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 P04807AM2)

Condition(s) targeted: Ulcerative Colitis

Intervention: Infliximab (Biological); Azathioprine (Drug); Azathioprine / Infliximab (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Schering-Plough

Official(s) and/or principal investigator(s):
Christian Antoni, MD, Study Director, Affiliation: Schering-Plough

Overall contact:
SP Clinical Trial Registry Call Center, Phone: 1-888-772-8734

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.

Official title: Comparison of the Efficacy and Safety of Infliximab, as Monotherapy or in Combination With Azathioprine, Versus Azathioprine Monotherapy in Moderate to Severe Active Ulcerative Colitis (Part 1) Comparison of Maintenance Versus Intermittent Infliximab Treatment in Maintaining Remission: A Follow-Up of Efficacy and Safety (Part 2)

Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Active Control, Parallel Assignment

Primary outcome:

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).

Average remission rate.

Secondary outcome:

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).

The proportion of subjects who are in remission

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subjects must be >=18 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.

SP Clinical Trial Registry Call Center, Phone: 1-888-772-8734

Investigational Site 5, Ottawa K1K 4L2, Canada; Recruiting

Investigational Site 4, London N6A 5A5, Canada; Completed

Investigational Site 6, Calgary T2N 4N1, Canada; Recruiting

Investigational Site 14, Quebec G1R 2J6, Canada; Recruiting

Investigational Site 3, Toronto M5G 1X5, Canada; Completed

Investigational Site 12, Montreal H3A 1A1, Canada; Completed

Investigational Site 69, Montreal H1T 2M4, Canada; Recruiting

Investigational Site 1, Vancouver V6K 2K5, Canada; Recruiting

Investigational Site 98, Hradec Kralove 50012, Czech Republic; Recruiting

Investigational Site 100, Praha 7 170 04, Czech Republic; Recruiting

Investigational Site 99, Olomouc 775 20, Czech Republic; Recruiting

Investigational Site 43, Frankfurt 60596, Germany; Recruiting

Investigational Site 139, Muenchen 81377, Germany; Recruiting

Investigational Site 42, Halle 06120, Germany; Recruiting

Investigational Site 114, Bekescsaba 5600, Hungary; Recruiting

Investigational Site 115, Roma 00152, Italy; Recruiting

Investigational Site 140, Rozzano 20089, Italy; Recruiting

Investigational Site 31, Roma 00133, Italy; Recruiting

Investigational Site 38, Napoli 80131, Italy; Recruiting

Investigational Site 67, Krakow 31-531, Poland; Recruiting

Investigational Site 91, Moscow 129 110, Russian Federation; Recruiting

Investigational Site 87, Moscow 123423, Russian Federation; Recruiting

Investigational Site 28, Madrid 28035, Spain; Recruiting

Investigational Site 18, Fuenlabrada 28942, Spain; Recruiting

Investigational Site 16, Madrid 28007, Spain; Recruiting

Investigational Site 7, Lausanne 1011, Sweden; Recruiting

Investigational Site 102, St Gallen 9007, Switzerland; Recruiting

Investigational Site 9, Zuerich 8091, Switzerland; Recruiting

Investigational Site 10, Bern 3010, Switzerland; Recruiting

Investigational Site 94, Simferopol 95017, Ukraine; Recruiting

Investigational Site 95, Vinnitsa 21014, Ukraine; Recruiting

Investigational Site 96, Donetsk 83017, Ukraine; Recruiting

Investigational Site 97, Kyiv 01021, Ukraine; Recruiting

Investigational Site 59, London E1 1BB, United Kingdom; Recruiting

Starting date: July 2007
Ending date: July 2011
Last updated: October 21, 2008