The purpose of this study is to evaluate the efficacy and safety of vedolizumab intravenous (IV) treatment compared to adalimumab subcutaneous (SC) treatment over a 52-week treatment period.
<b>BACKGROUND: </b>Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking.<b>METHODS: </b>In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52.<b>RESULTS: </b>A total of 769 patients underwent randomization and received at least one dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, -9.3 percentage points; 95% CI, -18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years.<b>CONCLUSIONS: </b>In this trial involving patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. (Funded by Takeda; VARSITY ClinicalTrials.gov number, NCT02497469; EudraCT number, 2015-000939-33.).
INTRODUCTION: Histologic remission is associated with superior long-term clinical outcomes in ulcerative colitis (UC). VARSITY, the first head-to-head comparison of biologic agents in UC (NCT02497469; EudraCT 2015-000939-33), showed superior clinical remission and endoscopic improvement at Week 52 with vedolizumab (VDZ), a gut-selective, humanized, α4β7 integrin monoclonal antibody, vs adalimumab (ADA), a systemic, human, anti-tumor necrosis factor (anti- TNF) monoclonal antibody.1 Both VDZ and ADA were generally safe and well-tolerated.1 This analysis compared histologic improvements with VDZ vs ADA in VARSITY. METHODS: Patients with moderately to severely active UC were randomized 1:1 to active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections or placebo IV/active ADA SC (160/80/40 mg). Prespecified histologic exploratory endpoints included histologic remission (Geboes score < 2 or Robarts Histopathology Index [RHI] score < 3) and minimal histologic disease activity (Geboes score < 3.2 or RHI score < 5) at Week 14 and Week 52. Histologic remission was also assessed based on previous anti-TNF use. RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Median (range) duration of exposure was 477 (127, 630) days for VDZ and 420 (71, 454) days for ADA. Mean (standard deviation) baseline histologic disease activity was similar between groups (Geboes: VDZ, 15.0 [4.92]; ADA, 15.1 [5.03]; RHI: VDZ, 19.5 [8.74]; ADA, 19.6 [8.89]). Histologic remission induced by VDZ at Week 52 was greater than with ADA in the overall (Geboes or RHI), anti-TNF naïve (Geboes or RHI), and anti-TNF failure (RHI only) groups (Table 1). Histologic remission at Week 14 favored VDZ over ADA, with larger differentiation when using RHI (Table 1). VDZ also outperformed ADA in achieving minimal histologic disease activity at Weeks 14 and 52 (Table 1). CONCLUSION: VARSITY showed that use of VDZ, compared with ADA, achieved higher rates of histologic remission and minimal histologic disease activity at Weeks 14 and 52 in patients with moderately to severely active UC. These data support the use of VDZ over ADA in UC. (Figure Presented).
Background: Despite a growing number of new therapeutic options for inflammatory bowel disease (IBD), no clinical studies to date have directly compared two biologic agents. We performed a headto‐ head study of the efficacy and safety of vedolizumab (VDZ) and adalimumab (ADA) for treatment over 52 weeks in adults with moderately to severely active ulcerative colitis (UC). Methods: This was a phase 3b, double‐blind, double‐dummy, multicentre, active‐controlled trial enrolling patients with moderately to severely active UC (Mayo score 6 to 12 and endoscopic sub‐score ≥2) who had failed other conventional therapies (NCT02497469; EudraCT 2015‐000939‐33). Prior tumour necrosis factor (TNF) antagonist exposure was capped at 25% of the patient population. Patients were randomised 1:1 to either: (1) active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections; or (2) placebo IV infusions/active ADA SC injections (160/80/40 mg). The dosing for each active drug followed the standard, approved regimens for induction and maintenance. Dose escalation was not permitted in either group. The primary endpoint was clinical remission, defined as a complete Mayo score ≤2 with no sub‐score >1 at week 52. Results: A total of 769 patients were randomised to VDZ (n = 383) or ADA (n = 386) at 330 sites in 37 countries and received at least one dose of study drug. At Week 52, VDZ showed significantly better rates of clinical remission (primary endpoint) and mucosal healing. Overall clinical remission rates at week 52 were 31.3% (n = 120/383) for VDZ and 22.5% (n = 87/386) for ADA (P = 0.0061). Mucosal healing (Mayo endoscopic sub‐score ≤1) at Week 52 was achieved in 39.7% (n = 152/383) of patients treated with VDZ and in 27.7% (n = 107/386) of patients treated with ADA (P = 0.0005). Corticosteroid‐free remission rates at Week 52 showed a numerical but non‐significant difference in favour of ADA. Overall, 62.7% and 69.2% of patients treated with VDZ and ADA, respectively, experienced an adverse event (AE). Serious AEs occurred in 11.0% and 13.7% of patients treated with VDZ and ADA, respectively. Exposure‐adjusted rates of infections were 33.5% and 43.5% in patients treated with VDZ and ADA, respectively; few infections were considered serious in either group. Conclusion: This is the first study to directly compare two biological agents in IBD. VDZ was superior to ADA in achieving clinical remission and endoscopic mucosal healing at Week 52, while VDZ and ADA were both generally safe and well‐tolerated, in patients with moderately to severely active UC.
INTRODUCTION: VARSITY is the first head-to-head trial comparing the efficacy and safety of 2 biologic therapies, vedolizumab (VDZ) and adalimumab (ADA), in patients with moderately to severely active ulcerative colitis (UC). We previously reported significantly higher rates of clinical remission (31.3% vs 22.5%; P = 0.0061) and endoscopic improvement (39.7% vs 27.7%; P5 0.0005) at Week (Wk) 52 with VDZ vs ADA.1 METHODS: VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study (NCT02497469; EudraCT 2015-000939-33). Here we report the predefined, exploratory endpoints of early clinical response and clinical remission (defined in the Table 1) within the first 14 wks, as well as durable clinical remission (patients in clinical remission at Wk 14 and Wk 52). RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Baseline characteristics were comparable between the 2 groups. A trend for separation in clinical response started to emerge at Wk 6 favoring VDZ vs ADA. Clinical response at Wk 14 favored VDZ vs ADA (257 [67.1%] vs 177 [45.9%]; treatment difference 21.2%). More patients achieved clinical remission at Wk 14 on VDZ vs ADA (102 [26.6%] vs 82 [21.2%]; treatment difference 5.3%). Patients on VDZ achieved higher rates of durable clinical remission (70 [18.3%] vs 46 [11.9%]); laboratory results correlated with these findings. Post hoc analyses showed a larger mean (standard deviation) change of C-reactive protein (CRP) from baseline to Wk 14 (232.88 [155.77] nmol/L VDZ vs 23.35 [260.81] nmol/L ADA) and to Wk 52 (250.87 [174.76] nmol/L VDZ vs 237.21 [169.17] nmol/L ADA) in favor of VDZ. Greater mean declines in fecal calprotectin (FCP) levels were seen in patients on VDZ compared with ADA (Wk 14: 21,551.3 [6,236.70] mg/kg VDZ vs 2 1,167.6 [4,647.67] mg/kg ADA;Wk 52: 22,187.3 [7,440.42] mg/kg VDZ vs 21,846.6 [4,560.55] mg/kg ADA). CONCLUSION: Patients on VDZ had numerically higher rates of both clinical response and clinical remission by Wk 14 compared with ADA. Patients on VDZ also achieved higher rates of durable clinical remission compared with ADA. CRP and FCP results correlated with these findings. These data on early clinical response and clinical remission, as well as durable remission, further support the use of VDZ over ADA in patients with moderately to severely active UC. (Figure Presented).
Background: Biologic therapy has become an important part of the management of ulcerative colitis (UC). However, to date, there is a paucity of clinical data to inform biologic treatment options in UC. Here, we report the results of VARSITY, the first head-to-head trial comparing the efficacy and safety of two biologic therapies, vedolizumab (VDZ) vs adalimumab (ADA), in patients with moderately to severely active UC. Methods: VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study at 330 study centers in 37 countries (NCT02497469; EudraCT 2015-000939-33). Adult patients enrolled had moderately to severely active UC (Mayo score 6-12 and endoscopic sub-score ≥2) and had failed other conventional therapies; patients could have prior exposure to one tumour necrosis factor (TNFα) antagonist other than ADA, but enrollment was restricted to 25%. Patients were randomized 1:1 to either: 1) active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections; or 2) placebo IV infusions/active ADA SC injections (160/80/40 mg). VDZ and ADA dosing followed standard approved regimens, and dose escalation was not permitted. The primary endpoint was clinical remission (complete Mayo score ≤2 with no sub-score >1) at week 52. Results: In total, 769 patients received at least one dose of VDZ (n=383) or ADA (n=386). Baseline characteristics were generally comparable between groups. The proportion of patients achieving clinical remission at week 52 was significantly greater with VDZ (31.3%) than with ADA (22.5%; p=0.0061). Mucosal healing (Mayo endoscopic sub-score ≤1) at week 52 was achieved in significantly more patients treated with VDZ (39.7%) than ADA (27.7%; p=0.0005). Corticosteroid-free remission rates at week 52 showed a numerical but non-significant difference in favor of ADA. Minimal histologic remission with Geboes Score (<3.2) and Robarts Histopathology Index (<5) was achieved in 33.4% and 42.3% of patients treated with VDZ, respectively, compared with 13.7% and 25.6% of patients treated with ADA, respectively (p<0.0001). Clinical response at week 14 was achieved in 67.1% of patients treated with VDZ compared with 45.9% of patients treated with ADA (p<0.0001). Differences in clinical response between groups were observed early in treatment (Figure). Overall adverse event (AE) rates were generally comparable between VDZ and ADA groups (62.7%% vs 69.2%, respectively). Exposure-adjusted rates of infections were lower with VDZ (33.5%) than with ADA (43.5%), with few serious infections in either group. Conclusions: The VARSITY trial demonstrated that VDZ achieved superior clinical and endoscopic efficacy versus ADA for the treatment of moderately to severely active UC. VDZ and ADA treatment were both generally safe and well tolerated.
INTRODUCTION: In VARSITY, vedolizumab (VDZ), an anti-a4b7 integrin antibody, achieved superior clinical, endoscopic and histologic outcomes vs adalimumab (ADA), an anti-tumor necrosis factor (TNF) agent, in patients with moderate-to-severe ulcerative colitis (UC) (1). In recent years, the therapeutic goal for UC has evolved from symptom relief to disease control across multiple outcomes. METHODS: This VARSITY post hoc analysis evaluated the trajectory of UC key endpoints and disease control with intravenous VDZ vs subcutaneous ADA between early (Week [W]14) and late (W52) time points. Evolution in disease control over time was assessed based on the proportion of patients who maintained, improved or lost treatment benefit from W14 to W52 for the efficacy endpoints clinical remission, endoscopic and histologic improvement (defined in Figure 1). Data were analyzed within treatment arms in the full analysis population and by prior anti-TNF use (anti-TNF näive or experienced). Observed data were reported without imputation. RESULTS: The study included 769 patients with UC (386 ADA, 383 VDZ). Most patients (56.0% ADA vs 60.8% VDZ) were male, were not using a corticosteroid at baseline (63.7% vs 63.9%) and were anti-TNF näive (79.0% vs 79.2%). Median UC duration was 4.5 (ADA) and 4.8 (VDZ) years. At W14 and W52, clinical remission, endoscopic and histologic improvement, and disease control were all achieved more frequently with VDZ vs ADA (Table 1). More patients maintained each efficacy outcome and disease control from W14 to W52 with VDZ vs ADA, in both anti-TNF subgroups (Figure 1). In both arms, more anti-TNF näive than anti-TNF experienced patients maintained efficacy (Figure 1). The numbers of patients who gained efficacy at W52 were more comparable between anti-TNF näive and experienced. At W52, the overall rate of disease control was higher with VDZ (47.3% anti-TNF näive vs 39.0% anti-TNF experienced) than ADA (32.7% vs 24.2%) (Table 1). Further analyses of early predictors of late disease control will be presented. CONCLUSION: VDZ treatment maintains greater early disease control than ADA in moderate-to-severe UC from W14 to W52, especially in anti-TNF näive patients. These data suggest that VDZ is superior to ADA during both induction treatment evaluated at W14 and maintenance treatment evaluated at W52. Most of the observed treatment differences in anti-TNF näive patients at W52 were established with early response to treatment between W0 and W14.
Background: Patients with ulcerative colitis experience substantial impairment in quality of life (QOL). Patient QOL endpoints are important measures of treatment outcome. We evaluated the effects of intravenous vedolizumab vs adalimumab on QOL in VARSITY, the first head-to-head trial comparing the efficacy and safety of biologics in patients with moderately to severely active ulcerative colitis. Methods: VARSITY was a phase 3b, double-blind, double-dummy, randomized trial (NCT02497469; EudraCT 2015-000939-33). QOL was assessed by the inflammatory bowel disease questionnaire (IBDQ) at baseline, Week 30, and Week 52. Endpoints included clinically meaningful IBDQ improvement (an increase in total score of ≥16 points from baseline to Week 52), IBDQ remission (a total score of?>170 points at Week 52) and change from baseline in IBDQ-specific domain scores (bowel symptoms, systemic symptoms, emotional function, and social function) at Weeks 30 and 52. Serum C-reactive protein and fecal calprotectin (FCP) were also assessed as indicators of inflammation and ongoing disease activity. Results: Among randomized patients, 383 (vedolizumab) and 386 (adalimumab) patients received ≥1 dose of study drug (N=769). At Week 52, clinically meaningful IBDQ improvement was observed in 52.0% (vedolizumab) vs 42.2% (adalimumab) of patients (treatment difference 9.7%; 95% confidence interval, 2.7%-16.7%), while IBDQ remission was achieved by 50.1% (vedolizumab) vs 40.4% (adalimumab) of patients (treatment difference 9.6%; 95% confidence interval, 2.8%-16.5%). Mean (standard deviation) changes in IBDQ total score from baseline for observed cases favored vedolizumab over adalimumab (Week 30: 61.3 [39.8] vs 52.6 [42.8]; Week 52: 66.1 [41.8] vs 60.4 [42.2]; Figure 1). IBDQ subscores showed similar favorable trends for vedolizumab (Figure 2). Mean (standard deviation) changes from baseline in C-reactive protein for patients treated with vedolizumab vs adalimumab were –5.46 (17.19) mg/L vs –2.30 (24.92) mg/L at Week 30 and –5.34 (18.35) mg/L vs –3.91 (17.77) mg/L at Week 52. Mean (standard deviation) changes from baseline in FCP were similar, with –1,835.8 (6,958.0) µg/g vs –1,373.4 (4,679.4) µg/g at Week 30 and –2,187.3 (7,440.4) µg/g vs –1,846.6 (4,560.6) µg/g at Week 52 for vedolizumab vs adalimumab treatment, respectively. Among patients with FCP?>250 µg/g at baseline, the proportion of patients achieving FCP ≤250 µg/g was 33.9% vs 24.5% at Week 30 and 35.2% vs 28.9% at Week 52 for patients treated with vedolizumab vs adalimumab, respectively. Conclusion: Based on IBDQ total score and subscores, more patients with ulcerative colitis treated with vedolizumab than with adalimumab achieved clinically meaningful improvement and clinical remission. Reduced inflammation, as indicated by improvements in C-reactive protein and FCP, was consistent with improvements in QOL.
Background and Aims: VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. Methods: Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. Results: In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%–13.9%], P <.0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%–15.2%], P =.0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%–26.2%], P <.0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%–23.8%], P <.0001) overall and in both anti–tumor necrosis factor (TNF)‐naïve and ‐failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti–TNF‐naïve vs ‐failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). Conclusions: Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti–TNF‐naïve and ‐failure subgroups. Registration: ClinicalTrials.gov NCT02497469; EudraCT 2015‐000939‐33
The purpose of this study is to evaluate the efficacy and safety of vedolizumab intravenous (IV) treatment compared to adalimumab subcutaneous (SC) treatment over a 52-week treatment period.
