Objectives To assess the symptomatic efficacy and the safety profile of 2 dose regimens of rituximab (RTX) in patients (pts) who had a EULAR response 6 months after a 1st cycle of 2 infusions of RTX 1g and who necessitated subsequent therapy
Methods Definite RA (1987 ACR criteria); active disease (DAS >3.2 and either SJC ≥6 and TJC ≥6 or CRP ≥10 mg/l or ESR ≥28 mm/1st hour; refractory or intolerant to at least one aTNF.
Study design: The 1st 24 week-period was a prospective multi-center non-controlled trial followed (from week (W) 24 to W104) by a randomized controlled trial. At W0, the 1st cycle of RTX consisted of 2 x 1g RTX two weeks apart. At W24, pts who experienced a EULAR response were randomized to receive RTX 1g in one single infusion (Arm A) or the licensed dose of RTX 2 x 1g (Arm B) as subsequent retreatment following assessment of disease activity every 6 months (e.g. DAS >3.2).
Outcome measures: DAS28-CRP, number of required cycles of RTX, time to a second retreatment.
Analysis: Non inferiority of Arm A versus (vs) Arm B on the DAS28-CRP Area Under the Curve (AUC) during 104 W, with a non-inferiority margin defined by 20% of the mean DAS AUC of the reference group (δ=444). Main analysis was performed on the per-protocol (PP) and intention to treat (ITT) population using a covariance analysis that included baseline DAS value as covariate.
Results Of the 234 screened pts, 224 received the 1st cycle of RTX. DAS28-CRP changed from 5.8±0.9 to 4.2±1.2 at W24, resulting in a EULAR response in 152 patients (71%). Pts (n=143) were randomized in the 2nd part of the study (ITT: 70/Arm A and 73/Arm B) without any inter-group difference. Following withdrawals and major protocol deviations, the final PP population was 51pts/Arm A and 49/Arm B. The DAS28-CRP AUC at W104 (PP) was 2761±508 in Arm A and 2666±490 in Arm A vs. Arm B, resulting in an adjusted inter-group difference of 51.4 with a 95% CI of [-131.2; 233.9] demonstrating the non-inferiority of retreatment in Arm A vs Arm B. Similar results have been shown for the ITT population. The number of required cycles per year after the first retreatment was similar in both arms (1.0±0.3) as was the estimated median time to a second retreatment using the Kaplan-Meier method (263 and 255 days in Arm A vs B, respectively). During the study the percentage of any and serious adverse events was similar (92% and 29% vs 96% and 37% in Arm A vs B, respectively). The percentage of pts with an IgG level below 6.82 g/L (LLN) at week 104 was 2% (1/48) and 11% (6/53) in Arm A vs B (p=0.12). The percentage of serious infections was 12% (8/66) and 3% (2/68) in Arm A vs B (p=0.05) corresponding to a serious infection rate of 7.2 and 1.5/100 pt-yrs.
Conclusions This study suggests that in case of a EULAR response after a first cycle of 2 infusions of RTX 1g, retreatment with a RTX 1g single infusion provides similar clinical outcomes compared with 2 x 1g infusions. The structural (radiographic) effect of these 2 strategies was not assessed in this study.
Disclosure of Interest M. Dougados Grant/Research support from: Roche, B. Combe Grant/Research support from: Roche, X. Le Loët Grant/Research support from: Roche, J. Tebib Grant/Research support from: Roche, J. Sibilia Grant/Research support from: Roche, S. Rouanet Employee of: Roche, R. Jourdan Employee of: Roche, X. Mariette Grant/Research support from: Roche
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