Ensayos clínicos

Inclusion Criteria:

• Male or female ≥ 16 and ≤ 75 years of age at Baseline.
  • Adolescent subjects at the age of 16 and 17 years old will be enrolled if approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects ≥ 18 years old will be enrolled.
  • Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40 kg and meet the definition of Tanner Stage 5 at the screening visit.
• Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available.
• Active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopic sub score of 2 to 3 (confirmed by central reader).
• Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following treatments including, oral aminosalicylates, corticosteroids, immunosuppressants and/or biologic therapies, in the opinion of the investigator as defined below:
  • Note: An inadequate response, loss of response, or intolerance to Oral Aminosalicylates will NOT count towards eligibility for the following countries:
    • Austria, Czechia, Finland, Ireland, Italy, Latvia, Lithuania, Norway, Poland, Portugal, Spain, Sweden and United Kingdom.
  • Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide):
    • Signs and symptoms of persistently active disease, in the opinion of the investigator, during a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide.
  • Corticosteroids:
    • Signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week, OR
    • Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease, OR
    • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone, OR
    • Unable to taper oral budesonide to at or below 6 mg/day without recurrent active disease, OR
    • History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection).
  • Immunosuppressants:
    • Signs and symptoms of persistently active disease despite a history of at least one 90 day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan only: ≥ 1.0 mg/kg/day), 6-MP (≥ 1 mg/kg/day; [for subjects in Japan, China, and Taiwan only: ≥ 0.6 mg/kg/day, rounded to the nearest available tablet of half tablet formulation] or a documented 6-TGN level of 230 –450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable MTX (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in Japan and Taiwan only: documented trough level of 5 –10 ng/mL); OR
    • History of intolerance to at least one immunosuppressant (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection).
      • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study unless these subjects were previously treated with aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate response to, loss of response to or intolerance to the therapy as defined above.
  • Biologic Agents for UC:
    • Signs and symptoms of persistently active disease despite a history of any of the following:
      • at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 6 weeks);
      • at least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous (SC) dose followed by one 80 mg SC dose [or one 80 mg SC dose, in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart);
      • at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed by one 100 mg SC dose at least 2 weeks apart);
      • at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2 and 6 weeks); OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify); OR
    • History of intolerance to at least one biologic agent (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection).
      • Note: Non-bio-IR subjects who have received a prior biologic for up to 1 year may be enrolled, however, subjects must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticorsteroids and/or immunosuppressants as defined above.
• Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior to study drug dosing.
  • Note: subjects with borderline serum pregnancy test at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of positive result.
  • For subjects in Ireland, a repeat serum pregnancy test ≥ 3 days later that is still borderline will result in screen failure.
  • If female, subject must meet the contraception criteria.
• Subject is judged to be in otherwise good health as determined by the Investigator based upon the results of medical history, laboratory profile, physical examination and a 12-lead electrocardiogram (ECG) performed during Screening.
• Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol. In Japan, if the subject is < 20 years old, a subject's parent or legal guardian must be willing to give written informed consent.

Exclusion Criteria:

• Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
• History of colectomy (total or subtotal) with ileoanal pouch, Kock pouch, or ileostomy for UC or is planning bowel surgery.
• Received treatment with rectal aminosalicylates or corticosteroids, other enemas/suppositories (other than required for endoscopy), within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
• Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to Baseline.
• Subjects who received azathioprine or 6-mercaptopurine within 10 days of Baseline.
• Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject on MTX or oral aminosalicylates who:
  • has not been on the current course of MTX for at least 42 days prior to Baseline, and has not been on stable doses for at least 28 days prior to Baseline;
  • has not been on stable doses of oral aminosalicylates for at least 14 days prior to Baseline;
  • has discontinued use of aminosalicylates within 14 days of Baseline.
• Subject on treatment with corticosteroids who meet the following:
  • Oral corticosteroid dose > 30 mg/day (prednisone or equivalent) or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral budesonide dose > 9 mg/day or has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral beclomethasone dose > 5 mg/day or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline.
  • Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject has active TB or meets TB exclusionary parameters.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject on UC-related antibiotics who has not been on stable doses for at least 14 days prior to Baseline or has discontinued these medications within 14 days of Baseline.
• Subjects who received any of the following biologic therapy:
  • infliximab, certolizumab, adalimumab, golimumab, vedolizumab, natalizumab, within 8 weeks prior to Baseline; OR
  • ustekinumab within 12 weeks prior to Baseline.
  • Note: If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib).
• Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topical NSAIDs and the use of low dose aspirin for cardiovascular [CV] protection) within 7 days prior to Baseline.
• Subject received traditional Chinese medicine within 30 days prior to baseline.
• Subject received live vaccine(s) within 30 days (8 weeks for Japan) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (8 weeks for Japan) after the last dose of study drug.
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers during the Screening Period and through the end of the study.
• Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during study treatment.
• Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to Baseline, whichever is longer or is currently enrolled in an interventional study.
• Subject with positive C. difficile toxin stool assay during Screening.
• Infection(s) requiring treatment with intravenous anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit.
• Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
• Subject has current or past history of recurrent or disseminated (even a single episode) herpes zoster.
• Subject has current or past history of disseminated (even a single episode) herpes simplex.
• Subject has HBV, HCV, or human immunodeficiency virus (HIV) infection defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for subjects who are hepatitis B core antibody (HBc Ab) positive (+) subjects (and for Hepatitis B surface antibody positive (+) subjects where mandated by local requirements);
  • HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab);
  • HIV: confirmed positive anti-HIV antibody (HIV Ab).
• Prior or current gastrointestinal (GI) dysplasia, other than completely removed lowgrade dysplastic lesion in any biopsy performed during or before the Screening endoscopy.
• History of any malignancy, except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
• History of gastrointestinal (GI) perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased risk of GI perforation per investigator's judgment.
• Screening laboratory and other analyses show any of the following abnormal results:
  • Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2 × upper limit of normal (ULN);
  • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
  • Total White Blood Cell (WBC) count < 2,500/μL;
  • Absolute neutrophil count (ANC) < 1,200/μL;
  • Platelet count < 100,000/μL;
  • Absolute lymphocytes count < 750/μL;
  • Hemoglobin < 9 g/dL.
• Female subject who is pregnant, breastfeeding or considering becoming pregnant during the study or within 30 days after the last dose of study drug, or has positive pregnancy test at Screening (serum) or Baseline (urine).
• History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
• History of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• For Japan subjects only: positive result of beta-D-glucan or two consecutive indeterminate results of beta-D-glucan (screening for Pneumocystis jiroveci infection).
• Received cytoapheresis treatment (GCAP, LCAP etc.) within 60 days prior to Baseline.
• For Japan subjects only: received ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline and metronidazole) during the Screening Period.
• Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting or Moderate to severe congestive heart failure (New York Heart Association class III or IV).
• Conditions that could interfere with drug absorption including but not limited to short bowel syndrome (e.g., history of gastric bypass surgery).
• History of clinically significant medical condition or any other reason which, in the opinion of the investigator, would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the protocol.