Colombel 2017.

Methods	Phase III, RCT, open‐label
Participants	Ileal, colonic (including rectal), or ileocolonic Crohn's disease (not more than 6 years prior to baseline). Moderately‐to‐severely active disease (CDAI 220 ‐ 450 if not receiving prednisone; CDAI 220 ‐ 450 if receiving prednisone ≤ 20 mg; CDAI 150 ‐ 450 if receiving prednisone > 20 mg greater than or equal to 7 days before baseline); active endoscopic disease (CDEIS > 6; sum of CDEIS subscores of > 6 in one or more segments with ulcers); CRP of 5 mg/L or more, fecal calprotectin of 250 μg/g or more, or both Exclusion criteria: Previous or current use of biologic or immunomodulators; more than two previous courses of corticosteroids, or current use of corticosteroids for more than 3 months before screening; fibrotic stricture/draining perianal fistulas/non‐perianal fistula; poorly controlled medical conditions; positive C. difficile stool assay at screening A total of 255 participants enrolled in the study and received the prednisone induction therapy. A total of 244 participants were randomly allocated to the tight control (n = 122) or clinical management (n = 122) groups. Age [Mean(SD) years]: clinical management group 31.1 (11.4); tight control group 32.1 (12.0) Gender: clinical management group (53 males, 69 females); tight control group (50 males, 72 females) Disease status [Mean(SD) CDAI score]: clinical management group 267.7 (58.4); tight control group 273.3 (59.5) Disease duration [Mean (SD) years]: clinical management group 0.9 (1.7); tight control group 1.0 (2.3) Loss to follow‐up: clinical management group (n = 29); tight control management group (n = 32)
Interventions	Tight Control Management ‐ customised therapy (after prednisone induction therapy, management escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine) based on disease activity (CDAI, high sensitivity C‐reactive protein, fecal calprotectin, and corticosteroid use) Dosing regimen: (i) Prednisone 40 mg/day for 2 weeks (max dose), followed by a taper with a schedule that was set by each investigator at his or her discretion for 6 weeks, however prednisone treatment could continue on the basis of the rapidity and tolerance of the taper (ii) Adalimumab 160 mg induction dose at week 0, followed by 80 mg at week 3 and 40 mg eow as a maintenance dose (participants who met any of the failure criteria 1 week before group allocation). Increase to 40 mg weekly if response inadequate and de‐escalated to 40 mg eow in participants who did not meet the treatment failure criteria (iii) Azathioprine 2.5 mg/kg/day (normal thiopurine methyltransferase [TPMT])/1.25 mg/kg/day oral (intermediate TMPT). Dose‐adjusted according to abnormalities of white blood cell (WBC) count, platelet count, liver function tests (LFTs; i.e. alanine transaminase [ALT], aspartate transaminase [AST], phosphatase), lipase, blood urea nitrogen (BUN), and serum creatinine. Therapy was escalated based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥ 250 µg/g, CRP ≥ 5 mg/L, CDAI ≥ 150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of 200; clinical management group after random assignment: CDAI decrease of < 100 points compared with baseline or CDAI ≥ 200, or prednisone use in the previous week). Participants who did not meet the treatment failure criteria stayed on their previously assigned treatment option. Mode of delivery: (i) sc (ii) oral (iii) oral Duration: 56 weeks (8 weeks of prednisone induction treatment and 48 weeks of intervention/active control treatment) Setting of trial: 22 countries at 74 hospitals and outpatient centres Comparision treatment: Clinical Management ‐ customised therapy (as per intervention group) based on disease activity (CDAI and corticosteroid use). Therapy was escalated according to prespecified failure criteria using less stringent criteria: CDAI decrease ≥ 70 (CR‐70) compared to baseline at visit 1 or CDAI < 200 at 1 week prior to visit 1; CDAI decrease of ≥ 100 (CR‐100) compared to baseline or CDAI < 200, and absence of prednisone during the preceding week at visit 3, 4, and 5 Co‐intervention: Not reported
Outcomes	Fatigue was assessed using the FACIT‐F. Quality of life was assessed using the IBDQ and the SF‐36. Adverse events were assessed for each Medical Dictionary for Drug Regulatory Affairs (MedDRA) system organ class and preferred term. Other outcomes assessed: Mucosal healing and no deep ulcerations; deep remission; biologic remission; endoscopic response; endoscopic disease activity; clinical disease activity; Crohn's disease flare; clinical remission; steroid‐free remission; hospitalisation; length of stay in hospital; CD‐related surgeries; Crohn's disease behaviour; High Sensitivity CRP; fecal calprotectin; total dose of prednisone; work productivity; depression; Assessment time points: Baseline, week 12, week 24, week 48
Notes	The study was funded and supported by AbbVie. Awaiting additional study information from AbbVie via the Vivli Platform
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"At week 9 (earlier if active disease present), patients were randomly assigned to the tight control or clinical management group in a 1:1 ratio, stratified by smoking status (yes or no), weight (< 70 kg or ≥ 70 kg) and disease duration (≤ 2 years or > 2 years). The patient number and group of each stratum were assigned by a central randomisation schedule generated by AbbVie (Chicago, IL, USA) using WebRando software for randomisation and ClinPhone, an interactive voice and web response system for patient allocation. The subject randomisation schedule was generated by a designated person in the AbbVie statistics department who was not involved in the rest of the study".
Allocation concealment (selection bias)	Low risk	"All patients were randomised centrally using an interactive voice and web response system (ClinPhone)".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Treatments were open‐label ‐ unblinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Subjective outcome and participants were not blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up relatively similar across the groups and reasons comparable
Selective reporting (reporting bias)	Unclear risk	Fatigue and quality of life outcomes assessed but not reported. Awaiting outcome data from trial authors
Other bias	Low risk	Baseline characteristics were similar between treatment groups. No apparent sources of bias