Sands BE, Peyrin‑Biroulet L, Loftus E, Danese S, Colombel JF, Toruner M, Jonaitis L, Abhyankar B, Chen J, Rogers R, Lirio RA, Bornstein JD, Schreiber S, for the VARSITY Study Group
N Engl J Med 2019;381:1215–26. doi: 10.1056/NEJMoa1905725
© Jonathan Blackwell
The management of Ulcerative Colitis (UC) increasingly involves the use of a biologic agent. Placebo-controlled trials have demonstrated the efficacy of both adalimumab, a tumour necrosis factor (TNF) inhibitor, and vedolizumab, an integrin inhibitor. However, variation in study design makes comparison between such trials difficult. This is particularly evident when comparing rates of clinical remission in the placebo groups of different trials. For example, in the ULTRA 2 trial, which established the superiority of adalimumab over placebo in moderate to severe UC, the 52-week clinical remission rate in the placebo group was just 8.5% compared to 15.9% in GEMINI 1, the placebo-controlled trial of vedolizumab [1,2]. In the absence of head-to-head trials between biologics there is a lack of data to inform clinicians of the best choice of agent. VARSITY is the first head-to-head trial to compare the efficacy and safety of vedolizumab and adalimumab in moderate to severely active UC.
The investigators conducted a 52-week, multicentre, phase 3b, randomised, double-blind, double-dummy, active-controlled superiority trial to compare vedolizumab and adalimumab in the management of moderate to severe UC. Patients were randomised to either 300 mg vedolizumab at weeks 0, 2, 6, 14, 22, 30, 38 and 46 or 160 mg of adalimumab at week 0, followed by 80 mg at week 2 and then 40 mg every 2 weeks until week 50. Dose escalation was not permitted in either arm of the trial. Up to 25% of patients were allowed to have previous exposure to a TNF inhibitor other than adalimumab and randomisation was stratified according to this.
The primary outcome was clinical remission at week 52. This was defined as a Mayo score of 2 or less with no subscore greater than 1. Endoscopic improvement (a subscore of 0 or 1 on the endoscopic component of the Mayo score) and steroid-free clinical remission at week 52 were secondary outcomes.
The investigators compared the proportion of patients in both treatment groups who fulfilled each outcome using the Cochran-Mantel-Haenszel chi-square test, adjusting for randomisation stratification factors (i.e. previous exposure to a TNF inhibitor and concomitant corticosteroid use).
In total, 383 patients were randomised to vedolizumab and 386 to adalimumab. At week 52, 31.3% of patients in the vedolizumab arm were in clinical remission compared with 22.5% of the adalimumab arm (8.8 percentage point difference; 95% confidence interval [CI] 2.5–15.0; p=0.006). Endoscopic improvement was also observed in a higher percentage of those treated with vedolizumab than those treated with adalimumab (39.7% vs 27.7%, 11.9 percentage point difference; 95% CI 5.3–18.5; p<0.001). By contrast, patients who received vedolizumab were less likely to achieve steroid-free remission at week 52 than those who received adalimumab (12.6% vs 21.8%, -9.3 percentage point difference; 95% CI -18.9 to 0.4), though the reason for this disparity is unclear. The proportion of patients achieving a clinical response at week 4 in the vedolizumab and adalimumab groups was similar (65.3% vs 59.3%). This is important as it challenges the perception that vedolizumab has a slower onset of action than TNF inhibitors .
Interestingly, in the analysis of patients who had received a previous TNF inhibitor, rates of clinical remission at week 52 were similar in the vedolizumab group and the adalimumab group (20.3% vs 16.0%, 4.2 percentage point difference, 95% CI -7.8 to 16.2). This was contrary to the expectation that adalimumab, a TNF inhibitor, would be inferior to vedolizumab in patients with previous TNF inhibitor exposure.
As expected, vedolizumab had lower exposure-adjusted incidence rates of both infections and serious infections compared with adalimumab (infections, 23.4 vs 34.6 events per 100 patient-years; serious infections, 1.6 vs 2.2 events per 100 patient-years). However, incidence rates of Clostridium difficile infection were higher with vedolizumab than adalimumab (1.1 vs 0.6 events per 100 patient-years).
VARSITY is the first head-to-head trial between any biologics in Inflammatory Bowel Disease. It demonstrated that vedolizumab is superior to adalimumab in moderate to severe UC for achieving both clinical remission and endoscopic improvement, though not steroid-free remission. While rates of clinical remission were higher with vedolizumab than with adalimumab, the magnitude of the difference was smaller than might have been inferred from previous placebo-controlled trials, highlighting the need for more head-to-head trials between different agents in IBD [1,2].
Jonathan Blackwell is a research fellow at St George’s, University of London, working as part of the POP-IBD group. He was awarded a grant by Crohn’s and Colitis UK to perform research using big data to conduct population based studies, exploring diagnostic delay and the psychological impact of IBD. He is a member of the IBD UK Data Analysis and Quality Improvement Group, working to improve standards of IBD care. He was St George’s Young Researcher of the Year in 2019 and runner-up in 2018, and was winner of the London IBD Forum Research Prize in 2019.