N Engl J Med 2021;384:599\609
N Engl J Med 2021;384:599\609. Objective The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)\associated vasculitis. Methods In this randomized, controlled trial, we assigned patients with ANCA\associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary endpoint) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], \6.0 to 12.8; value of 0.05 in sequence: first starting with noninferiority at 26?weeks, followed by noninferiority at 52?weeks, followed by superiority at 52?weeks. STUDY FINDINGS In total, 331 subjects were enrolled in the trial, with a mean age of 61?years and a male\to\female ratio of approximately 50% in both groups. ASP2397 Of subjects, 57% had a positive MPO status, and 43% had a positive PR3 status; 81% had renal disease. There were no significant differences in steroid doses during screening between the two groups. Approximately two thirds received standard of care with rituximab, whereas approximately ASP2397 one third received cyclophosphamide. The ADVOCATE trial met its primary endpoint at 26?weeks: 72.3% in the avacopan group versus 70.1% in the prednisone group demonstrated remission by week 26 (: 3.4%; 95% CI: ?6.0 to 12.8), achieving noninferiority (boundary: 20%; em P /em ? ?0.001), and 65.7% in the avacopan group versus 54.9% in the prednisone group had sustained remission at week 52 (: 12.5%; 95% CI: 2.6 to 22.3), achieving superiority ( em P /em ?=?0.007; boundary: 0%). Although there were several secondary outcomes analyzed, we will focus on two key findings, including Kaplan\Meier analysis predicting time to relapse between the prednisone and avacopan groups. Whereas 10.1% in the avacopan group had relapse, 21.0% had relapse in the prednisone group, yielding a hazard ratio of 0.46 (95% CI: 0.25\0.84). This means that patients in the avacopan group were 54% less likely to relapse compared with the prednisone group. Additionally, there was a higher mean improvement in eGFR from baseline in the avacopan group (7.3 mL/min/1.73 m2) compared with the prednisone group (4.1 mL/min/1.73 m2). STUDY IMPLICATIONS In analyzing the implications of this trial’s contribution to the field of rheumatology, it is important to analyze the study’s criteria for and adherence to the noninferiority trial design. To justify conducting a noninferiority trial, a drug under investigation should either be more cost effective, more convenient, better tolerated, or less toxic than the standard\of\care equivalent (8). In this case, rheumatologists are keenly aware of the significant toxicities of steroid therapy, as well as the implications of having an orally available equivalent option, especially true for pediatric patients. In this regard, the choice of noninferiority trial appears justified. To better understand the statistics, we must understand the concept of the noninferiority margin, or , which captures ASP2397 the essence of a treatment not being worse. This sets the boundary not to be exceeded by the lower limit (in this trial) of the confidence interval for the difference between the event rate for the standard of care ASP2397 versus new treatment groups. It corresponds to the smallest clinical evidence of inferiority that would warrant nonacceptance of the new therapy. It should be chosen in advance and clinically justified (9). In this Cdh5 case, a??20% was set in advance of trial conduction. Although the authors do not discuss in the manuscript their clinical rationale for the cut off of ?20%, it is also recognized that too conservative of a margin may lead to a large and unfeasible trial. On the contrary, too liberal a margin could allow potentially inferior therapies to become accepted based on insufficient evidence (7)..