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)

NCT00537316 | Terminated Phase 3 Results

• 1 other identifier: P04807
• Study Type: interventional
• Target: 242
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Ulcerative Colitis

Outcome Measures

Primary Outcomes (2)

• Proportion of Participants in Steroid-free Remission at Week 16

  Steroid-free remission is defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point, without the use of corticosteroids. The total Mayo score consists of the following 4 sub-scores: stool frequency, rectal bleeding, findings of endoscopy (sigmoidoscopy), and physician's global assessment.

  16 weeks

• Average Remission Rate During Part 2 of the Study

  Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study (Week 38 through Week 94 \[Week 22 through Week 78 for direct entry\]).

  up to Week 94 (Week 78 for direct entry)

Secondary Outcomes (4)

• Proportion of Participants in Response at Weeks 8 and 16

  Weeks 8 and 16

• Proportion of Participants With Mucosal Healing at Week 16

  16 weeks

• Proportion of Participants Who Are in Steroid-free Remission During Part 2 of the Study

  Weeks 38, 62 & 94 (Weeks 22, 46 and 78 for direct entry)

• Proportion of Participants With Mucosal Healing During Part 2 of the Study

  Weeks 38, 62 and 94 (Weeks 22, 46 and 78 for direct entry)

Study Arms (7)

Infliximab (IFX)

EXPERIMENTAL

Part 1: IFX 5 mg/kg of body weight intravenous (IV) infusions was to be administered at Weeks 0, 2, and 6 and placebo to AZA was to be taken orally every day for 16 weeks. Responders to IFX at Week 8, were to receive one more IFX infusion at Week 14; non-responders to IFX were to receive placebo IFX infusions at Weeks 8 and 10 and an additional IFX infusion at Week 14. Part 2: Participants in steroid-free remission at Week 16 of Part 1 were to be randomized to either maintenance (every 8 weeks \[q8w\]) or intermittent (upon relapse) open-label IFX (last IFX infusion administered at Week 86) plus double-blind oral AZA/placebo treatment as allocated in Part 1 (last dose at the final visit, Week 94). Responders at Week 16 who had not achieved steroid-free remission were to continue to receive IFX infusions every 8 weeks.

Biological: Infliximab (IFX); Drug: Placebo to Azathioprine; Drug: Placebo infusion

Azathioprine (AZA)

ACTIVE COMPARATOR

AZA 2.5 mg/kg of body weight orally every day for 16 weeks. Responders to AZA monotherapy at Week 8 were to continue on AZA therapy and receive one placebo infusion at Week 14; non-responders to AZA at Week 8 would be eligible to receive an IFX infusion at Weeks 8, 10, and 14. Participants in steroid-free remission at Week 16 were to continue on AZA monotherapy and were to be followed up for safety in Part 2. Participants who experienced a relapse of disease after Week 16 were to continue daily AZA monotherapy and receive 3 infusions of IFX (induction therapy at Weeks 0, 2, and 6) followed by infusions every 8 weeks (maintenance therapy).

Drug: Azathioprine (AZA); Drug: Placebo infusion

IFX/AZA

EXPERIMENTAL

IFX 5 mg/kg of body weight IV infusions at Weeks 0, 2, and 6 plus AZA 2.5 mg/kg orally every day for 16 weeks. Responders to IFX/AZA at Week 8 were to receive one more IFX infusion at Week 14; non-responders to IFX/AZA were to receive placebo infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14. Part 2: Participants in steroid-free remission at Week 16 of Part 1 were to be randomized to either maintenance (every 8 weeks \[q8w\]) or intermittent (upon relapse) open-label IFX (last IFX infusion administered at Week 86) plus double-blind oral AZA/placebo treatment as allocated in Part 1 (last dose at the final visit, Week 94). Responders at Week 16 who had not achieved steroid-free remission were to continue to receive IFX infusions every 8 weeks.

Biological: Infliximab (IFX); Drug: Azathioprine (AZA); Drug: Placebo infusion

Maintenance IFX/AZA (during Part 2)

EXPERIMENTAL

Participants randomized to maintenance IFX/AZA in Part 2 of the study were to receive IFX 5 mg/kg of body weight IV infusions every 8 weeks (beginning at Week 22, Week 6 for direct entry) plus AZA 2.5 mg/kg of body weight daily. Four participants were from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study.

Biological: Infliximab (IFX); Drug: Azathioprine (AZA)

Maintenance IFX (during Part 2)

EXPERIMENTAL

Participants randomized to maintenance IFX were to receive IFX 5 mg/kg of body weight IV infusions every 8 weeks (beginning at Week 22, Week 6 for direct entry) in Part 2 of the study. Placebo to AZA therapy was to continue as allocated in Part 1 of the study. All participants were from Part 1 of the study.

Biological: Infliximab (IFX)

Intermittent IFX/AZA (during Part 2)

EXPERIMENTAL

Participants randomized to intermittent IFX/AZA were to receive IFX 5 mg/kg of body weight IV infusions only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained) plus AZA 2.5 mg/kg of body weight daily in Part 2 of the study. Three participants were from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study.

Biological: Infliximab (IFX); Drug: Azathioprine (AZA)

Intermittent IFX (during Part 2)

EXPERIMENTAL

Participants randomized to intermittent IFX were to receive IFX 5 mg/kg of body weight IV infusions only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained). Placebo to AZA therapy was to continue as allocated in Part 1 of the study. One participant was from Part 1 of the study and 1 participant was enrolled directly into Part 2 of the study.

Biological: Infliximab (IFX)

Interventions

Infliximab (IFX) BIOLOGICAL

IFX intravenous (IV) infusion dosed at 5mg/kg of body weight

Also known as: Remicade

IFX/AZA; Infliximab (IFX); Intermittent IFX (during Part 2); Intermittent IFX/AZA (during Part 2); Maintenance IFX (during Part 2); Maintenance IFX/AZA (during Part 2)

Azathioprine (AZA) DRUG

AZA 50 mg tablet dosed at 2.5 mg/kg of body weight orally every day

Also known as: Imuran

Azathioprine (AZA); IFX/AZA; Intermittent IFX/AZA (during Part 2); Maintenance IFX/AZA (during Part 2)

Placebo to Azathioprine DRUG

Placebo to AZA tablet orally every day

Infliximab (IFX)

Placebo infusion DRUG

Placebo to IFX intravenous (IV) infusion

Azathioprine (AZA); IFX/AZA; Infliximab (IFX)

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• have severe extensive colitis as evidenced by:
• investigator judgment that the participant is likely to require colectomy within 12 weeks of Baseline
• 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);

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (2)

• Panaccione R, Ghosh S, Middleton S, Marquez JR, Scott BB, Flint L, van Hoogstraten HJ, Chen AC, Zheng H, Danese S, Rutgeerts P. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014 Feb;146(2):392-400.e3. doi: 10.1053/j.gastro.2013.10.052.

  PMID: 24512909 RESULT

• Hasskamp J, Meinhardt C, Patton PH, Timmer A. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2025 Feb 27;2(2):CD000478. doi: 10.1002/14651858.CD000478.pub5.

  PMID: 40013523 DERIVED

MeSH Terms

Conditions

Colitis, Ulcerative

Interventions

Infliximab; Azathioprine

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2007
• First Posted: October 1, 2007
• Study Start: July 1, 2007
• Primary Completion: February 1, 2010
• Study Completion: February 1, 2010
• Last Updated: April 12, 2017
• Results First Posted: December 16, 2011

Record last verified: 2017-03

Data Sharing

• IPD Sharing: Will share