Ultra-Low Doses of Rituximab for Retreatment of RA: A Randomized Controlled Non-Inferiority Trial

Lise Verhoef¹, Nathan den Broeder ¹, Rogier Thurlings ², Willemijn van der Laan ¹, Wilfred van der Weele ³, Marc Kok ⁴, Hein Bernelot Moens ⁵, Thasia Woodworth ⁶, Bart van den Bemt ¹, Frank van den Hoogen ¹ and Alfons den Broeder ¹, ¹Sint Maartenskliniek, Nijmegen, Netherlands, ²Radboudumc, Nijmegen, Netherlands, ³Reade, Amsterdam, Netherlands, ⁴Maasstad Hospital, Rotterdam, Netherlands, ⁵Ziekenhuisgroep Twente, Almelo, Netherlands, ⁶University of California, Los Angeles, CA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: rheumatoid arthritis (RA) and rituximab

Session Information

Date: Sunday, November 10, 2019

Title: 3S109: RA – Treatments II: Novel Treatments for RA (927–932)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Rituximab is an effective treatment for patients with RA. 1000mg (1×1000mg or 2×500mg) has similar six-month efficacy as the registered dose of 2×1000mg.(1) Based on several case reports and a case series even lower doses might be sufficient for maintenance treatment, potentially improving safety and decreasing costs.(2) The objective of this study was to compare effectiveness of rituximab retreatment with ultra-low doses (1×500mg or 1×200mg) to standard low dose (1×1000mg).

Methods: A six-month double-blind randomized controlled non-inferiority trial (REDO study (3)) was performed in five centers in the Netherlands. Patients with rheumatoid arthritis responding well to rituximab (based on DAS28-CRP< 2.9 or clinical judgement) were randomized (1:2:2) to 1×1000mg, 1×500mg or 1×200mg rituximab respectively. DAS28-CRP and peripheral CD19+ B-cells were measured at baseline, three and six months. Primary analysis (per protocol with last observation carried forward (LOCF)) consisted of a hierarchical testing procedure comparing ultra-low doses (1×500mg at three and six months, then 1×200mg at three and six months) to 1×1000mg using a non-inferiority margin of 0.6 (on DAS28-CRP). DAS28-CRP change of study groups was compared using linear regression, adjusted for baseline DAS28-CRP, RF/ACPA status and concomitant csDMARD use. Intention-to-treat (ITT) analyses were done similarly (including all cases without LOCF).

Results: The projected inclusion was met (n=142, table 1a). In both ultra-low dose groups two patients received an extra dose of 1000mg rituximab due to a flare. The 500mg dose was non-inferior to 1000mg at three months (-0.07 (95% CI -0.41 to 0.27)), but not at six months (0.29 (95% CI -0.08 to 0.65). The 200mg dose was non-inferior to 1000mg at both time points. Because of our pre-defined hierarchical testing, non-inferiority could not formally be inferred for the 200mg dose. ITT analyses showed non-inferiority for all comparisons. Mean DAS28-CRP scores remained low in all groups throughout the study, and B-cell counts decreased similarly at three months (figure 1). The incidence density of infections was lower in the 500mg group (rate ratio 0.42 (95% CI 0.21 to 0.83, p=0.01)) and in the 200mg group (rate ratio 0.44 (95% CI 0.22 to 0.88, p=0.02)) compared to the 1000mg group (table 1b).

Conclusion: Non-inferiority of retreatment with 1×500mg or 1×200mg rituximab versus 1×1000mg after 6 months could not formally be established. However, ultra-low doses appear similarly effective in the majority of RA patients, judged by non-inferiority of ITT analyses, DAS28-CRP course over time and B-cell results, with a better safety profile and possibly slightly more co-medication.

References
1. Bredemeier et al. Clin Rheumatol. 2015;34(10):1801-5
2. Shenoy et al. Arthritis Rheumatol. 2015;67(suppl 10).
3. den Broeder et al. Trials. 2017;30;18(1):403

Table 1

Figure 1

Disclosure: L. Verhoef, None; N. den Broeder, None; R. Thurlings, Roche, 9, AbbVie, 9, Cellgene, 9; W. van der Laan, None; W. van der Weele, None; M. Kok, None; H. Bernelot Moens, None; T. Woodworth, None; B. van den Bemt, AbbVie, 2, 5, 8, Biogen, 8, BMS, 2, Novartis, 5, Pfizer, 2, 5, Sandoz, 8, UCB, 2, 5, 8; F. van den Hoogen, AbbVie, 5, Actelion, 2, Amgen, 8, Biogen, 5, BMS, 2, Boehringer Ingelheim, 5, Celgene, 5, Celltrion Healthcare, 5, 8, Corbus, 8, Eli Lily, 2, Janssen, 8, Mundipharma, 5, Novartis, 5, Pfizer, 2, Roche, 8, Sandoz, 8, Sanofi Genzyme, 5; A. den Broeder, AbbVie, 9, Amgen, 8, Biogen, 9, BMS, 8, Boehringer Ingelheim, 8, Cellgene, 9, Fresenius, 8, Roche, 9.

To cite this abstract in AMA style:

Verhoef L, den Broeder N, Thurlings R, van der Laan W, van der Weele W, Kok M, Bernelot Moens H, Woodworth T, van den Bemt B, van den Hoogen F, den Broeder A. Ultra-Low Doses of Rituximab for Retreatment of RA: A Randomized Controlled Non-Inferiority Trial [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/ultra-low-doses-of-rituximab-for-retreatment-of-ra-a-randomized-controlled-non-inferiority-trial/. Accessed .

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