Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a serious, often life-threatening disease that includes three related forms of small-vessel vasculitis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss). GPA and MPA are thought to be triggered by the production of circulating autoantibodies against the neutrophil-expressed antigens myeloperoxidase (MPO) or proteinase 3 (PR3). The disease may present with a wide spectrum of clinical manifestations of varying degrees of severity including but not limited to skin lesions, sinonasal, pulmonary inflammation or hemorrhage, and glomerulonephritis.

The proinflammatory complement C5a ligand and its receptor C5aR (also referred to as CD88) appear to play a central role in the pathogenesis of ANCA-associated vasculitis [1-4]. When stimulated by inflammatory cytokines, activation of the terminal C5a/C5aR axis generates an autoamplification loop that drives the acute necrotizing vasculitic process from primed neutrophils resulting from their interaction with ANCAs. C5a acting on C5aR is a potent neutrophil chemoattractant and agonist [5], which increases neutrophil adhesion, induces neutrophil degranulation, and produces reactive oxygen intermediates. Activation of C5aR also decreases neutrophils’ deformability, slowing their ability to traverse small blood vessels particularly in the presence of ANCA [6]. Moreover, C5a activates vascular endothelial cells through C5aR, promoting their retraction and increased vascular permeability [7,8].

The current standard treatments for induction of remission for GPA and MPA rely on substantial immunosuppression and consist primarily of glucocorticoids combined with either cyclophosphamide (intravenous or oral) followed by oral azathioprine, or rituximab [9-11]. Despite these available therapies, patients with ANCA-associated vasculitis have a 9-fold increased risk of mortality in the first year compared with healthy controls, attributed to infection, active vasculitis, and the effects of renal insufficiency [12,13]. More than 50% of the 1-year mortality is attributed to treatment-related adverse events rather than active vasculitis [12,13]. Furthermore, substantial accumulated permanent damage can occur when the disease is insufficiently controlled; for example, 15% to 38% of patients develop end-stage renal disease within 5 years [14-19].

Although glucocorticoids have a relatively rapid onset of action, their use is associated with an overall negative impact on the patient’s health and health-related quality of life (HRQoL), attributable to known acute and chronic effects of these medications [20]. In the treatment of ANCA-associated vasculitis, these include increased risks of infection [21-23], diabetes mellitus, fractures, gastrointestinal bleeding, hypertension, cataracts, and progressive organ damage [24]. Weight gain, sleep disturbance, lipodystrophy, and neuropsychiatric disturbances (including irritability, anxiety, depression, and hyperactivity) have also been reported [25,26]. Moreover, an analysis of data from patients enrolled in several trials conducted by the European Vasculitis Study Group showed that the level of damage associated with the use of glucocorticoids in ANCA-associated vasculitis increased with length of exposure [24]. In relapsing disease, the repeated use of glucocorticoids leads to even further damage. Collectively, the data indicate a need for effective glucocorticoid-sparing treatments that can help avoid complications associated with exposure to glucocorticoids and limit organ damage through more rapid and sustained disease control.

Avacopan (previously known as CCX168) is a novel, orally bioavailable, highly selective human C5aR antagonist that lacks any other known pharmacology [27]. Importantly, avacopan does not inhibit the interaction of C5a with the related receptor C5L2 (also referred to as C5aR2), thought to have anti-inflammatory properties [27] and also shown to impart protective effects in a mouse model of anti-MPO-induced glomerulonephritis [28]. As a specific C5aR antagonist, avacopan does not interfere with the formation of the terminal complement complex or membrane attack complex C5b-9, which is necessary for clearance of pathogenic encapsulated bacteria such as Neisseria meningitidis.

Along with a favorable safety profile in a phase 1 dose escalation clinical trial in healthy volunteers, 30 mg of avacopan administered twice daily was shown to produce plasma concentrations that provided near complete inactivation of C5aR on blood neutrophils throughout the day, including ≥90% C5aR blockade at trough levels of the drug [27]. This exposure was sufficient to achieve optimal blockade of C5a-induced CD11b upregulation, as well as C5a-induced degranulation, reactive oxygen intermediate production, and C5a-directed migration of neutrophils ex vivo, forming the basis for the dose selected for avacopan in subsequent clinical studies of ANCA-associated vasculitis.

In a phase 2 clinical trial (NCT01363388) conducted in ANCA-associated vasculitis, 67 patients received one of the three treatments: avacopan with no prednisone, avacopan with low-dose (20 mg/day) prednisone (with taper), or placebo control with standard dose (60 mg/day) prednisone (with taper); treatment was administered along with either cyclophosphamide followed by azathioprine or rituximab. Avacopan was shown to replace glucocorticoids without compromising efficacy. Clinical response at week 12, defined as a 50% reduction in Birmingham Vasculitis Activity Score (BVAS) from baseline, was observed in 70% of the standard treatment group (placebo), 86% of the avacopan plus low-dose prednisone group (P=.002 for noninferiority, compared with standard care), 81% of the avacopan without prednisone group (P=.01 for noninferiority, compared with standard care), with a trend for faster control of disease in the avacopan groups relative to control [29]. Patients in the avacopan groups also had a rapid improvement in albuminuria (an indicator of preserved renal function), whereas the estimated glomerular filtration rate and hematuria improved in all treatment groups. Fewer glucocorticoid-associated adverse effects (primarily driven by a lower incidence of new-onset or worsening diabetes mellitus and psychiatric disorders) along with improvements in HRQoL (Medical Outcomes Study Short-Form 36 [SF-36] version 2, and EuroQOL [EQ-5D-5L]) were also associated with avacopan.

A second phase 2 trial of 12-week duration in 42 patients with ANCA-associated vasculitis (NCT02222155) was designed to examine the safety of avacopan when combined with standard of care therapy including glucocorticoids. Comparison of the avacopan versus placebo groups revealed that avacopan therapy when added to standard of care added no new safety signals beyond those associated with standard of care [30].

These phase 2 studies suggest that avacopan is well tolerated and that specific inhibition of the C5a/C5aR interaction on inflammatory cells may improve outcomes in ANCA-associated vasculitis, while reducing glucocorticoid exposure and their associated side effects observed with the standard of care. On the basis of these results, the underlying hypothesis for the phase 3 clinical trial protocol presented here (NCT02994927) is that avacopan is at least as effective as glucocorticoids in rapidly inducing and sustaining remission of signs and symptoms of ANCA-associated vasculitis when combined with either cyclophosphamide followed by azathioprine or with rituximab. As a selective anti-inflammatory agent, avacopan may also have safety advantages compared with glucocorticoids.

The primary objective of the trial is to evaluate the efficacy of avacopan to induce and sustain remission in patients with ANCA-associated vasculitis, when used in combination with immunosuppressive therapy, rituximab, or cyclophosphamide followed by azathioprine (or mycophenolate mofetil), but in the absence of months of treatment with glucocorticoids. As many patients in the trial are expected to have renal involvement due their vasculitis and methotrexate would be contraindicated in such patients, methotrexate was not an option for use following cyclophosphamide; this stipulation also aimed to reduce variation in the treatment groups. Disease remission is defined as achieving a BVAS score [31,32] of 0 (no evidence of active vasculitis) and no use of glucocorticoids for the treatment of ANCA-associated vasculitis within 4 weeks before week 26. Sustained remission is defined as remission at week 26 without relapse to week 52 (BVAS=0) and no use of glucocorticoids for ANCA-associated vasculitis within 4 weeks before week 52.

Secondary objectives include evaluation of the effect of treatment with avacopan versus standard of care on overall safety, glucocorticoid-related toxicity, rapidity of response, changes in HRQoL, changes in renal disease, and cumulative organ damage (vasculitis damage index).

Enrollment of 300 patients is planned across more than 200 sites in 20 countries on 4 continents. Patients who drop out following randomization are not replaced. Briefly, after an explanation of the study and obtaining written informed consent, potentially eligible patients are screened against the inclusion and exclusion criteria (Textboxes 1 and 2) to confirm eligibility including review of their medical history.

Patients are required to fast for at least 9 hours before the first dose of study drug to allow for baseline low-density lipoprotein–cholesterol measurements. Upon arriving at the study site, patients undergo baseline assessments including sample collections to test for autoimmune serologies, hematologic parameters, a comprehensive chemistry panel, urinalysis, and additional blood and urine sampling for research purposes; HRQoL questionnaires (SF-36 and EQ-5D-5L) and glucocorticoid toxicity index [33] are completed.

A minimization algorithm is used to assign patients dynamically to a treatment group, which seeks to balance treatment groups with respect to each stratification factor. Statistical analysis for categorical endpoints will be expressed as the number and percentage of unique patients for each category. For continuous variables, numbers, means, medians, ranges, SDs, and standard error of means will be calculated. Geometric means will be calculated for data that are not normally distributed. Results will be presented by treatment group and by stratum for each of the 3 stratification factors. Results will be presented for patients with and without renal involvement of disease at baseline.

To estimate sample size, a noninferiority margin of −20% was based on a thorough review and meta-analysis of all previous trials conducted in patients with ANCA-associated vasculitis as well as precedent. The proportion of patients with remission in the control group at week 26 was estimated to be 60%, which is based on a blended proportion of 64% and 53% observed in the rituximab and cyclophosphamide/azathioprine groups, respectively, in the RAVE study [10]. On the basis of these assumptions and a 2-sided significance level of 0.05, a sample size of 150 patients per group provides >90% power for the noninferiority analysis. For the determination of the primary efficacy endpoints, the proportion of patients achieving disease remission at week 26 and sustained disease remission at week 52, the 2-sided 95% CIs for the difference in proportions (avacopan group minus prednisone group) will be estimated. For the noninferiority tests at week 26 and week 52, if the lower bound of the 95% CI is greater than −0.20, the avacopan group will be considered not inferior to the control group. For the superiority test, if the lower bound of the 95% CI is greater than 0.0, the avacopan group will be considered superior to the control group.

The two primary endpoints will be tested sequentially using a gatekeeping procedure to preserve the type I error rate at 0.05. The sequence of testing will be as follows:

Continuous variables of the secondary efficacy endpoints will be analyzed using a mixed effect model for repeated measures with treatment group, visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as the covariate. Patients will be considered as repeated measure units over visits.

Each study site is required to obtain prior approval from an Institutional Review Board on both the protocol and patient informed consent before study initiation and in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines and the Declaration of Helsinki (amended by the 59th World Medical Association General Assembly, October 2008). Safety data and efficacy outcomes data are summarized and reviewed by an unblinded Data Monitoring Committee, regularly over the course of the study.

Patients or the public were not involved in the design of this trial. However, patients, through a collaboration with the Vasculitis Foundation, the leading international vasculitis patient advocacy group, were involved in increasing awareness of the trial (dissemination) within the vasculitis patient community. It is anticipated that patients will be involved disseminating the results of this research to other patients with vasculitis, once the trial is complete and the results are made public.

The current therapy for ANCA-associated vasculitis improves patients’ outcomes in terms of signs and symptoms of active vasculitis, but the burden of disease remains high with significant comorbidity and damage because of both glucocorticoids and disease. There is a role for targeted and less toxic treatment regimens [35]. There is increasing evidence that complement activation appears to play an important role in the pathogenesis of ANCA-associated vasculitis whereby C5aR activation augments neutrophil priming by ANCA, and directly acts as a key mediator of organ damage [4,36]. Promising results from two phase 2 studies of 12-week duration in anti-MPO- and anti-PR3-positive ANCA-associated vasculitis suggest that avacopan is well tolerated [29,30] and that its use in combination with either cyclophosphamide or rituximab may result in comparable clinical effectiveness (as assessed by the BVAS) with that of the standard-of-care glucocorticoid-containing regimen, with more rapid onset of disease control measured at week 4, as well as improved renal outcomes and quality of life [29]. Building on these observations, this larger phase 3 trial, with 1-year treatment duration and observation, aims to provide evidence for the effectiveness of C5aR inhibition for the treatment of ANCA-associated vasculitis, with potential to fundamentally change the treatment paradigm of MPA and GPA.

Given the heterogeneous clinical presentation of patients with ANCA-associated vasculitis, a large sample size is planned for this study to provide an adequate number of subjects across subgroups. Moreover, the 2 treatment groups are further balanced through stratification according to three key factors that could potentially influence patient outcomes, including ANCA subtype, new or relapsing disease, and baseline immunosuppressive therapy.

This study includes a broad range of newly diagnosed or relapsing patients with ANCA-associated vasculitis. The use, if warranted, in both treatment groups, of a limited amount of nonprotocol-specified glucocorticoids is allowed at baseline, as is the use of rescue glucocorticoids during the study. However, the protocol specifies the indication, dose, duration, and tapering schedule for nonprotocol-supplied glucocorticoids to limit the impact of their use on the study results.

The study incorporates frequent monitoring over the 1-year treatment period, along with a pharmacodynamic sampling program. Exploratory analyses may provide information on factors that impact rates and timing to disease remission, as well as the risk of relapse among the two treatment arms.