Sands 2014.

Study characteristics
Methods	Study design: 2 arm, double‐blind randomised trial Number of centres: multicentre Countries: multiple across North America, Europe, Asia, Africa and Australia Study dates: November 2010 to April 2012 Setting: NR
Participants	Induction or maintenance study: induction study Active or inactive disease at beginning of study: active Participants were considered for the primary outcome if they had failed TNF antagonists. They were also included for randomisation and some of the secondary outcomes if they were TNF antagonist naive. Inclusion criteria Aged 18–80 years CD with known ileal or colon (or both) involvement ≥ 3 months before enrolment (based on clinical and endoscopic evidence, corroborated by histopathology) At least moderately active CD (defined by CDAI score 220–400 within 7 days before enrolment) in addition to ≥ 1 of: CRP > 2.87 mg/L, colonoscopy within prior 4 months, fecal calprotectin > 250 μg/g during screening in conjunction with features of active CD on small bowel imaging Inadequate response, loss of response or intolerance to: TNF inhibitors, immunosuppressive or corticosteroids in past 5 years (for primary outcome population) Exclusion criteria Previous exposure to: vedolizumab, natalizumab, efalizumab or rituximab Concurrent lactation or pregnancy Unstable or uncontrolled medical condition Major neurological disorder Prior malignancies (except cancers where recurrence risk after adequate treatment was expected to be low) Active drug or alcohol dependence Active psychiatric disease or other complicating factors that could result in non‐adherence to study procedures Baseline disease characteristics CG = placebo IG = IV vedolizumab weeks 0, 2 and 6 Females: CG 57%, IG 56% Median age (years): CG 34.8 (IQR 19–77), IG 36.9 (IQR 20–69) Mean weight (kg): CG 71.3 (IQR 41–147), IG 69.5 (IQR 40–144) Median BMI (kg/m2): CG 23.3 (IQR 15–48), IG 23.3 (IQR 15–43) Mean CDAI: CG 301.3 (SD 55.0), IG 313.9 (SD 53.2) Mean CRP (mg/L): CG 18.5 (SD 22), IG 19.0 (SD 23.2) Mean fecal calprotectin (μg/g): CG 1426.5 (SD 2357.8), IG 1148.1 (SD 1878.6) Disease localisation – ileum only: CG 14%, IG 16% Disease localisation – colon only: CG 25%, IG 23% Disease localisation – both ileum and colon: CG 61%, IG 61% History of CD surgery: CG 43%, IG 44% History of fistulising disease: CG 37%, IG 34% Corticosteroid use: CG 52%, IG 53% Immunosuppressive use: CG 33%, IG 34% Mesalamine use: CG 29%, IG 33% Prior immunosuppressive exposure: CG 93%, IG 84% Prior TNF failure: CG 76%, IG 76%
Interventions	CG: IV placebo at weeks 0, 2 and 6 IG: IV vedolizumab 300 mg at weeks 0, 2 and 6 Duration of study: 10 weeks Measurement timepoints during study: weeks 6 and 10 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 Proportion of participants in clinical remission at week 6 (defined by CDAI ≤ 150) from the TNF antagonist failure population Secondary outcomes Proportion of participants in clinical remission at week 6 from the overall study population (including about 25% of TNF antagonist‐naive participants) Proportion of participants in clinical remission at week 10 (from the TNF antagonist‐failure populations in addition to the additional TNF‐naive population) Proportion of participants with a CDAI‐100 response at week 6 (from the TNF antagonist‐failure population)
Notes	Funding source: Takeda Pharmaceuticals International, Inc. Sponsored and funded by Millennium Pharmaceuticals, Inc (trading as Takeda Pharmaceuticals International Co). Conflicts of interest: (quote) "The authors disclose the following: Bruce Sands has received consulting and advisory board fees as well as clinical research/institutional grant support from AbbVie, Inc, Janssen Pharmaceuticals, Inc, and Takeda Pharmaceuticals International Co; Brian Feagan has received consulting fees and research grant support from Janssen Pharmaceuticals, Inc, Takeda Pharmaceuticals International Co, and UCB SA; Paul Rutgeerts has received consulting fees from Takeda Pharmaceuticals International Co. and UCB SA; Jean‐Frédéric Colombel has received consulting fees from Takeda Pharmaceuticals International Co. and UCB SA; William Sandborn has received consulting fees and research grants from Janssen Pharmaceuticals, Inc, Takeda Pharmaceuticals International Co, and UCB SA, and speaker fees from Janssen Pharmaceuticals, Inc; Richmond Sy has received consulting, lecture, and advisory board fees as well as research grant support from AbbVie, Inc, and Janssen Pharmaceuticals, Inc, and both advisory board fees and clinical trial support from Takeda Pharmaceuticals International Co; Geert D'Haens has received consulting and lecture fees from AbbVie, Inc, Janssen Pharmaceuticals, Inc, Takeda Pharmaceuticals International Co, and UCB SA, research grants from Janssen Pharmaceuticals, Inc, and speaking honoraria from UCB SA; Shomron Ben‐Horin has received consultancy and advisory board fees from Janssen Pharmaceuticals, Inc, and AbbVie, Inc, and an unrestricted research grant from Janssen Pharmaceuticals, Inc; Asit Parikh is an employee of Takeda Pharmaceuticals International, Inc; Jing Xu, Maria Rosario, Irving Fox, and Catherine Milch are employees of Takeda Pharmaceuticals International Co; and Stephen Hanauer has received consultancy and advisory board fees as well as clinical research/institutional grant support from AbbVie, Inc, Janssen Pharmaceuticals, Inc, Takeda Pharmaceuticals International Co, and UCB SA.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomization was computer‐generated centrally."
Allocation concealment (selection bias)	Low risk	Quote: "patient enrollment, monitored by an interactive voice response system."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "treatment‐qualified patient received a unique randomization number used to provide treatment assignments for dose preparation via the interactive voice response system. Saline bag covers and labels maintained blinding. Only the study site pharmacist was aware of treatment assignments."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Contacted study authors by e‐mail (Dr Bruce Sands), who confirmed that outcome assessors were blinded to treatment assignments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition in each group reported and balanced in all groups. Discontinuation due to adverse events reported and balanced between treatment and placebo groups.
Selective reporting (reporting bias)	Low risk	Although published protocol was reported to be available, we could not find it. According to trial registration and method section author reported relevant outcomes – proportion of participants in clinical remission and response (CDAI scores).
Other bias	Low risk	Baseline characteristics reported for and balanced in all groups. No other apparent sources of bias.