Reinisch 2010.

Methods	Study design: RCT, multicentre Setting: Austria, the Czech Republic, Germany and Israel ; 21 centres, 2002 to 2007
Participants	Inclusion: Male or female patients aged 18‐70 years with a diagnosis of CD confirmed by endoscopy and histology were eligible for screening if they had (1) undergone resection of the terminal ileum and partial colectomy with ileocolonic resection for complications of ileal CD with construction of an ileocolonic anastomosis in the preceding 6‐24 months; (2) not experienced clinical recurrence due to CD since resection; and (3) a Crohn’s disease activity index (CDAI) score <200 in the preceding 1‐2 weeks. Patients with moderate endoscopic recurrence (Rutgeerts grade i2a: >5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions) or severe endoscopic recurrence (i3‐i4: diffuse aphthous ileitis with diffusely inflamed mucosa, or diffuse inflammation with larger ulcers, nodules and/or narrowing) were recruited into the study Exclusion: Patients with a short bowel syndrome, an ileocolonic stoma, a thiopurine methyltransferase genotype, patients who had received treatment with immunosuppressant agents (methotrexate, ciclosporin, 6‐MP, azathioprine or 6‐thioguanine (6‐TG) or anti‐tumour necrosis factor a (TFNa) since resection, corticosteroids or oral antibiotics (e.g. metronidazole or ciprofloxacin) for >4 weeks since resection, non‐steroidal anti‐inflammatory drugs (NSAIDs) within the preceding 2 weeks (other than paracetamol or low‐dose acetylsalicylic acid); patients who currently had stricturoplasty (unless the present stricture plasty macroscopically showed no inflammation at the time of the index operation) or had serum creatinine >130 μmol/l. Patients were excluded if endoscopy revealed no lesions (grade i0), <5 aphthous lesions (grade i1) and/or if lesions were confined to the ileocolonic anastomosis (i.e. <1 cm long) (grade i2b). Patients in the latter category (grade i2b) were excluded since this presentation is associated with a lower risk of clinical recurrence Age (IG1 / IG2) mean: 35.8 ± 12.08 years overall; 35.5 ± 13.6 years versus 36.0 ± 10.7 years Sex (M:F): 44: 34 overall; (24:17) versus (20/17) Type of surgery: not reported Previous surgery (IG1+IG2): 1 or 2 surgeries‐114 (63/51)); >2 surgeries ‐12 (4/8) Start of intervention after surgery: 6 to 24 months Medication use (IG1+ IG2): Mesalazine ‐ 54 (28/26); Sulfasalazine‐ 5 (4/1); Budesonide‐ 22 (9/13); Corticosteroids‐ 39 (23/16); Azathioprine‐ 14 (6/8); Infliximab‐3 (2/1); Other ‐ 12 (6/6) Smoker (IG1 / IG2): 37 (17/20) Number randomised (N = 78): 41/37 Number analysed (N = 78): (41/41) versus (37/37) Post‐randomisation exclusion (n = 9): (4/41) versus (5/37) ; Lack of cooperation‐7 (4/3); lack of efficacy‐2 (0/2)
Interventions	Group 1: Azathioprine 2.0 ‐ 2.5 mg/kg/day (Azafalk 50 mg tablets) + placebo mesalazine tablets Group 2: Mesalazine 4 g/ day (Eudragit L‐coated 500 mg tablets (Salofalk)) + placebo azathioprine tablets All participants: Medications prohibited during the study: immunosuppressants other than study drug, allopurinol, oxipurinol or thiopurinol, azathioprine‐containing or mesalazine containing drugs other than study drug, anti‐TNF‐α therapy, oral antibiotics for >4 weeks or more than three cycles of 2 weeks, NSAIDs for >2 weeks, corticosteroids and cimetidine
Outcomes	Duration of study: 52 weeks 1. Therapeutic failure (Clinical relapse) defined as CDAI score ≥ 200 and an increase of ≥ 60 points from baseline or study drug discontinuation due to lack of efficacy or an intolerable adverse drug reaction 2. Endoscopic recurrence defined by endoscopic Rutgeerts score ≥ i2 only 3. Health‐related quality of life based on IBDQ score at 12 months 4. Adverse events 5.Clinical recurrence follow‐up defined as a Rutgeerts score between i2‐i4 within 24 months after the 1‐year treatment
Notes	Funding source: Dr Falk Pharma GmbH, Freiburg, Germany Conflict of interest: WR has received an unrestricted grant from Dr. Falk Pharma. EFS and KRH have received speaker’s honoraria. KD, RG and RM are employees of Dr. Falk Pharma. SA, WP, OS, ML, SB‐M, AT, ES and MS have no conflicts of interest to declare. In part, AT, ES and MS are supported by the Robert Bosch Foundation, Stuttgart, Germany Power calculation: The sample size calculation for the primary end point estimated that 62 evaluable patients (31 per treatment arm) were needed to have 80% power to detect a difference of 35% in favour of azathioprine versus mesalazine for the reduction in the 1 year therapeutic failure rate (one‐sided α=0.025). To allow for non‐evaluable patients, a population size of 76 patients (38 per treatment arm) was planned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “..a central randomisation was performed via five computer‐generated randomisation lists (using the program ‘Rancode +’ (version 3.6) of IDV, Gauting, Germany), which were generated for the five body weight classes (40‐50 kg, 51‐60 kg, 61‐75 kg, 76‐100 kg and 101‐128 kg), each in blocks of four, with medication distributed to each centre according to this list" Comment: Computer‐generated randomisation
Allocation concealment (selection bias)	Low risk	Centralized randomisation in blocks of 4
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "To maintain investigator and patient blinding, patients randomised to azathioprine received verum azathioprine tablets and placebo mesalazine tablets; those randomised to mesalazine received verum mesalazine tablets and placebo azathioprine tablets" Comment: a double‐blind, double‐dummy RCT
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to make judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The intention‐to‐treat (ITT) population was defined as all randomised patients who received 1 dose of study medication" Comment:The intention‐to‐treat (ITT) population was defined as all randomised patients who received 1 dose of study medication
Selective reporting (reporting bias)	Low risk	Trial registration available (NCT00946946) and all prespecified outcomes were reported
Other bias	Low risk	Quote: "Baseline characteristics were similar between treatment groups apart from a lower mean CDAI value in the azathioprine cohort (70 versus 102 in the mesalazine arm) and a higher proportion of azathioprine patients with a penetrating disease behaviour (66% versus 43%)" Comment: Some differences at baseline; study supported by Falk Pharma but conflict of interest declared. No other apparent sources of bias detected