Advocating for better trials in rheumatology

The ADVOCATE trial, which compared the novel C5a inhibitor avacopan with placebo for patients with ANCA-associated vasculitis (AAV), was an important step forward in rheumatology [1]. Substantive limitations of the trial, however, warrant further consideration. These include inadequate background therapy and an untested glucocorticoid tapering regimen—two issues that reflect trends in rheumatology trials writ large. ADVOCATE randomized patients with moderate-to-severe AAV to receive avacopan or a 20-week prednisone taper. At the discretion of the investigator, patients could receive induction therapy with cyclophosphamide followed by azathioprine maintenance therapy or rituximab followed by no maintenance therapy. The primary end point was non-inferiority with regard to sustained remission without glucocorticoid use in the 4 weeks prior. This outcome was met at week 26, and a prespecified secondary outcome measure of superiority at week 52 was also attained. Based on these results, avacopan received regulatory approval and endorsements by clinical practice guidelines for relapsing or severe AAV [2, 3]. The 26-week outcomes were encouraging, but inadequate maintenance therapy makes the 52-week outcomes difficult to interpret. Patients who received cyclophosphamide for induction went on to receive azathioprine and had similar rates of sustained remission at week 52 whether they were randomized to avacopan or placebo. Patients who received rituximab did not receive a maintenance dose at week 26. Given the rapidity of the steroid taper, such patients were protocolized to be untreated from week 20 to week 52. The difference in outcomes at week 52 appears to have been driven almost entirely by this arm, with remission rates of 56% in this group as compared with 71% among those who received rituximab and avacopan for maintenance therapy (Fig. 1). Important limitations to the design of the ADVOCATE trial Would this difference have materialized had patients been appropriately re-dosed with rituximab, as is the current standard of care [2–4]? It seems likely this difference would have narrowed. Other recent trials in rheumatology have also restricted background therapies. In the AURORA trial of the calcineurin inhibitor voclosporin for lupus nephritis, for instance, participating physicians were required to ask for permission to give the full prescribing dose of mycophenolate mofetil [4]. Upcoming studies of dermatomyositis are prohibiting intravenous immunoglobulin, despite promising results in a recent randomized controlled trial [5]. Especially in diseases where flares may be organ or life-threatening, participants should receive the current standard of care. The protocolized glucocorticoid taper in ADVOCATE, which was more aggressive than any prior trial in AAV, further exacerbated this issue. The concurrent PEXIVAS trial, which was published after ADVOCATE completed enrolment, established the safety of lower dose tapering regimens. Unlike PEXIVAS, ADVOCATE protocolized prednisone discontinuation at week 20. Whether prednisone should be withdrawn entirely within the first year of therapy remains an open question and is the subject of an ongoing clinical trial [6]. Finally, the sustained remission outcomes of ADVOCATE required individuals to be off prednisone for 4 weeks before measurement, creating protocol pressure for individuals to be on lower doses of prednisone. Would the superiority data at week 52 have persisted had patients in the prednisone arm been maintained on 5 mg of prednisone? Patients in the rituximab-placebo group, who received no protocol-based interventions from week 20 to week 52, seem particularly likely to have fared better. This would have come at the cost of glucocorticoid-related adverse events, but whether these would be higher than the burden of avacopan-related adverse events is unknown. The cost effectiveness of the decision has also not been studied, but given the current price of avacopan in the USA ($150 000 per year) and the inexpensiveness of prednisone, this deserves further study. Aggressive corticosteroid tapering protocols are also not unique to ADVOCATE. The pivotal trial of tocilizumab in giant cell arteritis (GiACTA) adopted a 26-week steroid-monotherapy taper as a comparator group, which few practicing clinicians would have recommended [7]. GiACTA went on to firmly establish the inadequacy of this regimen; only 14% of patients in that arm remained in remission at 1 year. Despite this, trials in giant cell arteritis continue to use a 26-week steroid taper as their control group. This both undercuts the scientific value of such studies and places trial participants at an unnecessary risk of harm [8]. The ADVOCATE study represents an important step forward for patients with AAV. Non-inferiority data at week 26 and improvements in the estimated glomerular filtration are practice-changing results, though limitations to the design make it difficult to interpret week 52 results [9]. Inadequate background therapies and aggressive steroid tapers have been used in the protocols of other recent and ongoing trials and represent important threats to the validity and interpretation of the rheumatology literature. Addressing this problem is straightforward; trials should protocolize a control arm that uses modern standards of care, both with respect to glucocorticoid tapers and background disease modifying antirheumatic drug therapies. Data will be made available upon reasonable request. M.P. is supported by a Rheumatology Research Foundation Scientist Development Grant. Disclosure statement: S.K.: none; M.J.: educational support from Roche; M.P.: participated in clinical trials by Abbvie (SELECT-GCA) and AstraZeneca (MANDARA) and has received consulting payments from Novartis. Patient and public involvement: There was no patient or public involvement with this manuscript.

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