Azathioprine in the Prevention of Ileal Crohn's Disease Postoperative Recurrence.

Azathioprine in the Prevention of Ileal Crohn's Disease Postoperative Recurrence: Systematic Versus Endoscopic-directed Treatment. A Multi-center, Randomized, Clinical Practice Evaluation Study.

The objective of this study is to evaluate if in the prevention of postoperative recurrence of ileal Crohn's disease immediate initiation of azathioprine postoperatively is superior to delayed (6- 12 mths.) introduction of azathioprine upon disease recurrence assessed by endoscopic criteria. The primary endpoint, disease recurrence, encompasses symptomatic and surgical recurrence as well as severe endoscopic lesions at the final, 2 year, assessment.

Study Overview

• Status: Terminated
• Conditions: Recurrence; Crohn Disease; Prevention; Azathioprine
• Intervention / Treatment: Drug: Azathioprine; Procedure: Ileocolonoscopy; Procedure: Small bowel follow trough; Drug: Azathioprine in case of endoscopic recurrence

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium
    • Imelda Ziekenhuis
  • Leuven, Belgium, 3000
    • UZ Leuven
• Czech Republic
  • Prague, Czech Republic
    • Univerzity Karlovy
• Greece
  • Athens, Greece
    • Evangelismos Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Scheduled surgery for Crohn's disease (CD) with ileocolonic resection. Diagnosis of CD confirmed at least 4 months prior to surgery based on radiology and/or endoscopy.
2. Having an increased risk for postoperative relapse for any of the following reasons: (1) active inflammatory disease with C-reactive protein level (CRP) elevated above 10 mg/L, or the use of antibiotics, steroids or biological therapy including infliximab for active ileal disease within 2 months before surgery which were administered for Crohn's disease and not for another unrelated intercurrent inflammatory or infectious disease; (2) perforating disease defined as the presence of entero-enteric or enterocutaneous fistulas or perivisceral abscess formation within 2 months before surgery. Perianal fistulizing disease will not be considered as an indication of perforating disease in the ileum or right-sided colon. (3) Previous ileo-colonic resection, (4) active smoking, (5) age below 30.
3. Males and females 16-75 years old.
4. Curative surgical resection. All macroscopically inflamed colonic segments (except for anorectal involvement) are to be removed at surgery. Stricturoplasties in small bowel segments not involving the anastomotic region are allowed.
5. Patients able to start oral nutrition and oral therapy within 14 days from surgery.
6. Patients able and willing to give written informed consent
7. Women of childbearing potential should have a negative pregnancy test at inclusion.

Exclusion Criteria:

1. Patients who only had strictureplasties or ileal/colonic resection without a new ileo-colonic anastomosis. Patients with ileorectal anastomosis.
2. Patients with no increased risk of postoperative relapse as defined before.
3. Patients with a known intolerance to azathioprine/6-mercaptopurine or with known homozygous thiopurine methyltransferase-low mutation.
4. Patients in whom more than 100 cm of small bowel has been previously resected.
5. Patients with active perianal disease or colorectal stenosis precluding ileocolonoscopy
6. Patients with sepsis or other postoperative complications necessitating use of antibiotics for more than 14 days after surgery.
7. Patients with liver test abnormalities (serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, bilirubin > 2 ULN), leucopenia (<3000 white blood cell count /µL, <1500 neutrophils /µL), thrombopenia with < 50.000 platelets/mm3.
8. Patients with severe renal, pulmonary or cardiac disease.
9. Pregnant or lactating women.
10. Ongoing alcohol or substance abuse.
11. Ongoing or recent (within 6 months) infectious disease (viral hepatitis, tuberculosis, AIDS, Herpes zoster related disease).
12. Known malignancy 5 years from surgery except for superficial epithelioma of the skin with curative resection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Systematic azathioprine group; Patients randomized to the systematic azathioprine group received 2.0-2.5 mg/kg azathioprine within 14 days from surgery and throughout 102 weeks.	Drug: Azathioprine; See arm/group descriptions; Procedure: Ileocolonoscopy; See arm/group descriptions; Procedure: Small bowel follow trough; See arm/group descriptions
Active Comparator: Endoscopy-driven azathioprine group; Patients randomized to the endoscopy-driven azathioprine group received no Crohn's disease specific treatment for 26 weeks postoperatively. A first ileocolonoscopy was performed at week 26. In case of endoscopic recurrence (Rutgeerts' score i2 or higher), azathioprine was introduced at a dose of 2.0-2.5 mg/kg until week 102. If not, an ileocolonoscopy was repeated at week 52, and azathioprine started in case of endoscopic recurrence. If no endoscopic recurrence was observed, no Crohn's disease-specific treatment was given until week 102.	Procedure: Ileocolonoscopy; See arm/group descriptions; Procedure: Small bowel follow trough; See arm/group descriptions; Drug: Azathioprine in case of endoscopic recurrence; See arm/group descriptions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endoscopic remission	The proportion of patients with endoscopic remission (Rutgeerts' postoperative endoscopic score i0 or i1) at 102 weeks	Week 102

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete endoscopic remission	The percentage of patients with a Rutgeerts' score of i0 at 102 weeks	Week 102
Absence of endoscopic relapse	The percentage of patients with a Rutgeerts' score of i0-i2 at 102 weeks	Week 102
Clinical remission	The percentage of patients in clinical remission (Crohn's disease activity index, CDAI <150) at 102 weeks	Week 102
Sustained clinical remission	Crohn's disease activity index, CDAI < 150 throughout the 102 weeks study period	Week 102
Radiological remission	The percentage of patients with radiological remission at 102 weeks.	Week 102

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: International organization for the study of inflammatory bowel disease (IOIBD)
• Investigators: Principal Investigator: Gert Van Assche, MD PhD, UZ Leuven

Publications and helpful links

General Publications

• Ferrante M, Papamichael K, Duricova D, D'Haens G, Vermeire S, Archavlis E, Rutgeerts P, Bortlik M, Mantzaris G, Van Assche G; International Organization for Study of Inflammatory Bowel Diseases. Systematic versus Endoscopy-driven Treatment with Azathioprine to Prevent Postoperative Ileal Crohn's Disease Recurrence. J Crohns Colitis. 2015 Aug;9(8):617-24. doi: 10.1093/ecco-jcc/jjv076. Epub 2015 Apr 29.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: September 19, 2014
• First Submitted That Met QC Criteria: September 19, 2014
• First Posted (Estimate): September 23, 2014

Study Record Updates

• Last Update Posted (Estimate): May 29, 2015
• Last Update Submitted That Met QC Criteria: May 28, 2015
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Recurrence; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azathioprine
• Other Study ID Numbers: ML3121