Treatment of chronic, recurrent and/or antibiotic refractory pouchitis with tofacitinib

Recruitment & Eligibility

Status: Pending

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

1)Subject must be at least 18 years of age.
2)Subject has a history of an IPAA for UC, all stages completed at least 6 months prior to day one of the start of the study.
3)Subject has chronic, recurrent and/or antibiotic refractory pouchitis, defined as a PDAI = 7 , with either
a)= 2 recurrent pouchitis episodes within 1 year prior to screening, necessitating treatment with antibiotics or other prescription, or;
b)Requiring maintenance antibiotic therapy for = 4 weeks to maintain clinical remission and a history of at least two attempts in the last 24 months to stop this therapy, resulting in a relapse of the pouchitis episodes.
4)Female subjects of childbearing potential, defined as biologically capable of having children and is sexually active, must agree to use a highly effective method of contraception throughout the study and for at least 4 weeks after the last dose of assigned treatment.
5)Female subjects of childbearing potential must have a negative pregnancy test prior to enrolment in the study.
6)Written informed consent must be obtained and documented.

Exclusion Criteria

1)Pouchitis due to surgery related conditions (such as an abscess, fistula, or sinus of the pouch).
2)Absence of a previous pelvic MRI to assess secondary causes of pouchitis.
3)Irritable pouch syndrome (symptoms without evidence of inflammation on endoscopy and histology).
4)Mechanical complications of the pouch (e.g. pouch stricture or pouch fistula).
5)Crohn’s disease of the pouch.
6)Patients with signs of severe systemic inflammation (at least two of the following symptoms: temperature > 38.5 °C, tachycardia > 100 bpm (after rehydration), systolic blood pressure < 100 mmHg).
7)Diverting ileostomy.
8)Chronic treatment for pouchitis with antibiotics. All antibiotics should be discontinued 4 weeks prior to baseline.
9)Positive stool sample for C. difficile, enteric pathogens, pathogenic ova or parasites at screening.
10)Subjects with clinically significant infections currently or within 6 months of baseline (e.g., those requiring hospitalization or parenteral antimicrobial therapy or opportunistic infections), a history of any infection requiring antimicrobial therapy within 2 weeks of baseline, or a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study.
11)Active herpes zoster infection or history of disseminated zoster infection.
12)Evidence of an active infection during screening, or known history of chronic HBV, HCV, HIV infection, or if subject is immunodeficient.
13)Active or latent infection with Mycobacterium tuberculosis (TB), regardless of treatment history.
14)Subjects who have been vaccinated with live or attenuated vaccine within 6 weeks of baseline or scheduled to receive these vaccines during study period or within 6 weeks after last dose of study medication. Subjects with history of any lymphoproliferative disorder (such as EBV-related lymphoproliferative disorder, as reported in some subjects on other immunosuppressive drugs), history of lymphoma, leukaemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current lymphatic disease.
15)Subjects with a history of pulmonary embolism and/or deep venous thrombosis.
16)Subjects with malignancies or a history of malignancies, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin.
17)Subjects with a history of bowel surgery within 6 months prior to baseline.
18)Subjects with significant trauma or major surgery within 4 weeks of screening visit.
19)Subjects likely to require any type of surgery during the study period.
20)Subjects with the following laboratory values at screening:
a)Hemoglobin levels <5.5 mmol/L or hematocrit <30%.
b)An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) or absolute neutrophil count of <1.2 x 109/L (<1200/mm3), or an absolute lymphocyte count of <0.5 x 109/L (<500/mm3).
c)Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3).
d)Subjects with estimated GFR <50 ml/min.
e)Subjects with total bilirubin, AST or ALT more than 1.5 times the upper limit of normal.
21)Subjects with evidence of or suspected liver disease i.e., liver injury due to methotrexate or primary sclerosing cholangitis.
22)Subjects with current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic (including uncontrolled hyperchol

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the safety and efficacy of 8 weeks of treatment with tofacitinib in chronic, recurrent and/or antibiotic refractory pouchitis, based on clinical, endoscopic, and histologic response.

Secondary Outcome Measures

Name	Time	Method
To contribute to the understanding of the mechanisms of action of tofacitinib and to possibly identify patients who will most likely respond, based on multi-omics analyses before and after treatment with tofacitinib. This will include the assessment of histologic disease activity, immune cell infiltration, gene expression of inflammatory cytokines and changes in the microbiome.