Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial

The MAINRITSAN trial was designed to compare four cycles of rituximab (500 mg × 2 at 6 months then 500 mg every 6 months × 3) with maintenance therapy with azathioprine following induction with cyclophosphamide in patients with AAV, largely with patients with newly diagnosed disease [13]. Fixed-interval rituximab was shown to be more effective in maintaining remission at 28 months. The MAINRITSAN trial has provided valuable information on the use of rituximab as a maintenance agent in AAV, although several important questions remain unanswered. Firstly, the MAINRITSAN study was underpowered to assess the effect of repeat-dose rituximab in the subgroup with the most need of a remission-maintenance strategy, namely patients with relapsing disease (only 23 of 115 patients had relapsing disease). Secondly, in many countries rituximab has now been granted a license for remission-induction in AAV, and is increasingly being used in place of cyclophosphamide. The optimal remission maintenance strategy following rituximab induction therapy is unknown. Thirdly, relapses do occur among patients treated with repeatedly-dosed rituximab, mostly in intervals of 6 more months [11, 12, 14]. Therefore, reducing the interval of repeated doses of rituximab to 4 months has the potential to further reduce relapse rates, and aims to maintain 100% B-cell depletion for the entire 24-month treatment phase. Finally, the total dose of rituximab for maintenance therapy in RITAZAREM is double that used in MAINRITSAN (5000 mg versus 2500 mg) which will permit comparison of the safety and longer-term efficacy of the two dosing regimens.

The RITAZAREM trial will address the question of the optimal treatment regimen for maintenance of remission following induction of remission with rituximab in AAV, and the possibility that prolonged B-cell depletion using high doses of rituximab, will lead, upon discontinuation of therapy, to sustained treatment-free remissions.

Enrollment and randomized allocation to treatment arm will be performed by an Internet-based website (TENELEA) provided by the Cambridge Clinical Trials Unit.

This is an open-label study. Several previous vasculitis studies that have had major influences on practice and have stood up to re-examination have been unblinded, and similar endpoints have been used, with processes developed in data management to check and manage potential bias. Blinding would have necessitated the administration of sham infusions and placebo tablet medications to all participants, which would have increased the complexity and cost of the trial and exposed participants to unnecessary interventions. A pragmatic approach of having the primary endpoint, relapse, independently assessed by expert adjudicators blinded to treatment allocation was decided.

To be eligible, participants must be aged 15 years and above and should have a diagnosis of AAV according to Chapel Hill Consensus Conference definitions [16], along with a current or historical positive test for proteinase 3/myeloperoxidase anti-neutrophil cytoplasmic antibody (PR3/MPO ANCA) by enzyme-linked immunosorbent assay (ELISA). All patients must have disease relapse defined by one major or three minor disease activity items on the BVAS/WG and they must have previously achieved remission following at least 3 months of induction therapy, with a combination of GC and an immunosuppressive agent (cyclophosphamide, rituximab, methotrexate, or mycophenolate mofetil (MMF)).

Key exclusion criteria include the receipt of any biological B-cell-depleting agents within the previous 6 months, alemtuzumab, or anti-thymocyte globulin (ATG) within the last 12 months, or intravenously administered immunoglobulin (IVIg), plasma exchange, or anti-TNF treatment within the last 3 months. Patients with other multisystem autoimmune disease such as eosinophilic granulomatous with polyangiitis (eGPA), systemic lupus erythematosus (SLE), anti-glomerular basement membrane (GBM) disease or cryoglobulinaemic vasculitis, or history of malignancy within the past 5 years are also excluded. Additional file 2 lists the full inclusion and exclusion criteria for the study.

Participants will be recruited from many centers participating in the European Vasculitis Society (EUVAS), the Vasculitis Clinical Research Consortium (VCRC), and from centers in Japan, Australia, and New Zealand.

See Additional file 3 for figure: RITAZAREM trial flow chart.

Time to relapse is the primary endpoint of the study. Patients experiencing their first minor relapse after randomization and before month 24 will remain on their randomized treatment and the dose of orally administered prednisone/prednisolone will be increased to 20 mg/day for 1 week decreasing in daily 2.5-mg increments each week until the dose is back to the dose before the relapse at which point the patient returns to the standard dosing schedule. The second minor relapse, or first major relapse, occurring before month 24, will result in the patient being withdrawn from protocolized treatment and the patient will be treated according to the investigator’s discretion. Any relapse occurring after the 24-month treatment phase will be treated according to local best medical practice.

Evaluations (including clinical, biochemical, and patient-reported outcomes) will be performed at months 0, 1.5, 3, 4, 8, 12, 16, 20, 24, 27, 30, 36, and every 6 months until the last patient has completed 36 months in the study (see Additional file 4 – SPIRIT figure: RITAZAREM schedule of events). The maximum duration in the study for any individual is 48 months. Assessments will also be performed at the time of relapse. Data will be collected on paper Case Report Forms, and entered into an electronic database hosted by the Cambridge Clinical Trials Unit.

Enrollment will be ongoing until 160 patients are randomized at their 4-month visits. It is anticipated that 190 patients will be required in order to randomize 160 patients. A power of 90% will be achieved under the alternative hypothesis of a hazard ratio of 0.42 at the 5% significance level with 58 observed relapses. Randomizing 160 patients will achieve this over the course of the study assuming a dropout rate up to 5% at 2 years and a relapse-free rate of 75% and 50% at 4 years in the experimental and control arms, respectively. The hazard ratio of 0.42 is based on assuming a relapse-free rate of 75% at 4 years in the rituximab arm versus 50% at 4 years in the standard treatment arm.

A statistical analysis plan, separate to the study protocol, will be finalized prior to any analyses being performed. The primary intention-to-treat analysis will be based on a Cox proportional hazard model. There will be a closed testing procedure. Hazard ratios and 95% confidence intervals will be reported. First, the null hypothesis will be for a hazard ratio of 1 at all time points. If this is rejected at a 5% level then two further subhypotheses will be examined using time-varying covariates:

RITAZAREM is funded by grants from Arthritis Research UK and Roche/Genentech. The Vasculitis Clinical Research Consortium (VCRC) (U54 AR057319 and U01 AR5187404) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and has received funding from the National Center for Research Resources (U54 RR019497). The primary sponsor is Cambridge University Hospitals NHS Foundation Trust and there are collaboration and data-sharing agreements with the University of Pennsylvania and the University of Miyazaki Hospital and Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences in Japan. A NIAMS Data and Safety Monitoring Board (DSMB) will provide oversight of this study. This is a standing DSMB that provides such oversight for all VCRC research studies, including randomized trials. The DSMB will meet at least every 6 months to discuss the study progress and more frequently, if needed. The Trial Steering Committee will provide overall supervision of the study on behalf of the principal funder, Arthritis Research UK. The Trial Steering Committee will monitor the progress of the study and maximize the chances of completing the study within the agreed time scale and budget. The Trial Management Committee is responsible for the design, conduct and overall management of the study. Cambridge Clinical Trials Unit has provided support in all phases of trial design, conduct, and management for this trial.

The design of the study was presented at multiple local, national, and international meetings with patient attendees with positive review and input received from patients with AAV. The Patient Information Sheet was reviewed and commented upon by a patient panel prior to submission to the Ethics Committee.

Enrollment was completed on 21 November 2016, and thus randomization will be complete by the end of March 2017. The primary endpoint will be reported in 2019, and the final trial report in 2020.