Efficacy and Safety Study of SHP647 as Induction Therapy in Participants With Moderate to Severe Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: Ontamalimab; Placebo
Intervention description: Participants will receive 1 mL of ontamalimab sterile aqueous buffered solution at an appropriate concentration to provide the intended dose of drug (25 or 75 mg).; Participants will receive 1 mL of sterile aqueous buffered solution.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 279.0
Sex: All
Minimum age: 16 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the efficacy of SHP647 in inducing remission, based
      on composite score of patient-reported symptoms and centrally read endoscopy, in participants
      with moderate to severe ulcerative colitis (UC).
    

Eligibility criteria:

        Inclusion Criteria:

        - Participants and/or their parent or legally authorized representative must have an
        understanding, ability, and willingness to fully comply with study procedures and
        restrictions.

          -  Participants must be able to voluntarily provide written, signed, and dated informed
             consent 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 mass
             index (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 documenting
             disease duration based upon prior colonoscopy. Note: If this documentation is not
             available at the time of screening, a colonoscopy with biopsy to confirm the diagnosis
             is 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 inclusion
             criteria 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, not
             limited to proctitis).

          -  Participants must have had an inadequate response to, or lost response to, or had an
             intolerance 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 of
             nonchildbearing potential.

        Exclusion Criteria:

          -  Participants with indeterminate colitis, microscopic colitis, non-steroidal
             anti-inflammatory drug-induced colitis, ischemic colitis, infectious colitis, or
             clinical/histologic findings suggestive of Crohn's disease.

          -  Participants with colonic dysplasia or neoplasia. (Participants with prior history of
             adenomatous 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, a
             history of bowel surgery within 6 months before screening, or who are likely to
             require surgery for UC during the treatment period.

          -  Participants at risk for colorectal cancer must have a colonoscopy performed during
             the screening period with results available within 10 days before the baseline visit,
             unless the participant has had a surveillance colonoscopy performed within 1 year
             prior to screening, and any adenomatous polyps found at that examination have been
             excised. Colonoscopy report and pathology report (if biopsies are obtained) from the
             colonoscopy performed during screening or in the prior year confirming no evidence of
             dysplasia 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 of
             colon (ie, distal to splenic flexure) for >=10 years before screening, regardless of
             age.

          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 the
             investigational product(s), closely related compounds, or any of the stated
             ingredients.

             - Participants have received anti-TNF treatment within 60 days before baseline.

             - Participants have received any biologic with immunomodulatory properties (other than
             anti-TNFs) within 90 days before baseline.

             - Participants have received any nonbiologic treatment with immunomodulatory
             properties (other than their current background UC treatment) within 30 days before
             baseline.

             - Participants have ever received anti-integrin/adhesion molecule treatment (example
             (eg): natalizumab, vedolizumab, efalizumab, etrolizumab, or any other investigational
             anti-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 30
                  days or 5 half-lives of investigational product used in the study (whichever is
                  longer) before baseline.

               -  Participants have received a live (attenuated) vaccine within 30 days before the
                  baseline visit.

               -  Participants with active enteric infections (positive stool culture and
                  sensitivity), Clostridium difficile infection or pseudomembranous colitis
                  [Participants with C. difficile infection at screening may be allowed re-test
                  after treatment], evidence of active cytomegalovirus infection or Listeria
                  monocytogenes, known active invasive fungal infections such as histoplasmosis or
                  parasitic infections, clinically significant underlying disease that could
                  predispose the participants to infections, or a history of serious infection
                  (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before
                  the baseline visit.

               -  Participants with abnormal chest x-ray findings at screening, such as presence of
                  active tuberculosis (TB), general infections, heart failure, or malignancy.

               -  Participants with evidence of active or latent infection with Mycobacterium TB or
                  participants with this history who have not completed a generally accepted full
                  course of treatment before randomization are excluded. All other participants
                  must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin
                  test or interferon gamma release assay (IGRA) performed.

        Participants who have no history of previously diagnosed active or latent TB are excluded
        if 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 performed
        locally, 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 product
             used and the test result must be in the participant's source documentation if
             performed locally. Acceptable IGRA products include QuantiFERON TB Gold Plus In-Tube
             Test.

          2. If the results of the IGRA are indeterminate, the test may be repeated, and if a
             negative result is obtained, enrollment may proceed. In participants with no history
             of treated active or latent TB, a positive test on repeat will exclude the
             participant. Participants with a history of active or latent TB infection must follow
             instructions for "Participants with a prior diagnosis of active or latent TB are
             excluded unless both of the following criteria are met" in this criterion.

          3. Participants with repeat indeterminate IGRA results, with no prior TB history, may be
             enrolled after consultation with a pulmonary or infectious disease specialist who
             determines low risk of infection (ie, participant would be acceptable for
             immunosuppressant [eg, anti-TNF] treatment without additional action). This
             consultation must be included in source documentation.

        Results from a chest x-ray, taken within the 12 weeks before or during screening must show
        no abnormalities suggestive of active TB infection as determined by a qualified medical
        specialist.

        Participants with a prior diagnosis of active or latent TB are excluded unless both of the
        following criteria are met:

          1. The participant has previously received an adequate course of treatment for either
             latent (eg, 9 months of isoniazid or an acceptable alternative regimen, in a locale
             where rates of primary multidrug TB resistance are <5%. Participants from regions with
             higher rates of primary multidrug TB resistance are excluded) or active (acceptable
             multidrug regimen) TB infection. Evidence of diagnosis and treatment must be included
             in source documentation. Consultation with a pulmonary or infectious disease
             specialist to confirm adequate treatment (ie, participant would be acceptable for
             immunosuppressant [eg, anti-TNF] treatment without additional action) must be
             performed during the screening period. The consultation report must be included in
             source documentation prior to enrollment.

          2. A chest x-ray performed within 12 weeks before screening or during screening indicates
             no evidence of active or recurrent disease, and documentation of interpretation by a
             qualified medical specialist must be included in source documentation.

               -  Participants with a pre-existing demyelinating disorder such as multiple
                  sclerosis or new onset seizures, unexplained sensory motor, or cognitive
                  behavioral, neurological deficits, or significant abnormalities noted during
                  screening.

               -  Participants with any unexplained symptoms suggestive of progressive multifocal
                  leukoencephalopathy (PML) based on the targeted neurological assessment during
                  the screening period.

               -  Participants with a transplanted organ. Skin grafts to treat pyoderma gangrenosum
                  are allowed.

               -  Participants with a significant concurrent medical condition at the time of
                  screening 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 active
             infection/infectious illness) that, in the investigator's judgment will substantially
             increase 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, or
             carcinoma in situ of the uterine cervix that has been treated with no evidence of
             recurrence).

          3. Presence of acute coronary syndrome (eg, acute myocardial infarction, unstable angina
             pectoris) 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 before
             the screening visit, or with any major elective surgery scheduled to occur during the
             study.

             - Participants with evidence of cirrhosis with or without decompensation.

             - Participants with primary sclerosing cholangitis.

             - Participants with evidence of positive hepatitis B surface antigen (HBsAg) or
             hepatitis B core antibody (HBcAb).

             Note: If a participant tests negative for HBsAg, but positive for HBcAb, the
             participant would be considered eligible if no presence of hepatitis B virus (HBV) DNA
             is confirmed by HBV DNA polymerase chain reaction (PCR) reflex testing performed in
             the 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 be
             considered 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 serum
                  chemistry profiles during screening.

             Note: Screening laboratory tests, if the results are considered by the investigator to
             be transient and inconsistent with the participant's clinical condition, may be
             repeated once during the screening period for confirmation. Results must be reviewed
             for eligibility prior to the screening endoscopy procedure.

          1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >=3.0×upper
             limit of normal (ULN).

          2. Total bilirubin level >=1.5×ULN or >2.0×ULN if the participant has a known documented
             history 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 <30
             ml/min/1.73m^2 based on the abbreviated Modification of Diet in Renal Disease Study
             Equation.

             Note: If platelet count is <150,000 cells/mm^3, a further evaluation should be
             performed to rule out cirrhosis, unless another etiology has already been identified.

               -  Participants with known human immunodeficiency virus (HIV) infection based on
                  documented history, with positive serological test, or positive HIV serologic
                  test at screening, tested at the site's local laboratory in accordance with
                  country requirements or tested at the central laboratory.

             Note: A documented negative HIV test within 6 months of screening is acceptable and
             does 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 dependency
             of any kind, including abuse of medical marijuana (cannabis).

             - Participants with any other severe acute or chronic medical or psychiatric condition
             or laboratory or electrocardiogram (ECG) abnormality that may increase the risk
             associated with study participation or investigational product administration or may
             interfere with the interpretation of study results and, in the judgment of the
             investigator, 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 female
                  participants who are planning to harvest or donate eggs, for the duration of the
                  study and through 16 weeks after last dose of investigational product.

               -  Participants who are investigational site staff members or relatives of those
                  site staff members or Participants who are Shire employees directly involved in
                  the conduct of the study.