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

Phase 2

Terminated

• Conditions: Crohn Disease; Recurrence; Azathioprine; Prevention
• Interventions: Drug: Azathioprine; Drug: Azathioprine in case of endoscopic recurrence; Procedure: Ileocolonoscopy; Procedure: Small bowel follow trough

• Registration Number: NCT02247258
• Lead Sponsor: Universitaire Ziekenhuizen KU Leuven

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2005-10
• Primary Completion: 2014-04
• Status Verified: 2014-09
• Study First Submitted: 2014-09-19
• Study First Submitted QC: 2014-09-19
• Study First Posted: 2014-09-23
• Study Completion: 2015-05
• Last Update Submitted: 2015-05-28
• Last Update Posted: 2015-05-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 63

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Systematic azathioprine group	Azathioprine	Patients randomized to the systematic azathioprine group received 2.0-2.5 mg/kg azathioprine within 14 days from surgery and throughout 102 weeks.
Systematic azathioprine group	Ileocolonoscopy	Patients randomized to the systematic azathioprine group received 2.0-2.5 mg/kg azathioprine within 14 days from surgery and throughout 102 weeks.
Systematic azathioprine group	Small bowel follow trough	Patients randomized to the systematic azathioprine group received 2.0-2.5 mg/kg azathioprine within 14 days from surgery and throughout 102 weeks.
Endoscopy-driven azathioprine group	Azathioprine in case of endoscopic recurrence	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.
Endoscopy-driven azathioprine group	Ileocolonoscopy	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.
Endoscopy-driven azathioprine group	Small bowel follow trough	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.

Primary Outcome Measures

Name	Time	Method
Endoscopic remission	Week 102	The proportion of patients with endoscopic remission (Rutgeerts' postoperative endoscopic score i0 or i1) at 102 weeks

Secondary Outcome Measures

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

Trial Locations

Locations (4)

Univerzity Karlovy; 🇨🇿 Prague, Czech Republic

Evangelismos Hospital; 🇬🇷 Athens, Greece

Imelda Ziekenhuis; 🇧🇪 Bonheiden, Belgium

UZ Leuven; 🇧🇪 Leuven, Belgium