• Proportion of subjects in remission at Week 16 (ie, total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, without the use of corticosteroids). [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
• Average remission rate. [ Time Frame: over duration of treatment ] [ Designated as safety issue: No ]

• Proportion of subjects in response at Week 8 (a decrease in the partial Mayo score of ≥1 point) and Week 16 (ie, a decrease in total Mayo score of ≥3 points and at least 30% lower than baseline Mayo score). [ Time Frame: 8 and 16 weeks ] [ Designated as safety issue: No ]
• The proportion of subjects who are in remission [ Time Frame: Week 38, 62 & 94 (Weeks 22, 46, and 78 for direct entry). ] [ Designated as safety issue: No ]

Part 1 of this study is a 3-arm, randomized, active-controlled, parallel-group, multicenter, double-blind, double-dummy, 16-week study to compare the efficacy and safety of infliximab, as monotherapy or in combination with AZA versus AZA monotherapy in adults with moderate to severe active UC. Subjects who qualify at the Baseline Visit will be eligible to be randomized to one of the three active treatment groups.

Subjects in the infliximab/AZA combination therapy and infliximab monotherapy cohorts will receive infliximab infusions at Weeks 0, 2, and 6 and daily oral AZA/placebo, respectively; subjects in the AZA cohort will receive daily oral AZA and placebo infusions at Weeks 0, 2, and 6. At Week 8, all subjects will be evaluated for response.

Subjects responding to infliximab treatment at Week 8, either as monotherapy or in combination with AZA, will receive one more infliximab infusion at Week 14; nonresponders to infliximab therapy will receive placebo infusions at Weeks 8 and 10 and one additional infliximab infusion at Week 14.

Subjects responding to AZA monotherapy at Week 8 will continue on AZA therapy and receive one infliximab placebo infusion at Week 14; nonresponders to AZA will be eligible to receive infliximab at Weeks 8, 10, and 14.

Part 2: Subjects in remission on infliximab monotherapy or infliximab/AZA treatment at Week 16 will be randomized to either maintenance or intermittent open-label infliximab treatment; randomization will be stratified based on oral AZA/placebo treatment in Part 1. Oral AZA/placebo treatment will continue to be double-blinded. All subjects will continue to receive oral AZA/ placebo for the duration of the study.

In addition, to facilitate enrollment into Part 2, subjects who received treatment outside of Part 1 and who are in remission on infliximab with or without AZA/6-MP will be allowed to enter directly into Part 2. In the Czech Republic, direct entry into Part 2 of the study is not allowed. Subjects will be randomized to either maintenance or intermittent open -label infliximab treatment. Subjects will continue with open-label oral AZA/6-MP, if applicable. These subjects will be stratified based on oral AZA/6-MP use.

Subjects randomized to maintenance infliximab treatment will receive scheduled infusions every 8 weeks beginning at Week 22 (Week 6 for direct entry). If subjects lose response, or if treatment has to be discontinued because of an adverse event, these subjects are considered treatment failures, and should be followed up for safety at the scheduled 6-month visits (Weeks 38, 62, and 94 [Weeks 22, 46, and 78 for direct entry]). These subjects will receive standard of care per their personal physician.

Subjects randomized to intermittent infliximab treatment will be evaluated every 8 weeks. Subjects will receive infliximab only upon relapse of disease. Infliximab treatment will be initiated at Weeks 0, 2, and 6 of the individual treatment cycle and will continue every 8 weeks until remission is regained. Throughout the study, individual treatment cycles will be repeated whenever a subject relapses.

• Biological: Infliximab
• Drug: Azathioprine
• Drug: Azathioprine / Infliximab

Inclusion Criteria:

• Subjects must be >=21 years of age at the time of informed consent, of either sex, and of any race;
• Subjects must have endoscopic evidence of UC, as determined by sigmoidoscopy, within 14 days prior to Baseline;
• Subjects must have a total Mayo score of 6 to 12 points at Baseline;
• Subjects must have responded inadequately to corticosteroid treatment (ie, the last or current UC flare did not respond adequately to a standard course of corticosteroids) with or without 5 aminosalicylic acid (5-ASA);
• Subjects must be off corticosteroids or on a stable dose of corticosteroid for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroid at Baseline must not exceed the equivalent of 30 mg of prednisone;
• Subjects must be naïve to infliximab and other tumor necrosis factor-alpha (TNF-α) antagonists;
• Subjects must be either naïve to AZA/6-MP or have not received AZA/6-MP for at least 3 months before enrollment in the study;

• Subjects are considered eligible according to the following tuberculosis (TB) screening criteria:

  • Have no history of latent or active TB prior to Screening;
  • Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination;
  • Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of infliximab;
  • Within 1 month prior to the first administration of infliximab, either have negative tuberculin skin test OR have a newly identified positive tuberculin test during Screening in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of infliximab.
  • Subjects must have a chest X-ray (posterior-anterior and lateral views), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old active TB;
• Subjects who have had UC for more than 10 years should have had a full colonoscopy within 2 years prior to Screening for the surveillance of dysplasia;
• Subjects' Screening and Baseline clinical laboratory tests (complete blood count [CBC] and blood chemistries) must be within predetermined parameters
• Subjects who had been on antibiotics for the treatment of UC (eg, ciprofloxacin and metronidazole) must have been discontinued from them at least 3 weeks prior to Screening;
• Subjects must be free of any clinically significant condition or situation, other than UC that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study;
• Subjects are willing and able to adhere to the study visit schedule and other protocol requirements;
• Subjects are capable of providing written informed consent, which must be obtained prior to conducting any protocol-specified procedures;
• Women of child-bearing potential and all men must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 6 months after stopping the medication. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), oral or injectable hormonal contraceptive, and surgical sterilization (eg, hysterectomy or tubal ligation). Women of child-bearing potential who are not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study;
• Female subjects of childbearing potential must have a negative serum pregnancy test (beta-hCG) at Screening and a negative urine pregnancy test at Baseline.

Exclusion Criteria:

• Subjects have severe extensive colitis as evidenced by:

  • Investigator judgment that the subject is likely to require colectomy within 12 weeks of Baseline OR

  • Subjects with at least 4 of these symptoms at Screening or Baseline visits, as follows:

    • diarrhea with >=6 bowel movements/day with macroscopic blood in stool;
    • focal severe or rebound abdominal tenderness;
    • persistent fever (>=37.5 degrees C) for at least 3 days prior to baseline;
    • tachycardia (>100 beats/minute);
    • hemoglobin <8.5 g/dL (5.3 mM/L).
• Subjects who require, or are required within the 2 months prior to baseline, surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage or other conditions possibly confounding the evaluation of disease activity;
• Subjects who have severe, fixed symptomatic stenosis of the large or small intestine;
• Subjects who have current evidence of colonic obstruction or history within the 6 months prior to baseline, confirmed with objective radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation of the colon proximal to the stricture on barium radiograph or an inability to traverse the stricture at endoscopy);
• Subjects who have a history of colonic mucosal dysplasia;
• Presence on screening endoscopy of adenomatous colonic polyps, if not removed prior to study entry, or history of adenomatous colonic polyps that were not removed;
• Subjects who have the presence of a stoma;
• Subjects who have a history of extensive colonic resection that would prevent adequate evaluation of clinical disease activity (eg, less than 30 cm of colon remaining);
• Have a positive stool culture for enteric pathogens, pathogenic ova or parasites within 4 months prior to Baseline unless subject has received treatment and had a negative stool examination 1 week or longer after the end of treatment;
• Subjects who have a concomitant diagnosis of congestive heart failure (CHF), including medically controlled asymptomatic subjects;
• Subjects who have had serious infections (eg, active hepatitis, pneumonia, or pyelonephritis) within 2 months of screening. Less serious infections (such as acute upper respiratory tract infection [colds] or a simple urinary tract infection) need not be considered as an exclusion at the discretion of the investigator;
• Subjects who have had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months prior to Screening;
• Subjects who have a known infection with human immunodeficiency virus (HIV) and/or hepatitis B or hepatitis C;
• Subjects who have a history of a known allergy to murine proteins or allergy/sensitivity to study drug or its excipients;
• Subjects who have current signs and symptoms of systemic lupus erythematosus, or severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral diseases;
• Subjects who have a known history of demyelinating disease suggestive of multiple sclerosis or optic neuritis;
• Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening);
• Subjects who have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (eg, nodes in the posterior triangle of the neck, infra-clavicular, epitrochlear, or periaortic areas), or splenomegaly;
• Subjects who have any current known malignancy or malignancy within 5 years prior to screening (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence);
• Subjects who have poor tolerability of venipuncture or lack of adequate venous access for required blood sampling and infusion of study drug during the study period;
• Subjects who have had a known substance abuse or dependency (drug or alcohol) within 3 years of Screening;
• Subjects who require chronic (>=1 month) and frequent use (>=3 days per week)of nonsteroidal anti-inflammatory drugs (NSAIDs) except low-dose aspirin for prevention of heart attacks, unstable angina, or transient ischemic attacks;
• Subjects who have other inflammatory diseases that might interfere with the evaluation of the ulcerative colitis;
• Subjects who have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to Screening.
• Subjects who have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of Screening.
• Subjects who have a chest X-ray within the 3 months prior to the first administration of study agent that shows an abnormality suggestive of malignancy or current active infection, including TB.
• Subjects who have received any specified prohibited treatment more recently than the indicated washout period prior to Screening;
• Subjects who are participating in any other clinical study or who have received treatment with any investigational drug or device within 3 months prior Screening;
• Subject who is part of the staff or a family member of the staff personnel directly involved with this study.