Pouchitis
Conditions
Brief summary
The researchers propose conducting a multi-center, randomized, placebo-controlled study to investigate the potential role of etrasimod for the primary and secondary prevention of pouchitis among high-risk patients submitted to total proctocolectomy (TPC) with ileal-pouch anal anastomosis (IPAA) for medically refractory disease. The trial will be conducted in compliance with this protocol, Good Clinical Practice guidelines, and Institutional Review Board requirements.
Detailed description
This is a multi-center, randomized, double-blind, placebo-controlled study to investigate the efficacy of etrasimod as primary and secondary prevention of pouchitis among high-risk ulcerative colitis (UC) patients who have undergone TPC + IPAA and have no evidence of pouchitis (i.e., are in remission) at time of enrollment. Eligible patients will be randomized (1:1 ratio) to receive either etrasimod (2 mg once daily) or placebo for 48 weeks. Randomization will be stratified by the presence of medical history of primary sclerosing cholangitis (yes or no) and by the presence of medical history of at least one prior episode of acute pouchitis (yes or no).
Interventions
DRUGetrasimod
2 mg once daily for 48 weeks
DRUGPlacebo
matching placebo for 48 weeks
Sponsors
Maia Kayal
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged ≥ 18 years (verified at screening) * Ability to provide written informed consent and to be compliant with protocol assessments (verified at screening) * Diagnosed with UC and underwent TPC with IPAA for medically refractory disease or dysplasia (verified at screening) * Screening may take place at any time from one month to two years after the final surgical stage * High-risk of developing acute pouchitis - defined as fulfilling at least one of the criteria defined in section 2 (verified at screening) * Patients with 1 prior episode of acute pouchitis can be enrolled - after a minimum period of 4 weeks after completion of a course of antibiotics and resolution of symptoms of pouchitis * Symptomatic remission defined by a symptom mPDAI subscore ≤2 points at the baseline visit (verified at screening, baseline) * Adequate hematological function defined by white blood cell count ≥ 3.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute lymphocyte count (ALC) ≥ 0.8 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL (verified at screening) * Healthcare professional-confirmed history of varicella or a full course of vaccination against varicella zoster virus (VZV) or a positive antibody test to VZV (verified at screening) * 12-lead electrocardiogram (ECG) that showed no clinically significant abnormalities as defined by the clinician's judgement (verified at screening) * Females must be non-pregnant, as determined by qualitative urine hCG testing, non-lactating, and if premenopausal, must agree to using a highly effective contraception method (that can achieve a failure rate of less than 1% per year when used consistently and correctly) during treatment and for one week after stopping treatment with etrasimod (verified at screening)
Exclusion criteria
* Isolated cuffitis (verified at screening pouchoscopy) * Diagnosis of Crohn's disease (verified at screening) * Diagnosis of Crohn's disease-like pouch inflammation (verified at screening) o Crohn's disease-like pouch inflammation is defined as ulcerations of the pre-pouch ileum extending \> 10 cm above the inlet, strictures in the pre-pouch ileum or pouch body outside of the anastomoses, and/or fistulae of the pre-pouch ileum, pouch body, or perineum * Diagnosis of chronic pouchitis (verified at screening) o Chronic pouchitis is defined as persistent (\> 4 weeks) or recurrent (\> 4 episodes/year) symptoms of pouchitis * Anastomotic stenosis or other mechanical complications of the pouch (verified at screening pouchoscopy) * Treatment with probiotics ≤ 3 months prior to screening (verified at screening) * Treatment with topical rectal 5-ASA, or steroids ≤ 2 weeks prior to or during screening (verified at screening) * Any use of a biologic or small molecule approved for moderately to severely active UC or investigational, after TPC with IPAA (verified at screening) * Any prior exposure to a S1P receptor modulator therapy, at any time (verified at screening) * Any investigational or biologic agent within 30 days of screening pouchoscopy (verified at screening) * Have the following cardiovascular history (verified at screening): * In the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure * Have a history or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker * A history of symptomatic bradycardia, recurrent cardiogenic syncope, Mobitz type I second-degree AV block, or severe untreated sleep apnea * Significant QT prolongation (QTcF interval ≥ 450 ms in male or ≥ 470 ms in females) * Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs * Clinically significant or serious active infection ≤ 28 days prior to baseline - including but not limited to (verified at screening): * Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or * positive test for Clostridioides difficile toxin at screening * Active tuberculosis * Acute or chronic hepatitis B or hepatitis C * HIV infection * Pregnancy, lactation, or a positive urine pregnancy test measured during screening * Severe hepatic impairment (Child Pugh Class C) (verified at screening) * Have a known history of macular edema or retinopathy (verified at screening) * History of cancer within the last 5 years (excluding in situ squamous or basal cell carcinoma of the skin that has been excised and resolved) or current malignancy (verified at screening) * History of posterior reversible encephalopathy syndrome (PRES) * Have a history of any clinically significant medical condition that, in the investigator's opinion, precludes participation in the study (verified at screening)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with at least 1 episode of acute pouchitis | 48 weeks | The proportion of patients with at least 1 episode of acute pouchitis during the 48 weeks of treatment. Acute Pouchitis defined as: modified pouchitis disease activity index (mPDAI) score ≥ 5 points OR an increase of ≥ 2 points vs. baseline, AND Endoscopic component of the mPDAI Score \>= 2 points (within 7 days prior or post the collection date of the symptomatic component of the mPDAI score) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first episode of acute pouchitis | end of study at 48 weeks | Time to first episode of acute pouchitis (days) |
| Proportion of patients with acute pouchitis | Weeks 12, 24 and 36 | Proportion of patients with acute pouchitis by Weeks 12, 24 and 36 Acute Pouchitis defined as: mPDAI\* score ≥ 5 points OR an increase of ≥ 2 points vs. baseline, AND Endoscopic component of the mPDAI Score \>= 2 points (within 7 days prior or post the collection date of the symptomatic component of the mPDAI score) |
| Number of participants with clinical remission | end of study at 48 weeks | Clinical remission based on mPDAI score at Week 48 Clinical remission is defined as a mPDAI score \< 5 points. The modified PDAI (mPDAI) is calculated from 2 separate 6-point scales assessing clinical symptoms and endoscopic findings with full scale scored from 0-12. Patients are classified as either having pouchitis (PDAI score ≥5) or as not having pouchitis (PDAI score \<5). Greater clinical scores and endoscopy scores correspond to worse disease severity. |
| Number of episodes of acute pouchitis | end of study at 48 weeks | Number of episodes of acute pouchitis during the 48-week treatment period |
| Change in Inflammatory Bowel Disease (IBD) Disability Index | Baseline and at Weeks 12, 24, 36 and 48 | Change from baseline in total score on the IBD Disability Index at Weeks 12, 24, 36 and 48 Total score on scale from 0-100. Higher score indicates more disability |
Countries
United States
Contacts
CONTACTMaia Kayal, MD
PRINCIPAL_INVESTIGATORMaia Kayal, MD
Principal Investigator
Outcome results
None listed