Efficacy & Safety of Infliximab Monotherapy Vs Combination Therapy Vs AZA Monotherapy in Ulcerative Colitis (Part 1) Maintenance Vs Intermittent Therapy for Maintaining Remission (Part 2)(Study P04807)
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: Infliximab (IFX); Azathioprine (AZA); Placebo to Azathioprine; Placebo infusion
Intervention description: IFX intravenous (IV) infusion dosed at 5mg/kg of body weight; AZA 50 mg tablet dosed at 2.5 mg/kg of body weight orally every day; Placebo to AZA tablet orally every day; Placebo to IFX intravenous (IV) infusion
Intervention MeSH terms: Infliximab; Azathioprine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 242.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No

Summary:

      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
      (IFX), as monotherapy or in combination with azathioprine (AZA) versus AZA monotherapy in
      adults with moderate to severe active ulcerative colitis (UC). Participants who qualify at
      the Baseline Visit will be eligible to be randomized to one of the three active treatment
      groups.

      Participants in the IFX/AZA combination therapy and IFX monotherapy cohorts will receive IFX
      infusions at Weeks 0, 2, and 6 and daily oral AZA/placebo, respectively; participants in the
      AZA cohort will receive daily oral AZA and placebo infusions at Weeks 0, 2, and 6. At Week 8,
      all participants will be evaluated for response.

      Participants responding to IFX treatment at Week 8, either as monotherapy or in combination
      with AZA, will receive one more IFX infusion at Week 14; non-responders to IFX therapy will
      receive placebo infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14.

      Participants responding to AZA monotherapy at Week 8 will continue on AZA therapy and receive
      one placebo infusion at Week 14; nonresponders to AZA will be eligible to receive IFX at
      Weeks 8, 10, and 14.

      Part 2: Participants in remission on IFX monotherapy or IFX/AZA treatment at Week 16 will be
      randomized to either maintenance or intermittent open-label IFX 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 participants will continue to receive oral AZA/ placebo
      for the duration of the study.

      Participants randomized to maintenance IFX treatment will receive scheduled IFX infusions
      every 8 weeks beginning at Week 22 (Week 6 for direct entry). If participants lose response,
      or if treatment has to be discontinued because of an adverse event, these participants 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 participants
      will receive standard of care per their personal physician.

      Participants randomized to intermittent IFX treatment will be evaluated every 8 weeks.
      Participants will receive IFX only upon relapse of disease. Treatment with IFX 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.

      In addition, to facilitate enrollment into Part 2, participants who received treatment
      outside of Part 1 and who are in remission on IFX with or without AZA/6-mercaptopurine (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.

      A higher than expected incidence of serious infusion reactions observed in the intermittent
      treatment arm of another study (Protocol P04563, NCT0358670) conducted in participants with
      moderate to severe psoriasis resulted in the termination of that study. Based on the
      similarities in study design between the intermittent treatment arm of P04563 and the
      intermittent treatment arm of Part 2 of this study, enrollment to Part 2 of this study was
      put on hold, for precautionary reasons. At the same time, all participants already enrolled
      in the intermittent treatment arm of Part 2 were asked to discontinue from the trial. In
      October 2009, a decision was made by the sponsor to terminate the whole study (Part 1 and 2).
      At that time, participants enrolled in Part 1 of the study were allowed to complete their
      treatment up to Week 16.
    

Eligibility criteria:

        Inclusion Criteria:

          -  must be >=21 years of age at the time of informed consent, of either sex, and of any
             race;

          -  must have endoscopic evidence of UC, as determined by sigmoidoscopy, within 14 days
             prior to Baseline;

          -  must have a total Mayo score of 6 to 12 points at Baseline;

          -  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);

          -  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;

          -  must be naïve to infliximab and other tumor necrosis factor-alpha (TNF-α) antagonists;

          -  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;

          -  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 IFX;

               -  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 IFX.

               -  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;

          -  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;

          -  screening and Baseline clinical laboratory tests (complete blood count [CBC] and blood
             chemistries) must be within predetermined parameters

          -  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;

          -  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;

          -  willing and able to adhere to the study visit schedule and other protocol
             requirements;

          -  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 participants of childbearing potential must have a negative serum pregnancy
             test (beta-human chorionic gonadotropin) at Screening and a negative urine pregnancy
             test at Baseline.

        Exclusion Criteria:

          -  have severe extensive colitis as evidenced by:

               -  investigator judgment that the participant is likely to require colectomy within
                  12 weeks of Baseline

        OR

          -  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).

                    -  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;

                    -  have severe, fixed symptomatic stenosis of the large or small intestine;

                    -  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);

                    -  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;

                    -  have the presence of a stoma;

                    -  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 had a positive stool culture for enteric pathogens, pathogenic ova or
                       parasites within 4 months prior to Baseline unless participant has received
                       treatment and had a negative stool examination 1 week or longer after the
                       end of treatment;

                    -  have a concomitant diagnosis of congestive heart failure (CHF), including
                       medically controlled asymptomatic subjects;

                    -  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;

                    -  have had a nontuberculous mycobacterial infection or opportunistic infection
                       (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months
                       prior to Screening;

                    -  have a known infection with human immunodeficiency virus (HIV) and/or
                       hepatitis B or hepatitis C;

                    -  have a history of a known allergy to murine proteins or allergy/sensitivity
                       to study drug or its excipients;

                    -  have current signs and symptoms of systemic lupus erythematosus, or severe,
                       progressive, or uncontrolled renal, hepatic, hematologic, endocrine,
                       pulmonary, cardiac, neurologic, or cerebral diseases;

                    -  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);

                    -  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;

                    -  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);

                    -  have poor tolerability of venipuncture or lack of adequate venous access for
                       required blood sampling and infusion of study drug during the study period;

                    -  have had a known substance abuse or dependency (drug or alcohol) within 3
                       years of Screening;

                    -  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;

                    -  have other inflammatory diseases that might interfere with the evaluation of
                       the ulcerative colitis;

                    -  have a history of latent or active granulomatous infection, including TB,
                       histoplasmosis, or coccidioidomycosis, prior to Screening.

                    -  have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of
                       Screening.

                    -  have had 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.

                    -  have received any specified prohibited treatment more recently than the
                       indicated washout period prior to Screening;

                    -  who are participating in any other clinical study or who have received
                       treatment with any investigational drug or device within 3 months prior
                       Screening;

                    -  who is part of the staff or a family member of the staff personnel directly
                       involved with this study.