Sandborn 2013 – Maintenance Phase.

Study characteristics
Methods	Study design: 3‐arm double‐blind randomised trial Number of centres: multicentre Countries: multiple Study dates: December 2008 to May 2012 Setting: NR
Participants	Induction or maintenance study: maintenance trial Active or inactive disease at beginning of study: inactive disease People who had a clinical response with vedolizumab in the 6‐week induction phase were included (CDAI ≥ 70 decrease). Combination of people randomised to vedolizumab in the induction trial (220 participants), in addition to a cohort of 747 open‐label participants Inclusion criteria Aged 18–80 years Able to voluntarily give informed consent Contraception criteria CD duration ≥ 3 months (histopathology report) or ≥ 6 months (if report unavailable) CDAI score within range and 1 of the following: CRP > 2.87 mg/L; ≥ 3 non‐anastomotic ulcerations or fecal calprotectin > 250 μg/g Ileal or colonic disease, or both Colonoscopy within 12 months for long‐standing disease Colon cancer screening up‐to‐date Inadequate response, lost response, or intolerance to corticosteroids, immunosuppressives, or TNF antagonists Stable dose of 5‐ASA Stable doses of steroids Stable doses of probiotics Antidiarrhoeal use Stable doses of azathioprine or 6‐mercaptopurine Stable dose of methotrexate Stable dose of antibiotics Exclusion criteria Gastrointestinal exclusion criteria Abdominal abscess or toxic megacolon Extensive colonic resection, subtotal or total colectomy > 3 small‐bowel resections or short bowel syndrome Tube feeding/formula diet/hyperalimentation within 21 days Ileostomy, colostomy or symptomatic Use of non‐biological therapies (e.g. ciclosporin, thalidomide) within 30 days Investigational use of non‐biological therapy within 30 days Investigational use of approved non‐biological therapy within 30 days Adalimumab use within 30 days Infliximab use within 60 day Certolizumab pegol use within 60 days Investigational or approved agents use within 60 days Exposure to natalizumab, efalizumab or rituximab 5‐ASA or steroid enema or suppository use within 2 weeks of first dose Clostridium infection within 60 days or other intestinal pathogen within 30 days Need for surgical intervention for CD during study Presence of adenomatous colonic polyps Colonic mucosal dysplasia Diagnosis of ulcerative colitis or indeterminate colitis Infectious disease exclusion criteria Chronic HBV or chronic HCV History of tuberculosis Missing baseline tuberculosis test results Tuberculosis on chest x‐ray within 3 months Congenital or acquired immunodeficiency Live vaccines within 30 days Extraintestinal infection within 30 days General exclusion criteria Previous exposure to vedolizumab Positive pregnancy test Any unstable major medical disorder Surgical procedure requiring general anaesthesia within 30 days History of malignancy History of major neurological disorder Positive PML subjective checklist Haemoglobin < 8 g/dL White blood cell count < 3 × 109/L Lymphocyte count < 0.5 × 109/L Platelet count < 100 × 109/L or > 1200 × 109/L Alanine aminotransferase or aspartate aminotransferase level > 3 × ULN Alkaline phosphatase level > 3 × ULN Serum creatinine level > 2 × ULN Substance abuse Active psychiatric problems Inability to attend all study visits or comply with study Baseline disease characteristics CG = placebo IG1 = IV vedolizumab 300 mg 8 weekly IG2 = IV vedolizumab 300 mg 4 weekly Mean age (years): CG 37.3 (SD 12), IG1 35.1 (SD 12.2), IG2 34.9 (SD 12.2) Males: CG 47%, IG1 44%, IG2 53% White race: CG 92%, IG1 88%, IG2 87% Weight (kg): CG 69.0 (SD 18.2), IG1 68.5 (SD 18.6), IG2 71.5 (SD 18.4) Current smoker: CG 31%, IG1 31%, IG2 25% Mean duration of disease (years): CG 9.6 (SD 8.9), IG1 8.4 (SD 7.3), IG2 7.7 (SD 6.8) Mean CDAI score: CG 325 (SD 66), IG1 326 (SD 69), IG2 317 (SD 66) Median CRP (μg/L): CG 9.8, IG1 8.6, IG2 9.8 Median fecal calprotectin (μg/g): CG 684, IG1 584, IG2 776 Disease localisation – ileal: CG 12%, IG1 19%, IG2 22% Disease localisation – colonic: CG 28%, IG1 18%, IG2 31% Disease localisation – ileocolonic: CG 59%, IG1 64%, IG2 47% Concomitant Crohn's medications – corticosteroids only: CG 37%, IG1 38%, IG2 38% Concomitant Crohn's medications – immunosuppressives only: CG 15%, IG2 18%, IG2 20% Concomitant Crohn's medications – corticosteroids and immunosuppressives: CG 17%, IG1 15%, IG2 14% Concomitant Crohn's medications – no corticosteroids or immunosuppressives: CG 31%, IG1 29%, IG2 28% Median prednisolone equivalent dose (mg): CG 20, IG1 20, IG2 20 Prior anti‐TNF use: CG 54%, IG1 57%, IG2 54% Prior failure of ≥1 TNF antagonist: CG 51%, IG1 55%, IG2 50% Prior failure of ≥2 TNF antagonist: CG 35%, IG1 30%, IG2 32% Mean haemoglobin (g/L): CG 126.5 (SD 15.1), IG1 125.1 (SD 17.4), IG2 126.7 (SD 17.3) Mean white cell count (× 109/L): CG 9.1 (SD 3.4), IG1 9.2 (SD 3.4), IG2 9 (SD 3.3) Prior surgery for CD: CG 37%, IG1 37%, IG2 40% History of fistulising disease: CG 37%, IG1 31%, IG2 32% Draining fistulae at baseline: CG 12%, IG1 11%, IG2 14%
Interventions	Interventions (maintenance trial) CG: IV placebo IG1: IV vedolizumab 300 mg 8 weekly IG2: IV vedolizumab 300 mg 4 weekly Duration of study: 46 weeks Measurement timepoints during study: study visits were conducted every 4 weeks during the maintenance trial. The primary and secondary outcomes were assessed at week 52 from time of induction (46 weeks into maintenance study) Follow‐up measurements after study end: those who had no unacceptable adverse events or did not require CD‐related surgery were continued in the open‐label GEMINI long‐term safety trial.
Outcomes	Primary outcomes as defined by study authors Clinical remission at week 52 (in maintenance therapy trial) Secondary outcomes as defined by study authors CDAI‐100 response Glucocorticoid‐free remission (defined as clinical remission at week 52 without glucocorticoid therapy) Durable clinical remission (defined as clinical remission at ≥ 80% of study visits, including the final visit) at week 52
Notes	Funding source: Millennium Pharmaceuticals Conflicts of interest: NR
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was computer‐generated and was performed at a central location."
Allocation concealment (selection bias)	Low risk	Quote from protocol "treatment assignments will be obtained through the interactive voice response system (IVRS) and for dose preparation according to the procedures outlined in the Study Manual. Information regarding the treatment assignments will be kept securely at Millennium per its standard operating procedures." Quote: "Randomization schedules will be generated by the Millennium Biostatistics Group and archived within the Biostatistics and Medical Writing Department of Millennium. Each patient who is qualified for treatment will be assigned a unique randomization number. The IVRS will provide treatment assignments based on these randomization numbers."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "all patients and all study personnel except for those directly involved with study drug preparation will be blinded to study drug assignment for the entire study." Comment: use of placebo was described in protocol. During the maintenance phase all arms of the study (IV vedolizumab 8 weekly, 4 weekly and placebo) would receive either placebo or study drug 4 weekly to maintain the blind. IV cover bags were also used to maintain blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "after the Induction Phase has been completed, select and pre‐specified personnel at Millennium will become unblinded to patient‐level data in order to conduct the analyses and reporting of the Induction Phase data. As these activities will occur while the Maintenance Phase is ongoing, proper procedures will be in place to protect the blind until completion of the Maintenance Phase."
Incomplete outcome data (attrition bias) All outcomes	Low risk	According to the flowchart of Supplementary Figure 1 (S1), attrition was balanced in all groups with adequate reasons provided for loss in numbers.
Selective reporting (reporting bias)	Low risk	No published protocol found. According to trial registration, authors reported relevant data accordingly – clinical response and clinical remission (CDAI scores) at relevant intervals.
Other bias	Low risk	Baseline characteristics reported and balanced for participants in all groups. No other apparent sources of bias.