VARSITYMust knowUC · Head-to-head
Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis
Sands BE, et al.
N Engl J Med 2019 · PMID 31553834 (PubMed, opens in a new tab) · doi 10.1056/NEJMoa1905725 (full paper, opens in a new tab)
| Outcome | Vedolizumab | Adalimumab | Estimate (confidence interval) | P |
|---|---|---|---|---|
| Clinical remission, Primary endpoint · total Mayo ≤2, no subscore >1 (primary) | 31.3% | 22.5% | +8.8 (95% CI 2.5–15.0) | P=0.006 |
| Endoscopic improvement, Mayo endoscopic subscore 0–1 | 39.7% | 27.7% | +11.9 (95% CI 5.3–18.5) | P<0.001 |
| Corticosteroid-free remission, Third in the testing hierarchy | 12.6% | 21.8% | −9.3 (95% CI −18.9 to 0.4) |
Corticosteroid-free remission leaned toward adalimumab and its interval crosses zero: the one ranked endpoint that did not favour vedolizumab.
Source: Sands 2019, abstract (all values). Endpoints were tested hierarchically: clinical remission, then endoscopic improvement, then corticosteroid-free remission (no P value reported).
Structured abstract
BackgroundBiologics were widely used in UC, but no two had been compared head to head in IBD; choices relied on indirect comparisons of placebo-controlled trials.
MethodsPhase 3b, double-blind, double-dummy, randomised superiority trial (245 centres, 34 countries), 52 weeks. 769 patients. Primary endpoint: Clinical remission at week 52 (total Mayo ≤2, no subscore >1).
ResultsPrimary result. 31.3% vs 22.5%; difference 8.8 percentage points (95% CI 2.5–15.0); P=0.006
Take-homeIn the first head-to-head biologic trial in IBD, vedolizumab beat adalimumab for clinical remission and endoscopic improvement at 52 weeks in UC.
| Patients | 769 |
|---|---|
| Population | Adults with moderately to severely active UC; prior exposure to a TNF inhibitor other than adalimumab allowed in up to 25% |
| Comparison | Vedolizumab 300 mg IV (day 1, weeks 2 and 6, then every 8 weeks) vs adalimumab SC 160/80 mg then 40 mg every 2 weeks; no dose escalation in either arm |
| Drugs | vedolizumab, adalimumab |
| Classes | Anti-integrin, Anti-TNF |
| Published | Sands BE, et al. N Engl J Med 2019;381:1215–26. |
Key points
- Endoscopic improvement (Mayo endoscopic subscore 0–1) at week 52: 39.7% vs 27.7%; difference 11.9 points (95% CI 5.3–18.5); P<0.001.
- Corticosteroid-free remission did not favour vedolizumab: 12.6% vs 21.8% (difference −9.3 points, 95% CI −18.9 to 0.4).
- Infections: 23.4 vs 34.6 events per 100 patient-years; serious infections 1.6 vs 2.2 per 100 patient-years.
- The first head-to-head trial of two biologics in IBD.
Limitations
- No dose escalation was allowed, although adalimumab is often escalated in practice.
- Mostly anti-TNF-naive patients (prior anti-TNF capped at 25%), so it says little about choice after anti-TNF failure.
- Corticosteroid-free remission numerically favoured adalimumab.
Commentary
Why it matters. Before VARSITY, choices between biologics in UC relied on indirect comparisons across placebo-controlled trials. VARSITY gave direct randomised evidence and supported vedolizumab as a first-line advanced therapy in moderate to severe UC.
Caveats for teaching. The steroid-free remission result went the other way numerically, and adalimumab could not be escalated, which may have disadvantaged it.
Related. GEMINI 1 (PMID 23964932) and ULTRA 2 (PMID 22062358) are the placebo-controlled trials for each drug. A different gut-selective antibody, etrolizumab, failed to beat infliximab in GARDENIA.
Journal club
Design
Phase 3b, double-blind, double-dummy, randomised superiority trial (245 centres, 34 countries), 52 weeks. 769 patients.
Primary result. 31.3% vs 22.5%; difference 8.8 percentage points (95% CI 2.5–15.0); P=0.006
Validity and applicability
- No dose escalation was allowed, although adalimumab is often escalated in practice.
- Mostly anti-TNF-naive patients (prior anti-TNF capped at 25%), so it says little about choice after anti-TNF failure.
- Corticosteroid-free remission numerically favoured adalimumab.
Where it sits now
In the first head-to-head biologic trial in IBD, vedolizumab beat adalimumab for clinical remission and endoscopic improvement at 52 weeks in UC.
- GARDENIA (2022): Etrolizumab, an anti-β7 integrin antibody, did not beat infliximab in anti-TNF-naive UC, and it never became a treatment option.
Questions for discussion
- Adalimumab could not be escalated. Would the result hold in a setting where escalation is routine?
- Corticosteroid-free remission leaned toward adalimumab. How much weight should the third endpoint in a testing hierarchy carry?
- Prior anti-TNF exposure was capped at 25%. What does VARSITY tell you about a patient who has already failed an anti-TNF?