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Randomized Controlled Trial
. 2017 Sep;28(9):2756-2767.
doi: 10.1681/ASN.2016111179. Epub 2017 Apr 11.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

David R W Jayne  1 , Annette N Bruchfeld  2 , Lorraine Harper  3 , Matthias Schaier  4 , Michael C Venning  5 , Patrick Hamilton  5 , Volker Burst  6 , Franziska Grundmann  6 , Michel Jadoul  7 , István Szombati  8 , Vladimír Tesař  9 , Mårten Segelmark  10 , Antonia Potarca  11 , Thomas J Schall  11 , Pirow Bekker  11 ; CLEAR Study Group
Affiliations
Randomized Controlled Trial

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

David R W Jayne et al. J Am Soc Nephrol. 2017 Sep.

Abstract

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Keywords: ANCA; ANCA-associated vasculitis; avacopan; complement; complement 5a; complement 5a receptor.

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Figures

Figure 1.
Figure 1.
Consort diagram of patient flow through the study. Of 87 patients screened, 67 were enrolled. The main reasons for study exclusion were insufficient disease activity, low white blood cell count, and severe disease activity. AE, adverse event; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell count.
Figure 2.
Figure 2.
Changes in disease activity, urinary abnormalities and quality of life indices in the three treatment groups during the study. (A) BVAS percent change from baseline for each patient, presented by treatment group. (B) BVAS mean±SEM percent change from baseline for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=21 (▲). (C) First morning UACR percent change from baseline, calculated as 100 × (geometric mean at the study visit)/(geometric mean at baseline) for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=20 (▲); *P<0.05, **P<0.01, and ***P<0.001 for avacopan compared with control by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (D) First morning urinary MCP-1–to-creatinine ratio percent change from baseline, calculated as 100 × (geometric mean at the study visit)/(geometric mean at baseline) for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=21 (▲); **P<0.01, and ***P<0.001 for avacopan compared with control by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (E) And (F) health-related quality-of-life measurement Medical Outcomes Study SF-36 version 2 Physical Functioning and Role Emotional components, respectively, expressed as mean±SEM over the course of the treatment period for placebo plus high-dose prednisone, n=10 (♦); avacopan plus reduced-dose prednisone, n=14 (■); and avacopan without prednisone, n=9 (▲); the scale ranges from 0 to 100, from low to high functioning; *P<0.05 for avacopan compared with control regarding change or percent change from baseline by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (G) Health-related quality-of-life measurement EQ-5D-5L visual analog scale expressed as mean±SEM for placebo plus high-dose prednisone, n=10 (♦); avacopan plus reduced-dose prednisone, n=14 (■); and avacopan without prednisone, n=9 (▲); the scale is measured from 0 to 100, from low to high self-perception of health status; *P<0.05 for avacopan compared with control regarding change from baseline by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate.
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