AvacoStar is a noninterventional, multinational, prospective cohort study enrolling approximately 500 patients with newly diagnosed or relapsing severe, active GPA or MPA from Germany and the United Kingdom who are receiving treatment as part of routine clinical practice. Inclusion and exclusion criteria are outlined in Textbox 1.

Patients are enrolled into 1 of the 2 groups: those treated with avacopan plus a standard of care at local investigators’ discretion (usually an RTX- or CYC-based regimen; the avacopan group) and a second cohort treated with a CYC- or RTX-based induction regimen without avacopan (the non-avacopan group). Avacopan and the standard of care are prescribed in the usual manner in accordance with the corresponding summary of product characteristics (SmPC) under the sole decision of the investigator. As per the SmPC, avacopan in combination with an RTX or CYC regimen is indicated for the treatment of adult patients with severe, active GPA or MPA [26]. Participants may start or stop avacopan during the study in line with usual practice. The baseline visit is defined as the day on which induction treatment (avacopan or non-avacopan standard of care with CYC or RTX) is started for active AAV. Patients are being enrolled prospectively, but up to 6 months of data may be collected retrospectively if necessary. The overall study duration is anticipated to be up to 7 years, including a recruitment period of approximately 3 years. Follow-up of enrolled patients will continue until the last patient last visit milestone, 4 years after the last participant is enrolled (Figure 1). Participants in the non-avacopan group who initiate avacopan during follow-up due to disease flare will be withdrawn from the study at that time but may cross over and re-enroll in the avacopan group if eligibility criteria are met and recruitment is still ongoing. Re-enrollment will require a new informed consent form (ICF) and assignment of a new patient identification number. Participants in the avacopan group who discontinue avacopan treatment during follow-up will remain in the study, and data will be collected as part of the avacopan group. All decisions on therapeutic or diagnostic procedures, treatments, disease management, timing of visits, and resource use are made following the investigator’s usual clinical practice. Individual participant follow-up data will be collected periodically at routine clinic visits from enrollment until the last patient last visit.

The primary objective of this study is to evaluate the incidence of defined MESIs in patients with AAV commencing avacopan. This includes the incidence (number and percentage of patients with events and total number of events), incidence per patient year, and exposure-adjusted incidence rate (EAIR) per patient year with 95% CIs of defined MESIs (liver injury, cardiac safety, serious infection, and malignancy). The secondary objectives of this study are outlined in Textbox 2. This protocol fulfills the requirements of the European Medicines Agency to conduct a PASS as a postmarketing commitment.

Statistical analyses will be exploratory in nature, performed using the SAS statistical software (version 9.4 or later; SAS Institute). All variables will be analyzed descriptively using appropriate statistical methods: categorical variables will be analyzed via frequency tables (absolute and relative frequencies), and continuous variables will be analyzed via descriptive statistics (ie, number of patients, mean, SD, minimum, median, quartiles, and maximum). Continuous variables will be summarized via absolute value and changes from baseline per analysis time point if applicable. Where appropriate, 95% CIs will be provided. Comparisons between treatment groups will be performed using appropriate methods to adjust for potential bias. A propensity score will be constructed by estimating the probability of exposure by regressing the treatment assignment on baseline characteristics using logistic regression. Treatment group comparisons will be conducted using 2 methods: adjustment (the propensity score is included in the regression model) and inverse probability weighting. The proportion of patients with at least 1 event will be analyzed using logistic regression (using the Firth correction if the event is rare), and results will be reported as odds ratios with 95% CIs and 2-sided P values, along with estimated event proportions (least squares mean) and their 95% CIs. Incidence rates (IRs; unique IR, EAIR, and unique EAIR) per patient year will be analyzed using negative binomial regression (SAS GENMOD), with results reported as rate ratios with 95% CIs and 2-sided P values, along with the corresponding estimated rates per patient year and their 95% CIs. Outcomes of statistical comparisons will be interpreted with caution.

The sample size of 250 participants in the avacopan group was considered reasonable; given an expected attrition rate of 15% or 10% per year, the power of the study to detect a single event will be 77% or 81%, respectively, for an AE with an IR per year of 0.2% for a follow-up duration of 4 years. Malignancy related to immunosuppression is the most infrequent form of the expected AEs, with the literature reporting an incidence of 1.4% per year. A sample size sufficient to detect an AE with an IR of 0.2% per year is well placed to detect a malignancy event related to immunosuppression. Skin cancer is the most common malignancy related to immunosuppression after organ transplantation, with a US study reporting a 1.4% annual incidence, well within the detection limit of this study [27].

For MESIs, the incidence (number and percentage of patients with events and total number of events), as well as the incidence per patient year, will be provided for the avacopan group. For each MESI, both the IR and EAIR will be calculated with CIs. The EAIR will account for individual differences in patient follow-ups. The EAIR per patient year will be calculated as (number of MESIs)/(total patient years of exposure). Total patient years of exposure is calculated as the sum of each patient’s individual treatment duration measured from treatment initiation to the end of the exposure period. The incidence of MESIs will be presented by year as well as cumulatively over the full period of observation. To determine whether MESIs occurring after avacopan has been discontinued should be reported as part of the avacopan group, appropriate risk windows will be used. Malignancy events will be analyzed using an indefinite risk window irrespective of last avacopan dose, whereas other events (liver injury, cardiac safety, and serious infections) will be analyzed using a risk window of 9 weeks at either the end of follow-up or last avacopan dose.

IRs of AEs leading to discontinuation of therapy, serious adverse drug reactions, and adverse drug reactions for the avacopan group will be presented. For AEs, SAEs, and MESIs, the incidence as well as the incidence per patient year will be provided by treatment group, overall, and by Medical Dictionary for Regulatory Activities system organ classes and preferred terms. All AEs and treatment-emergent AEs will be reported separately. For SAEs and MESIs, treatment groups will be compared for the proportion of patients with at least 1 event and the number of events per year, and for the IRs per patient year, the unique IR, EAIR, and unique EAIR will be reported. Descriptive statistics will also be provided by treatment group for change in Vasculitis Damage Index (VDI), change in laboratory assessments over time, proportion of GC-free patients over time, concomitant and cumulative immunosuppression over time, incidence of disease flares, and time to first flare as assessed using the Birmingham Vasculitis Activity Score (BVAS) for patients achieving remission. The duration of treatment with avacopan by reason for treatment discontinuation will be summarized descriptively.

Baseline data being collected include demographics; smoking history; MPA or GPA diagnosis; medical history and comorbidities; prior treatment with immunosuppressive drugs; treatment group and exposure; investigator’s reason for choosing the treatment group; ANCA titers; and laboratory values, BVAS, and VDI. Variables for each of the treatment groups being collected during the follow-up period include information on the use of immunosuppressives alongside avacopan- and non–avacopan-based regimens, ANCA titers, laboratory values, BVAS, VDI, AEs, MESIs, SAEs, selected safety laboratory tests, disease-related damage, flares, and use of concomitant immunosuppression and GCs. Data on AEs observed from baseline, including the seriousness, timing of onset, duration, causal relationship to avacopan, action taken with regard to avacopan administration and dosing in response to the event, and outcome of the event will also be collected. The expected timings for the collection of each variable are presented in Table 1. The study team will ensure data quality through targeted on-site verification of critical variables to confirm accuracy against source documents. Remote monitoring will enable continuous oversight, timely query resolution, and early detection of inconsistencies and deviations from the protocol. Periodic data review and ongoing data cleaning will further ensure that the final dataset is complete, reliable, and fit for analysis.

This study is being conducted within an approved indication in accordance with the Declaration of Helsinki, the International Society for Pharmacoepidemiology Guidelines for Good Publication Practice, the European Medicines Agency guideline on good pharmacovigilance practices module VI and VIII for PASSs, and local laws and regulations as applicable in each participating country [28-30]. The PASS will comply with Revision 6 of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance methodological standards for study protocols, the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance Checklist for Study Protocols, and the guidelines for good publication practice of the International Society for Pharmacoepidemiology, as well as the data vendor’s (IQVIA) quality management system [31-33]. Additionally, guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use concerning good clinical practice are being followed whenever possible [34].

Each study site has received approval from their regulatory authority or ethics committee before study initiation. A full list of the ethics committees and application IDs is available in Multimedia Appendix 1.

Written informed consent must be obtained from the patient (or their legally authorized representative) before participation in the study and in accordance with the local requirements. The informed consent process and signed ICF must be documented and included in their medical file, and a copy of the signed ICF (with certified translation if applicable) must be provided to the patient or representative. All signed and dated ICFs must be retained in the study file and be available for monitoring at any time. Patients may withdraw consent at any time without it affecting their medical care or access to treatment. Participants in the non-avacopan group who initiate avacopan during follow-up may re-enroll in the avacopan group if eligibility criteria are met and recruitment remains open, and they must resign the ICF at re-enrollment. Patients will not receive any compensation for their participation in this study.

Patient data are collected in a pseudonymized or deidentified form. Any new information that might influence the evaluation of the benefit and risk balance of the product shall be immediately communicated to competent authorities of member states. The analysis will be performed on the pseudonymized or deidentified patient-level dataset. The data system will be maintained and secured as required by applicable laws and regulations. Processes assuring data security will be used during data extraction, storage, and backup. The progress reports and final analysis will be reviewed and evaluated by a medical monitor and/or pharmacovigilance delegate.

Despite current treatments for AAV, disease burden still has a high impact on the quality of life of individuals with GPA or MPA [17,18,35], and many do not achieve or sustain remission [36,37]. Existing treatments cannot induce sustained disease control in all patients, and immunosuppressive agents, including GCs, are associated with frequent clinically relevant AEs and comorbidities, both resulting in impaired quality of life [13,15]. There is an unmet need for alternative, more targeted, and less toxic therapeutic options [38].

The avacopan-based regimen in combination with RTX or CYC may be considered for induction of remission in AAV as part of a strategy to substantially reduce exposure to a tapering prednisone regimen [10,11,17,39]. However, the safety of avacopan beyond 52 weeks has not been assessed. Therefore, it is of interest to monitor the drug in daily use as per clinical practice and generate long-term safety data in real-world settings. This information will be gathered in the context of this study. The main rationale for this PASS is to further understand the identified and potential risks of avacopan described above by studying the use of avacopan among patients in a real-world context, where treatment may extend beyond 1 year. The AvacoStar study is designed to assess long-term safety and observe avacopan in daily use in a real-world context.

Given the heterogeneous clinical presentation of patients with AAV, the planned multicenter, multinational large sample size will provide an adequate representative number of patients. The data collected in this study will be frequently monitored during the study lifetime. Data collection will ensure that applicable variables of interest and critical data elements are routinely collected as part of real-world clinical care and are available via medical charts and physician reporting.

To our knowledge, this is the largest European prospective real-world evidence study of avacopan in patients with GPA or MPA. This study evaluates long-term safety data on the use of avacopan and is the longest study to date. This study will also generate data that reflect real-world management of AAV. Although we are recruiting from a European population, the multicenter, multinational study design will facilitate the generalizability of the study results.

As this is a noninterventional study, there are several potential confounding factors to be considered. Although several steps were taken to minimize bias, it is likely that some residual bias remains and, therefore, the results of any direct comparisons between the avacopan and non-avacopan groups will need to be interpreted with this in mind. For example, avacopan may be used by clinicians preferentially in patient subgroups where randomized controlled trial data have shown the greatest benefit (eg, severe, active renal disease or presence of GC-related comorbidities). Eligibility criteria have been selected to ensure that baseline characteristics in the non-avacopan group are similar to those of the avacopan group, and all participants enrolled in the study will be potentially eligible to receive avacopan according to the European SmPC even if they are enrolled into the non-avacopan group. Additionally, detailed information will be collected at baseline on potential confounding factors, including those related to disease severity, diagnosis, prior immunosuppression exposure, and MESI-related risk factors. To account for the risk of bias resulting from confounding factors, treatment groups will be compared using propensity scoring methodology.

The AvacoStar study will be a large, prospective real-world evidence study that evaluates the long-term safety of avacopan in GPA or MPA. The study is expected to yield important insights on the use of avacopan in GPA or MPA in a real-world setting, including treatment beyond 12 months.