Eligibility, Outcome Measures Need Uniformity Across AAV Clinical Trials, Review Says

Clinical trials testing new treatments for people with ANCA-associated vasculitis (AAV) need more uniformity in the patients they recruit and in the outcome measures used for efficacy assessments, a new review indicates.

The review, “Randomized clinical trials in ANCA-associated vasculitis: a systematic analysis of the WHO — International Clinical Trials Registry Platform,” was published in the Orphanet Journal of Rare Diseases.

Noteworthy improvements have been seen in recent years in the treatment of AAV, accompanied by more clinical trials being done for the autoimmune disease. Researchers note that, in order to get meaningful results from such clinical trials, it is critical that they be properly designed. That means enrolling exactly the right population and using outcome measurements that are meaningful both clinically and to people with AAV, among other criteria.

Assessing the designs of recent clinical trials can help to ensure that these goals are being consistently met, and identify areas for future improvement.

In the new study, the researchers conducted an analysis of 40 AAV clinical trials conducted between 2008 and 2018, primarily in Europe or North America.

Almost all (95%) of the studies used a parallel arm design, commonly used in clinical trials generally. In this design, different groups are given treatment(s) or a placebo for the duration of the trial. A majority of the studies (65%) were not funded by industry.

The median number of participants the trials planned to enroll was 68. Nearly all (92.5%) recruited participants over age 65. In 40% of trials, only individuals who were positive for ANCAs were eligible for enrollment.

Half of the studies recruited participants with the most common types of AAV: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), or renal-limited AAV. Five included people with MPA, GPA, and also the less common subtype eosinophilic granulomatosis with polyangiitis (EGPA); 11 trials included only one subtype of AAV.

Almost all (95%) of the trials were investigating the efficacy of pharmacological interventions for AAV. The most common types of therapies evaluated were monoclonal antibodies, which are a lab-made protein (16 trials), and glucocorticoids, or corticosteroid hormone (5 trials). Some studies also tested complement antagonist (3 trials), and conventional immunosuppressing medications (3 trials). The two non-pharmacological interventions investigated were procedures such as plasma exchange.

The most common objectives for these trials had to do with remission — either inducing remission (16 trials), maintaining remission (13 trials), or both (4 trials). Consistently, the most commonly used efficacy measurements were either remission (16 trials) or relapses (13 trials). However, the exact criteria that were used to determine what constituted remission or relapse varied somewhat among the different trials.

The outcomes used in the trials were classified by the researchers conducting the review as either “patient important” or not — that is, of actual relevance to the lived experience of people with AAV or not — based on previous research in the field. Seven trials had primary outcomes that were not considered patient important.

“RCTs [randomized clinical trials] conducted in AAV in the last decade were mainly single-country [with the entire study conducted within one nation], two parallel arms, late development studies investigating the efficacy of pharmacological treatments to induce or maintain remission,” the researchers concluded. “The majority of primary outcomes were considered to be patient-important, but definitions of disease states such as remission were heterogeneous, and only one primary outcome was [patient-reported].”

A few trends in trial design over time were noted by the researchers. For instance, more trials done in recent years tested a single subtype of AAV and were not funded by industry. Additionally, more recent trials tended to plan to enroll more participants, with a median of 98 patients for studies between 2014-2018, as compared with 40 for trials between 2009-2013.

Overall, this review is indicative of the advancements in clinical testing for AAV treatments that has occurred in recent years, which have “tremendously contributed to improve the care of AAV patients,” the researchers wrote.

The review also highlights areas for improvement in the design of future trials: “A better harmonization of eligibility, and outcome criteria across studies is an important objective to pursue in next future,” the researchers concluded.