A Phase 3 Randomized, Double-blind, Placebo-controlled, Parallel-group Efficacy and Safety Study of SHP647 as Induction Therapy in Subjects With Moderate to Severe Ulcerative Colitis (FIGARO UC 301)
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).
16 Years to 80 Years
Accepting Healthy Volunteers?
- 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.
- 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.
- 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 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, general infections, heart failure, or malignancy.
- Participants with evidence of active or latent infection with Mycobacterium tuberculosis (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 tuberculosis 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 randomization. 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 tuberculosis, a positive test on repeat will exclude the participant. Participants with a history of active or latent tuberculosis infection must follow instructions for "Participants with a prior diagnosis of active or latent tuberculosis 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 3 months 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 tuberculosis 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 3 months prior to 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 HBV DNA is confirmed by HBV DNA PCR reflex testing performed in the central laboratory.
- Participants with chronic hepatitis C (HCV) (positive HCVAb and HCVRNA). Note: Participants who are HCVAb positive without evidence of HCVRNA 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.
a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels >=3.0×upper limit of normal (ULN).
b. Total bilirubin level >=1.5×ULN or >2.0×ULN if the participant has a known documented history of Gilbert's syndrome.
c. Hemoglobin level <=80 gram per liter (g/L) (8.0 gram per deciliter [g/dL]). d. 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).
e. 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 (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.