopic items in
existing indices as *inappropriate* based on face validity. Most notably was
*edema,* which is assessed in each index with an endoscopic disease activity
component. In addition, several novel items for assessing pouchitis disease
activity were identified. Together, these findings suggest that existing
pouchitis indices are suboptimal. A post-RAND reliability study provided
further support for the inadequacy of these indices by demonstrating suboptimal
reliability for some items and substantial reliability and strong correlation
with overall pouchitis disease activity for items not currently included in
pouchitis disease activity indices. The responsiveness of these items to
changes in disease activity has yet to be determined.

Most recently, we assessed the face validity of clinical, endoscopic, and
histologic items in the current pouchitis indices with RAND/UCLA
appropriateness methodology and found significant uncertainty among experts
regarding the appropriateness of many clinical, endoscopic, and histological
items.22 Despite this uncertainty, experts agreed that stool frequency and
fecal urgency were appropriate pouchitis symptoms to assess. In addition,
experts deemed the assessment of endoscopic disease activity in the pouch body
at least 10 cm above the pouch outlet as appropriate.

Experts agreed that erosions and ulcers, percentage of ulcerated area, and the
percentage of the pouch affected area were appropriate endoscopic items to
evaluate in pouchitis. For histopathology, the degree of lamina propria chronic
inflammation (lymphocytes and plasma cells), epithelial neutrophils, and the
presence of erosions and ulcerations were all considered appropriate existing
histologic items for assessing pouchitis. In addition, experts recommended
lamina propria neutrophils and epithelial damage (including surface epithelial
injury and crypt destruction), which are assessed in the Geboes score and
Robarts Histopathology Index (RHI) for UC, be assessed in pouchitis. The
reliability and responsiveness of existing indices and items/descriptors for
pouchitis, as well as indices commonly used in inflammatory bowel disease
(IBD), will be evaluated in this study and a novel pouchitis disease activity
index potentially developed.

The primary objective of this study is to evaluate the reliability and
responsiveness of patient reported symptoms and endoscopic and histologic items
for assessing pouchitis disease activity in patients undergoing SOC antibiotic
therapy.

A secondary objective of this study is to develop a novel index for assessing
pouchitis disease activity.

This is a prospective, open-label, observational study of patients with acute
pouchitis being treated with SOC antibiotic therapy (a known effective therapy
in most patients), to evaluate the reliability and responsiveness of existing
pouchitis indices and component items for assessing pouchitis disease activity.
A total of 43 participants are planned to be enrolled at clinical sites in
North America and Europe.


All participants with suspected acute pouchitis will undergo a SOC pouchoscopy
at Screening with study-related biopsy sample collection. Participants will be
prescribed antibiotic therapy as per current SOC guidelines for a 4-week (28
day) course of antibiotic treatment. For study sites in the Netherlands,
appropriate antibiotic treatment for pouchitis will be defined according to
local country guidelines, where participants failing to respond to 2 weeks of
the initially prescribed antibiotic will have the option to switch antibiotic
treatment and can be treated with the other agent for 2 to 4 weeks.

Participants will collect stool samples, using study-provided at-home stool
sample collection kits, for the purposes of fecal calprotectin (FC),microbiome,
and metabolomics analyses at 3 time points in the study: Screening, End of
Treatment (EOT), and Week 6 (End of Study [EOS]). Blood samples will be
collected at Screening and Week 6 (EOS) for metabolomics, serology, proteomics,
and RNA-Sequencing analyses.

Participants will rate their pouchitis symptoms in an electronic diary
(*Patient eDiary*) at the Screening Visit, for symptoms experienced prior to
the initiation of antibiotic treatment, and then once daily following the
initiation of antibiotic therapy through to the Week 6 (EOS) Visit.

Participants will return to the clinic at Week 6 for a follow-up pouchoscopy
with biopsies for endoscopic and histologic assessments of disease activity,
respectively, as well as clinical assessment. The total anticipated duration of
individual patient participation is approximately 6 weeks after initiating
antibiotic therapy.

Endoscopic and Histologic Disease Activity Assessments
A total of 3 blinded expert endoscopists and histopathologists will serve as
central readers for this study and score pouchoscopy videos and histologic
slide images, respectively. Paired pouchoscopy videos and histologic slide
images (Baseline [Screening] and Week 6) of adequate quality will be scored by
central readers (see Outcome Measures). Each central reader will score all Week
6 pouchoscopy videos and histologic slide images twice, 2 weeks apart, for
assessing reliability, and all Screening pouchoscopy videos/slide images will
be scored once to be compared to post-treatment scores for assessing
responsiveness.

Novel Pouchitis Disease Activity Index Development
A novel index will be developed using multiple linear regression with items
that have moderate reliability and responsiveness. The index will be internally
validated using the bootstrap method with 2000 replicates.

In this real-world observational study of patients with pouchitis prescribed
SOC antibiotic therapy, the potential risks associated with study participation
beyond their usual treatment are minimal. SOC assessments may differ according
to local site and/or region-specific guidelines.

Study-specific assessments not considered SOC may include: biopsy during the
pouchoscopy at Screening (the Screening pouchoscopy itself is SOC), an
additional pouchoscopy with biopsy at Week 6 (End of Study [EOS]), stool sample
collection, blood sample collection, and completion of a daily Patient eDiary:
• Pouchoscopy and biopsies are generally well tolerated, although there is
increased risk of bleeding and in rare cases, pouch perforation.
• Participants will collect stool samples using an at-home stool sample
collection kit at Screening, End of Treatment (EOT), and Week 6 (EOS). The
burden will be minimized by providing the stool collection kits in advance and
allowing for samples to be mailed into the clinic or returned to the clinic
in-person for the Screening and EOT samples.
• Blood sample collection at Screening and Week 6 (EOS) to allow for
study-specific metabolomics, serology, proteomics, and RNA-Sequencing analyses.
Risks associated with blood collection include pain, bruising, and a minimal
risk of infection at the venipuncture site and dizziness.
• Lastly, participation in the current study will involve completion of a daily
electronic diary of pouchitis symptoms (*Patient eDiary*). Although there is an
increased burden associated with diary completion, the burden is minimized by
participants being able to complete the diary electronically (i.e., on a
personal mobile device or computer).

The potential benefit to participants includes closer monitoring of their
pouchitis symptoms. Study results are expected to benefit future patients by
potentially developing a fully validated index for assessing pouchitis disease
activity that will stimulate the development of novel therapies for chronic
pouchitis. In addition, this study may identify less invasive prognostic
biomarkers of antibiotic responsiveness, which could help clinicians identify
patients unlikely to respond to antibiotics and prevent prescribing a
potentially ineffective first-line therapy and result in quicker delivery of an
effective therapy.

Overall, the risk-to-benefit ratio is considered favorable, with the potential
benefits to future patients outweighing the minimal risks to study
participants.