A Phase 2B, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Dose Ranging Study of Oral PF-06651600 and PF-06700841 as Induction and Chronic Therapy in Subjects with Moderate to Severe Ulcerative Colitis [VIBRATO]

1. Male and/or female subjects *18 years to *75 years of age at the time of informed consent. For subjects in Korea: Male and/or female subjects *19 years to *75 years of age at the time of informed consent.
2. Diagnosis (endoscopic and histological) of UC for *3 months prior to entry into the study. A report supporting disease duration and extent (eg, proctosigmoiditis, left-sided colitis, or pancolitis) based upon prior endoscopy including a biopsy report must be available in the source documentation.
3. Subjects with moderate to severe active UC as defined by a total Mayo score of *6, with a rectal bleeding subscore of *1 and an endoscopic subscore of *2. Endoscopy (colonoscopy or flexible sigmoidoscopy) must be performed within 10 days of baseline, preferably 5 to 7 days prior to baseline to allow calculation of Total Mayo Score. The endoscopic subscore assessed by the Central Reader must be available at the baseline visit and will be used to derive the total Mayo score to determine study eligibility.
4. Active disease beyond the rectum (>15 cm of active disease from the anal verge at the screening endoscopy).
5. Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC:
- Steroids;
- Immunosuppressants (azathioprine [AZA], 6-MP, or methotrexate [MTX]);
- Anti-TNF inhibitors (eg, infliximab, adalimumab, or golimumab);
- Anti-integrin inhibitors (eg, vedolizumab). ;See Appendix 1 of the protocol for guidance only. Local standards of care, as well as investigator assessment should be considered in any assessment.;6. Subjects currently receiving the following treatment for UC are eligible providing they have been on stable doses as described below:
- Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline. If oral 5-ASA treatment has been recently discontinued, it must have been stopped for at least 2 weeks prior to baseline.
- Oral corticosteroids (dose equivalent to prednisone up to 25 mg/day; budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline. If oral corticosteroids have been recently discontinued, they must have been stopped at least 2 weeks prior to baseline. Decreases in steroid use due to adverse events are allowed.
7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
9. Female subjects of childbearing potential (Women of child-bearing potential: WOCBP) must test negative for pregnancy at screening visit and baseline visit.
10. Female subjects considered to be of non-childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure. ;All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.

1. Female subjects who are pregnant or wish to become pregnant; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use 2 effective methods of contraception (at least one highly affective method) as outlined in the protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
2. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, and diverticular disease associated with colitis, or clinical findings suggestive of Crohn*s disease (eg, fistulae, granulomas on biopsy).
3. Subjects with known colonic stricture and subjects with history of colonic or small bowel obstruction or resection.
4. Subjects with significant trauma or major surgery within 4 weeks of screening.
5. Subjects considered in imminent need for surgery or with elective surgery scheduled to occur during the study.
6. Subjects with a history of bowel surgery within 6 months prior to baseline.
7. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
8. Subjects with primary sclerosing cholangitis.
9. Subjects with history of colonic or small bowel stoma.
10. Subjects with evidence of colonic dysplasia, adenomas or neoplasia. However, subjects with adenomatous polyps identified on screening endoscopy will be eligible if the polyps have been completely removed and follow-up surveillance per local guidelines is negative.
11. Subjects who meet either of the 2 criteria below are considered at risk for colorectal cancer and must have a colonoscopy prior to randomization. The colonoscopy and pathology reports (if biopsies obtained) must be available in the source documentation:
- If the subject is *50 years of age, a colonoscopy within 10 years of screening is required to exclude adenomatous polyps. Subjects with adenomatous polyps identified on screening endoscopy will be eligible after complete polypectomy and follow-up surveillance per local guidelines is negative.
- If the subject has had extensive (ie, greater than left sided) 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 screening visit is required to survey for dysplasia. Subjects with dysplasia or cancer identified on biopsies will be excluded.
12. Subjects receiving the following therapies within the time period described below or expected to receive any of these therapies during the study period:
- >9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 2 weeks prior to baseline.
- IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline.
- Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline.
- Anti-TNF inhibitors (or biosimilars thereof) as described below:
o Infliximab within 8 weeks prior to baseline;
o Adalimumab within 8 weeks prior to baseline;
o Golimumab within 8 weeks prior to baseline.
o Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.
- Interferon therapy within 8 weeks prior to baseline.
- Subjects with prior treatment with lymphocyte-depleting agents/therapies within 1 year prior to baseline(eg, CamPath® [alemtuzumab], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc).
- Subjects who have received rituximab or other selective B lymphocyte-depleting agents within 1 year prior to baseline.
- Subjects previously receiving leukocyte apheresis, including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
- Other marketed immunosuppressants or biologics with immunomodulatory properties within 3 months prior to baseline.
- Other investigational procedures(s) or product(s), such as immunosuppressants used in transplantation (eg, mycophenolate mofetil, cyclosporine, rapamycin, or tacrolimus) or live (attenuated) vaccine within 30 days prior to baseline.
- Other JAK inhibitors within 3 months prior to baseline. Subjects who have not responded to or have been intolerant of other JAK inhibitors.
Participation in other studies involving investigational drug(s) within 30 days, or 5 half lives of investigational product (IP) (whichever is greater), prior to study entry and/or during study participation.;Please refer to the protocol for additional exclusion criteria