Efficacy and Safety Study of SHP647 as Induction Therapy in Participants With Moderate to Severe Ulcerative Colitis

Inclusion Criteria:

• Participants and/or their parent or legally authorized representative must have anunderstanding, ability, and willingness to fully comply with study procedures andrestrictions.
• Participants must be able to voluntarily provide written, signed, and dated informedconsent and/or assent, as applicable, to participate in the study.
• Participants less than (<) 18 years of age must weigh >=40 kg and must have body massindex (BMI) >=16.5 kilogram per square metre (kg/m^2).
• Participants must have a documented diagnosis of UC for >=3 months before screening.The following must be available in each participant's source documentation: a. A biopsy report to confirm the histological diagnosis. b. A report documentingdisease duration based upon prior colonoscopy. Note: If this documentation is notavailable at the time of screening, a colonoscopy with biopsy to confirm the diagnosisis required during the screening period.
• Participants must be willing to undergo a flexible sigmoidoscopy or colonoscopy,including biopsy sample collection, during screening after all other inclusioncriteria have been met.
• Participants must have moderate to severe active UC, defined as a total Mayo score of >=6, including a centrally read endoscopic subscore >=2, rectal bleeding subscore >=1,and stool frequency subscore >=1 at baseline.
• Participants must have evidence of UC extending proximal to the rectum (ie, notlimited to proctitis).
• Participants must have had an inadequate response to, or lost response to, or had anintolerance to at least 1 conventional treatment such as mesalamine (5-aminosalicylate [ASA]), glucocorticoids, immunosuppressants (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]), or anti-tumor necrosis factor (TNF).
• Participants receiving any treatment(s) for UC are eligible provided they have been,and are anticipated to be, on a stable dose for the designated period of time.
• Participants are males or nonpregnant, nonlactating females who, if sexually active,agree to comply with the contraceptive requirements of the protocol, or females ofnonchildbearing potential.

Exclusion Criteria:

• Participants with indeterminate colitis, microscopic colitis, non-steroidalanti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis, orclinical/histologic findings suggestive of Crohn's disease.
• Participants with colonic dysplasia or neoplasia. (Participants with prior history ofadenomatous polyps will be eligible if the polyps have been completely removed.)
• Participants with past medical history or presence of toxic megacolon.
• Participants with colonic stricture, past medical history of colonic resection, ahistory of bowel surgery within 6 months before screening, or who are likely torequire surgery for UC during the treatment period.
• Participants at risk for colorectal cancer must have a colonoscopy performed duringthe screening period with results available within 10 days before the baseline visit,unless the participant has had a surveillance colonoscopy performed within 1 yearprior to screening, and any adenomatous polyps found at that examination have beenexcised. Colonoscopy report and pathology report (if biopsies are obtained) from thecolonoscopy performed during screening or in the prior year confirming no evidence ofdysplasia and colon cancer must be available in the source documents. Participants at risk for colorectal cancer include, but are not limited to:

1. Participants with extensive colitis for >=8 years or disease limited to left side ofcolon (ie, distal to splenic flexure) for >=10 years before screening, regardless ofage.
2. Participants >=50 years of age at the time of signing of the informed consent form.

• Participants have had prior treatment with ontamalimab (formerly PF-00547659,SHP647).
• Participants with known or suspected intolerance or hypersensitivity to theinvestigational product(s), closely related compounds, or any of the statedingredients.
• Participants have received anti-TNF treatment within 60 days before baseline.
• Participants have received any biologic with immunomodulatory properties (other thananti-TNFs) within 90 days before baseline.
• Participants have received any nonbiologic treatment with immunomodulatoryproperties (other than their current background UC treatment) within 30 days beforebaseline.
• Participants have ever received anti-integrin/adhesion molecule treatment (example (eg): natalizumab, vedolizumab, efalizumab, etrolizumab, or any other investigationalanti-integrin/adhesion molecule).
• Participants have received parenteral or rectal glucocorticoids, or rectal 5-ASA,within 14 days before screening endoscopic procedure.
• Participants have received leukocyte apheresis or selective lymphocyte, monocyte,or granulocyte apheresis or plasma exchange within 30 days before baseline.
• Participants have participated in other investigational studies within either 30days or 5 half-lives of investigational product used in the study (whichever islonger) before baseline.
• Participants have received a live (attenuated) vaccine within 30 days before thebaseline visit.
• Participants with active enteric infections (positive stool culture andsensitivity), Clostridium difficile infection or pseudomembranous colitis [Participants with C. difficile infection at screening may be allowed re-testafter treatment], evidence of active cytomegalovirus infection or Listeriamonocytogenes, known active invasive fungal infections such as histoplasmosis orparasitic infections, clinically significant underlying disease that couldpredispose the participants to infections, or a history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks beforethe baseline visit.
• Participants with abnormal chest x-ray findings at screening, such as presence ofactive tuberculosis (TB), general infections, heart failure, or malignancy.
• Participants with evidence of active or latent infection with Mycobacterium TB orparticipants with this history who have not completed a generally accepted fullcourse of treatment before randomization are excluded. All other participantsmust have either the Mantoux (purified protein derivative [PPD]) tuberculin skintest or interferon gamma release assay (IGRA) performed. Participants who have no history of previously diagnosed active or latent TB are excludedif they have a positive Mantoux (PPD) tuberculin skin test (ie >=5 millimeter [mm]induration) or a positive IGRA (the latter to be tested at the site's local laboratory)during screening or within 12 weeks before screening. If IGRA test cannot be performedlocally, a central laboratory may be used, with prior agreement from the sponsor.

1. An IGRA is strongly recommended for participants with a prior Bacillus Calmette-Guerin (BCG) vaccination, but may be used for any participant. Documentation of IGRA productused and the test result must be in the participant's source documentation ifperformed locally. Acceptable IGRA products include QuantiFERON TB Gold Plus In-TubeTest.
2. If the results of the IGRA are indeterminate, the test may be repeated, and if anegative result is obtained, enrollment may proceed. In participants with no historyof treated active or latent TB, a positive test on repeat will exclude theparticipant. Participants with a history of active or latent TB infection must followinstructions for "Participants with a prior diagnosis of active or latent TB areexcluded unless both of the following criteria are met" in this criterion.
3. Participants with repeat indeterminate IGRA results, with no prior TB history, may beenrolled after consultation with a pulmonary or infectious disease specialist whodetermines low risk of infection (ie, participant would be acceptable forimmunosuppressant [eg, anti-TNF] treatment without additional action). Thisconsultation must be included in source documentation. Results from a chest x-ray, taken within the 12 weeks before or during screening must showno abnormalities suggestive of active TB infection as determined by a qualified medicalspecialist. Participants with a prior diagnosis of active or latent TB are excluded unless both of thefollowing criteria are met:
4. The participant has previously received an adequate course of treatment for eitherlatent (eg, 9 months of isoniazid or an acceptable alternative regimen, in a localewhere rates of primary multidrug TB resistance are <5%. Participants from regions withhigher rates of primary multidrug TB resistance are excluded) or active (acceptablemultidrug regimen) TB infection. Evidence of diagnosis and treatment must be includedin source documentation. Consultation with a pulmonary or infectious diseasespecialist to confirm adequate treatment (ie, participant would be acceptable forimmunosuppressant [eg, anti-TNF] treatment without additional action) must beperformed during the screening period. The consultation report must be included insource documentation prior to enrollment.
5. A chest x-ray performed within 12 weeks before screening or during screening indicatesno evidence of active or recurrent disease, and documentation of interpretation by aqualified medical specialist must be included in source documentation.

• Participants with a pre-existing demyelinating disorder such as multiplesclerosis or new onset seizures, unexplained sensory motor, or cognitivebehavioral, neurological deficits, or significant abnormalities noted duringscreening.
• Participants with any unexplained symptoms suggestive of progressive multifocalleukoencephalopathy (PML) based on the targeted neurological assessment duringthe screening period.
• Participants with a transplanted organ. Skin grafts to treat pyoderma gangrenosumare allowed.
• Participants with a significant concurrent medical condition at the time ofscreening or baseline, including, but not limited to, the following:

1. Any major illness/condition or evidence of an unstable clinical condition (eg, renal,hepatic, hematologic, gastrointestinal (except disease under study), endocrine,cardiovascular, pulmonary, immunologic [eg, Felty's syndrome], or local activeinfection/infectious illness) that, in the investigator's judgment will substantiallyincrease the risk to the participant if he or she participates in the study.
2. Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell carcinoma, squamous cell carcinoma, orcarcinoma in situ of the uterine cervix that has been treated with no evidence ofrecurrence).
3. Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable anginapectoris) within 24 weeks before screening.
4. History of significant cerebrovascular disease within 24 weeks before screening.

• Participants who have had significant trauma or major surgery within 4 weeks beforethe screening visit, or with any major elective surgery scheduled to occur during thestudy.
• Participants with evidence of cirrhosis with or without decompensation.
• Participants with primary sclerosing cholangitis.
• Participants with evidence of positive hepatitis B surface antigen (HBsAg) orhepatitis B core antibody (HBcAb). Note: If a participant tests negative for HBsAg, but positive for HBcAb, theparticipant would be considered eligible if no presence of hepatitis B virus (HBV) DNAis confirmed by HBV DNA polymerase chain reaction (PCR) reflex testing performed inthe central laboratory.
• Participants with chronic hepatitis C virus (HCV) (positive HCV antibody [HCVAb]and HCVRNA). Note: Participants who are HCVAb positive without evidence of HCV RNA may beconsidered eligible (spontaneous viral clearance or previously treated and cured [defined as no evidence of HCVRNA at least 12 weeks prior to baseline]).
• Participants with any of the following abnormalities in hematology and/or serumchemistry profiles during screening. Note: Screening laboratory tests, if the results are considered by the investigator tobe transient and inconsistent with the participant's clinical condition, may berepeated once during the screening period for confirmation. Results must be reviewedfor eligibility prior to the screening endoscopy procedure.

1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >=3.0×upperlimit of normal (ULN).
2. Total bilirubin level >=1.5×ULN or >2.0×ULN if the participant has a known documentedhistory of Gilbert's syndrome.
3. Hemoglobin level <=80 gram per liter (g/L) (8.0 gram per deciliter [g/dL]).
4. Platelet count <=100×10^9 per liter (/L) (100,000 cells per cubic millimeter [mm^3])or >=1000×10^9/L (1,000,000 cells/mm^3).
5. White blood cell count <=3.5×10^9/L (3500 cells/mm^3).

• Absolute neutrophil count (ANC)<2×10^9/L (2000 cells/mm^3).
• Serum creatinine level >1.5 × ULN or estimated glomerular filtration rate <30ml/min/1.73m^2 based on the abbreviated Modification of Diet in Renal Disease StudyEquation. Note: If platelet count is <150,000 cells/mm^3, a further evaluation should beperformed to rule out cirrhosis, unless another etiology has already been identified.
• Participants with known human immunodeficiency virus (HIV) infection based ondocumented history, with positive serological test, or positive HIV serologictest at screening, tested at the site's local laboratory in accordance withcountry requirements or tested at the central laboratory. Note: A documented negative HIV test within 6 months of screening is acceptable anddoes not need to be repeated.
• Participants who have, or who have a history of (within 2 years before screening),serious psychiatric disease, alcohol dependency, or substance/drug abuse or dependencyof any kind, including abuse of medical marijuana (cannabis).
• Participants with any other severe acute or chronic medical or psychiatric conditionor laboratory or electrocardiogram (ECG) abnormality that may increase the riskassociated with study participation or investigational product administration or mayinterfere with the interpretation of study results and, in the judgment of theinvestigator, would make the participant inappropriate for entry into this study.
• Female participants who are planning to become pregnant during the study period.
• Participants who do not agree to postpone donation of any organ or tissue,including male participants who are planning to bank or donate sperm and femaleparticipants who are planning to harvest or donate eggs, for the duration of thestudy and through 16 weeks after last dose of investigational product.
• Participants who are investigational site staff members or relatives of thosesite staff members or Participants who are Shire employees directly involved inthe conduct of the study.