Preventing Postoperative Relapse in Crohn's Disease Patients at Risk: Azathioprine Versus Mesalazine

Double-blind, Double-dummy, Randomised, Multicentre, Comparative Study on the Efficacy and Safety of Azathioprine Versus Mesalazine for Prevention of Clinical Relapses in Crohn's Disease Patients With Postoperative Moderate or Severe Endoscopic Recurrence

This study aims to compare azathioprine versus mesalazine tablets for the prevention of clinical relapse in postoperative Crohn's disease (CD) patients with moderate or severe endoscopic recurrence.

Study Overview

• Status: Completed
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Azathioprine; Drug: Mesalazine placebo; Drug: Mesalazine; Drug: Azathioprine placebo

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Universitaetsklinik für Innere Medizin III, Abteilung Gastroenterologie and Hepatologie
• Germany
  • Stuttgart, Germany, Postfach 501120
    • Robert-Bosch Krankenhaus, Innere Medizin I

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent,
• Man or woman between 18 and 70 years of age,
• Diagnosis of Crohn's disease confirmed by endoscopic and histological, or endoscopic and radiological criteria within one year or by histopathological criteria during resection,
• Clinical remission defined as Crohn´s Disease Activity Index (CDAI) < 200, within the last two weeks. No clinical relapse due to Crohn's disease since resection,
• Moderate (i2a) or severe endoscopic recurrence (i3-i4) within 6 to 24 months after curative resection of the terminal ileum and partial colectomy with ileocolonic resection for complications of ileal Crohn´s disease and with a construction of an ileocolonic anastomosis,
• Within the neoterminal ileum at least more than 5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions,
• Negative pregnancy test at screening visit in females of childbearing potential,
• Use of appropriate contraceptive methods for females of childbearing potential and males with procreative capacity during treatment and at least up to 3 months after the end of treatment.

Exclusion Criteria:

• Lesions confined to the ileocolonic anastomosis (i.e., < 1 cm in length)
• Short bowel syndrome,
• Serious secondary illnesses of an acute or chronic nature, which in the opinion of the Investigator renders the patient unsuitable for inclusion into the study,
• Serum creatinine levels exceeding 1.5 mg/dL or 130 umol/L,
• Presence of an ileo-/colonic stoma,
• Genotype: thiopurine methyltransferase (TPMT) -/-,
• Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years),
• Treatment with cytostatics or immunosuppressants, methotrexate, cyclosporine, 6-MP, Azathioprine, 6-TG or anti-TFN-alpha therapy since resection; postoperative treatment with corticosteroids for more than 4 weeks or postoperative treatment with oral antibiotics (e.g., metronidazole, ciprofloxacin) for more than 4 weeks,
• Application of non-steroidal anti-inflammatory drugs (NSAIDS) within 2 weeks before Screening visit except low dose acetylsalicylic acid and except paracetamol,
• Known intolerance/hypersensitivity to study drugs or drugs of similar chemical structure or pharmacological profile,
• Scheduled or intended active immunisation with living vaccines within the next 12 months,
• Well-founded doubt about the patient's cooperation,
• Existing pregnancy, lactation, or intended pregnancy or impregnation within the next 15 months,
• Non-use of appropriate contraceptives in males with procreative capacity and females of childbearing potential (e.g. condoms for males, intrauterine device [IUD], hormonal contraception for females, or a means of contraception for a particular patient considered adequate by the responsible investigator) during treatment and within 3 months after the end of treatment,
• Participation in another clinical trial within the last 30 days, simultaneous participation in another clinical trial, or previous participation in this trial,
• Present stricture plasty (no exclusion if the present stricture plasty was macroscopically without any relevant finding of inflammation seen during index surgery.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azathioprine; 2.0-2.5 mg/kg/BW azathioprine tablets/day AND mesalazine placebo tablets	Drug: Azathioprine; 2.0-2.5mg/kg/BW azathioprine /day and mesalazine placebo tablets; Other Names: Azafalk 50mg tablets; Drug: Mesalazine placebo; 2.0-2.5mg/kg/BW azathioprine /day and mesalazine placebo tablets
Active Comparator: Mesalazine; 4g mesalazine tablets/day AND azathioprine placebo tablets	Drug: Mesalazine; 4g Mesalazine tablets/day AND azathioprine placebo tablets; Other Names: Salofalk 500mg tablets; Drug: Azathioprine placebo; 4g Mesalazine tablets/day AND azathioprine placebo tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary endpoint was therapeutic failure at one year, defined as CDAI score ≥200 and an increase of ≥60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction.	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
endoscopic improvement at month 12, defined as ≥1 point reduction in Rutgeerts' score.	12 months
change in CDAI score	12 months
adverse events	12 months

Collaborators and Investigators

• Sponsor: Dr. Falk Pharma GmbH
• Investigators: Principal Investigator: Walter Reinisch, Prof, Universitaetsklinik für Innere Medizin III, Abteilung Gastroenterologie and Hepatologie, Vienna, Austria

Publications and helpful links

General Publications

• Reinisch W, Angelberger S, Petritsch W, Shonova O, Lukas M, Bar-Meir S, Teml A, Schaeffeler E, Schwab M, Dilger K, Greinwald R, Mueller R, Stange EF, Herrlinger KR; International AZT-2 Study Group. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial. Gut. 2010 Jun;59(6):752-9. doi: 10.1136/gut.2009.194159.

Study record dates

Study Major Dates

• Study Start: February 1, 2002
• Primary Completion (Actual): May 1, 2007
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: July 24, 2009
• First Submitted That Met QC Criteria: July 24, 2009
• First Posted (Estimate): July 27, 2009

Study Record Updates

• Last Update Posted (Estimate): June 26, 2012
• Last Update Submitted That Met QC Criteria: June 25, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Prevention; Randomized; Crohn's Disease; Azathioprine; mesalamine; mesalazine; TPMT
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azathioprine; Mesalamine
• Other Study ID Numbers: AZT-2/CDP