RCTs conducted in AAV in the last decade were mainly single-country, two parallel arms, late development studies investigating the efficacy of pharmacological treatments to induce or maintain remission. Most of the studies were designed to include more than one disease and ANCA-positive patients. The majority of primary outcomes were considered to be patient-important but heterogeneity in definitions of disease states such as remission was observed and only one primary outcome was a PRO. The number of RCTs investigating a single disease, not funded by industry, incorporating GC use in primary outcomes, together with the expected sample size increased over time.
Building evidence for heterogeneous and rare diseases like AAV represents a challenge for the scientific community [22–25]. The main study’s limitations highlighted in this paper can represent a starting point to improve future study design.
Patient samples included in RCTs were quite heterogeneous. First, in most cases more than one disease was investigated. Although this represents the obvious solution to get a needed sample size in such rare diseases, the differences in clinical presentation and evolution among AAV could unfortunately hamper the translation of study results in clinical setting. Moreover, disease definition relied on different criteria, among which ACR criteria and/or Chapel-Hill nomenclature were used in about half of studies, whereas in the other half, only a clinical diagnosis was required. Additionally, the set of trials retrieved was split in almost two equal-sized groups of ANCA positive and mixed ANCA positive and negative patients. This means that slightly less than half of studies did not incorporate ANCA negative patients who represent about 10–20% of GPA [26] and up to 70% of EGPA population [7], with a consequent obvious impaired generalizability of study conclusions.
The intended number of patients to be enrolled has gradually increased over time. This marks a step forward in the study of these diseases on a global scale. The efforts of national and international vasculitis-centered scientific networks are among the factors explaining this finding.
Interestingly the majority of study outcomes was considered to be ‘patient-important’. Most of trials were designed to assess the efficacy of treatments given to induce or maintain remission, or their safety, which are undoubtedly hard outcomes. The choice of ‘patient-important’ outcome has been recognized as a priority to avoid waste of time and resources and represents a successful achievement in the field [27]. It has to be pointed out, however, that the definitions of main outcomes investigated such as remission were inconsistent across the studies. For example, original BVAS or later versions were nearly always used to rule out the occurrence of an active disease on a clinical basis, but GC use was not systematically incorporated in the definition of remission or different minimal GC doses were required; in only 11 studies GC use was part of primary outcomes. This contrasts with EULAR guidelines [11] which recommended to define remission taking also into account the allowable dose or dose range of GC and the period during which such dose should be kept stable. Methodological agreement is crucial to enable inter-study comparison, and enable uniform management in future studies. This point would hopefully deserve to be object of further research. Additionally, it has to be remarked that in only one trial a patient-reported outcome was chosen as primary study endpoint. Efforts are needed to incorporate needs and perspectives of patients in main study outcomes [28].
This study has some limitations. First, we could have missed some clinical trials that were not registered. Second, some important study features such as the criteria used to establish the diagnosis could have been provided only in final publications and not in online databases and consequently not analyzed in our study.
In conclusion, a higher number of trials (overall and targeting single diseases) with an increasing sample size have been designed and conducted in the last decade, but studies were inconsistent in terms of criteria to identify the diseases, number of diseases investigated, and definition of main study outcomes such as remission.