Assessment of Patients With Acute Pouchitis Treated With Antibiotics

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the reliability and responsiveness of symptoms, endoscopic, and histological items for assessing pouchitis disease activity in patients undergoing standard of care (SOC) antibiotic therapy for treatment of pouchitis, in order to develop a novel pouchitis disease activity index.

Detailed Description
-----------------
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 subjects will be recruited and enrolled at clinical sites in North America and Europe. All subjects with suspected acute pouchitis will undergo pouchoscopy with biopsies and blood and stool sample collection at screening and receive 28 days of antibiotic therapy. Subjects will return to the clinic for a follow-up clinical assessment, pouchoscopy with biopsies forendoscopic and histologic assessments of disease activity, respectively, and blood and stool sample collection for inflammatory biomarker, molecular, and microbiome analyses approximately 6 weeks after starting antibiotic therapy. Subjects will collect an additional stool sample for fecal calprotectin (FC) and microbiome analyses and metabolomics at Week 4 and return the sample to the clinic in person or by mail. Subjects will rate their pouchitis symptoms in an electronic diary beginning at least 3 days before initiation of antibiotic therapy through to the Week 6 study visit. Total anticipated duration of subject participation is approximately 6 weeks after initiating antibiotic therapy. Endoscopic and Histologic Disease Activity Assessments: 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 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 baseline pouchoscopy videos/slide images once to be compared to scores posttreatment 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. Primary Objective: 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 standard of care (SOC) antibiotic therapy. Secondary Objective: A secondary objective of this study is to develop a novel index for assessing pouchitis disease activity. Exploratory Objectives: Identify biomarkers associated with (non)response to antibiotics in pouchitis; Identify biomarkers associated with patient-reported symptoms, endoscopic, and histologic component scores and items, and pouchitis disease activity indices; Describe the dynamics of the microbiome following introduction and withdrawal of antibiotics in pouchitis. Additional exploratory analyses may be established during the review of the study results.

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

Conditions
-----------------
Pouchitis, Ulcerative Colitis

Intervention / Treatment
-----------------
* Other: Observational, No intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients ≥ 18 years of age IPAA for UC (J-pouch only) ≥ 6 months prior to screening Diagnosis of acute pouchitis at screening by stool frequency (an absolute value of ≥ 6 stools / day AND an increase of ≥ 3 stools / day above the post-IPAA baseline), and local endoscopy (presence of ≥ 1 erosion or ulceration of the pouch on endoscopy [not including ulceration occurring within 1 cm of the pouch staple or pouch suture line]). Not currently taking antibiotics for pouchitis or previous systemic antibiotic use for any reason within 4 weeks of screening. Prior to the Screening pouchoscopy. Note: Initiation of antibiotics for treatment of acute pouchitis prior to the Screening pouchoscopy will be permitted only if the participant initiates treatment within 48 hours prior to the Screening pouchoscopy; use outside of the 48-hour window will not be permitted and these patients should not be included in the study Current treatment with 5-aminosalicylic acid drugs, immunosuppressants, antidiarrheals, antimotility agents, and probiotics is permitted, if patient has received a stable dose for ≥ 4 weeks prior to screening. Dose of concomitant therapy must remain stable during the study period. Able to participate fully in all aspects of this clinical trial. Written informed consent must be obtained and documented Exclusion Criteria: Pouch formations besides J-pouch (e.g., W-, S- and Kock pouches). IPAA for familial adenomatous polyposis. Pouchitis caused by other inflammatory etiologies (e.g., ischemia or infection). Antibiotic-dependent pouchitis, defined by ≥ 3 months of cumulative antibiotic use over the 12 months prior to screening. Isolated cuffitis, pouch-anal or pouch-ileal anastomotic stricture, perforating complications, or pelvic sepsis. Known Crohn's disease (CD) or suspected CD of the pouch, defined as complex perianal/pouch fistula and/or extensive length of prepouch ileitis with deep ulceration. Anticipated changes in therapy during study period. Use of oral corticosteroids. Participants must have discontinued oral corticosteroids within 1 month prior to screening. Current use of any advanced oral small molecule drug (e.g Janus kinase [JAK] inhibitors for the treatment of pouchitis. Participants must have discontinued oral small molecule therapy within 2 weeks prior to screening. Failed (i.e., inadequate response with, loss of response to, or intolerance to) 2 or more compounds or classes of advanced therapies such as biologics and/or small molecule drugs (i.e., 1 biologic and 1 JAK inhibitor, 2 biologics in the same class, or 2 biologics from different classes) for the treatment of pouchitis Participant who are pregnant or breastfeeding. Known history of allergy, intolerance, or are refractory to ciprofloxacin AND metronidazole AND any component of amoxicillin/potassium clavulanate combination. Unable to undergo endoscopic evaluation. Serious underlying disease other than acute pouchitis and UC that in the opinion of the investigator may interfere with the participant's ability to participate fully in the study. History of alcohol or drug abuse that in the opinion of the investigator may interfere with the participant's ability to comply with the study procedures. Prior enrollment in the current study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Open-label observational study<br>This study will evaluate the reliability and responsiveness of patient-reported symptoms and endoscopic and histologic items for assessing pouchitis disease activity in 43 patients undergoing standard of care (SOC) antibiotic therapy. | Other: Observational, No intervention<br>* Open-label observational study that will evaluate the reliability and responsiveness of patient-reported symptoms and endoscopic and histologic items for assessing pouchitis disease activity in 43 patients undergoing standard of care (SOC) antibiotic therapy.<br>* Other names: Observational;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Screening Clinical Global Impressions of Severity at Week 6 | Site investigators will rate the severity of pouchitis symptoms using the Clinical Global Impressions of Severity (CGI-S) at baseline and Week 6 and change in pouchitis symptoms using the CGI of Change (CGI-C) scale at Week 6. | Baseline and Week 6 | 
| Change from Screening Patient's Global Impression of Severity at Week 6 | Participants will rate their symptoms using the Patient's Global Impression of Severity (PGI-S) at beginning at least 3 days prior to initiating antibiotic therapy through to Week 6. The weekly component will be completed at baseline and every 7 days following initiation of therapy. Change in symptoms using the PGI of Change (PGI-C) scale will be completed at Week 4 and Week 6. | Duration of study, approximately 6 weeks. | 
| Symptoms and Impacts Questionnaire for Pouchitis | The Symptoms and Impacts Questionnaire for Pouchitis (SIQ-UC) is a self-administered tool that includes daily records of bowel movements, symptoms, and an assessment of ulcerative colitis impact on activities of daily living. For this study, the SIQ-UC has been adapted for use in pouchitis. | Duration of study, approximately 6 weeks | 
| Visual Analog Scale for Pouchitis Symptoms | Throughout the study, participants will rate their pouchitis symptoms daily on a 100-mm VAS,where 0 indicates no pouchitis symptoms, and 100 indicates the worst pouchitis symptoms ever. | Duration of study, approximately 6 weeks | 
| Visual Analog Scale of Fecal Urgency | Throughout the study, participants will rate fecal urgency on a 100-mm VAS, where 0 indicates no sense of urgency to defecate and 100 indicates I was not able to make it to the toilet in time. | Duration of study, approximately 6 weeks | 
| Visual Analog Scale of Abdominal Cramps Severity | Throughout the study, participants will rate fecal urgency on a 100-mm VAS, where 0 indicates no abdominal cramps and 100 indicates  worst abdominal cramps ever. | Duration of study, approximately 6 weeks | 
| Change from Baseline St. Mark's Fecal Incontinence Score (Vaizey Score) at Week 6 | The St. Mark's Fecal Incontinence Score (Vaizey Score) will be completed at Screening and EOS (Week 6). Four items for incontinence and lifestyle impact are assessed on a 5-point frequency scale and 3 items are assessed with a binary yes/no response to provide a total score ranging from 0 to 24 points, with higher scores indicating greater fecal incontinence and impact on lifestyle | Baseline and Week 6 | 
| Endoscopic Disease Activity | Trained central endoscopy readers will score pouchitis endoscopic disease activity in the worst affected area of the pouch body. | Week 6 | 
| Histologic Disease Activity | Trained central histopathology readers will score pouchitis histologic disease. | Week 6 |