An open label exploratory analysis of the histological, immunological and microbiome changes of the colonic mucosa during treatment with tofacitinib for moderate-severe ulcerative colitis

1. Subject must be at least 18 years of age., 2. Males and females with a
documented diagnosis of UC * 4 months prior to entry into the study. A biopsy
report supporting the diagnosis must be available in the source documents., 3.
Subjects with moderately to severely active UC as defined by a total Mayo score
of * 6 with an endoscopic (sigmoidoscopy) subscore of * 2 on the Mayo score
determined within 7 days of starting the study treatment (tofacitinib)., 4.
Subjects must have failed or be intolerant (discontinued the medication due to
an adverse event as determined by the investigator) of at least one of the
following treatments for UC:, - Oral corticosteroids, - Azathioprine or
6-mercaptopurine (6-MP)., - Anti-TNF therapy: infliximab, adalimumab or
golimumab, 5. No evidence of active or latent or inadequately treated infection
with Mycobacterium tuberculosis (TB) as defined by negative QuantiFERON*-TB
Gold (QFT-G) In-Tube test and a chest radiograph, taken at or within the 3
months prior to a given screening visit, without changes suggestive of active
TB infection as determined by a qualified radiologist. , 6. If a subject has
previously received an adequate course of therapy for either latent (9 months
of isoniazid in a locale where rates of primary multi-drug TB resistance are
less than 5% or an acceptable alternative regimen) or active (acceptable
multi-drug regimen) TB infection, neither a QFT-G test nor a PPD test is
needed, but a chest radiograph must still be obtained if not performed within 3
months prior to a given Screening visit. , 7. Female subjects of childbearing
potential 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. A subject is of childbearing potential if, in the opinion of the
investigator, he/she is biologically capable of having children and is sexually
active., 8. Women of childbearing potential must have a negative pregnancy test
prior to study enrolment., 9. Subjects who are willing and able to comply with
scheduled visits, treatment plan, laboratory tests, daily diary listing, and
other study procedures.

1. Presence of indeterminate colitis, microscopic colitis, ischemic colitis,
infectious colitis, or clinical findings suggestive of Crohn*s disease., 2.
Subjects without previous treatment for UC (ie, treatment-naïve)., 3. Subjects
displaying clinical signs of fulminant colitis or toxic megacolon., 4.Subjects
with evidence of colonic adenomas or dysplasia. However, subjects with prior
history of adenomatous polyps will be eligible if the polyps have been
completely removed and the subjects are free of polyps at baseline., 5.
Subjects at risk for colorectal cancer must have a Colonoscopy. Colonoscopy
report and pathology report (if biopsies are obtained) must be available in the
source document
* If the subject is >50 years of age, a colonoscopy within 10 years of the
screening visit is required to exclude adenomatous polyps. Subjects whose
adenomas have been completely excised at baseline will be eligible., * If the
subject has extensive colitis for >8 years or disease limited to left side of
colon (ie, distal to splenic flexure) for >10 years, regardless of age, a
colonoscopy within 1 year of the screening visit is required to survey for
dysplasia. Subjects with dysplasia or cancer identified on biopsies will be
excluded., 6. Subjects who have had surgery for UC or in the opinion of the
Investigator, are likely to require surgery for UC during the study period., 7.
Subjects who have positive stool examinations for enteric pathogens, pathogenic
ova or parasites, or Clostridium difficile toxin at screening. , 8. Subjects
with clinically significant infections currently or within 6 months of
baseline(eg those requiring hospitalization or parental antomicrobial therapy
for oppurtunistic infection , 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., 9. Subjects with a history of more than one
episode of herpes zoster, a history of disseminated herpes zoster or
disseminated herpes simplex., 10. Subjects infected with human immunodeficiency
virus (HIV) or hepatitis B or C viruses (Subjects with negative HBV surface
antigen but positive HBV core antibody must have further testing for HBV
surface antibody and if negative for HBV surface antibody, will be excluded
from study enrollment). , 11. 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., 12. 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, leukemia,
myeloproliferative disorders, multiple myeloma, or signs and symptoms
suggestive of current lymphatic disease., 13. 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., 14. Subjects
with a history of bowel surgery within 6 months prior to baseline., 15.
Subjects with significant trauma or major surgery within 4 weeks of screening
visit., 16. Subjects likely to require any type of surgery during the study
period., 17. Subjects with the following laboratory values at screening:, *
Hemoglobin levels less than 9.0 g/dL or hematocrit less than 30%., * An
absolute white blood cell (WBC) count of less than 3.0 x 109/L (less than
3000/mm3) or absolute neutrophil count of less than 1.2 x 109/L (less
than1200/mm3), or an absolute lymphocyte count of less than 0.5 x 109/L (less
than 500/mm3) , * Thrombocytopenia, as defined by a platelet count less than
100 x 109/L (less than 100,000/mm3)., * Subjects with estimated GFR less than
50 ml/min based on Cockcroft-Gault calculation., * Subjects with total
bilirubin, AST or ALT more than 1.5 times the upper limit of normal., 18.
Subjects with evidence of or suspected liver disease ie, liver injury due to
methotrexate or primary sclerosing cholangitis.
For all other exclsuion criteria , see protocol