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Abstract Number: 954

Effectiveness of Different Dosages of Retreatment of Rituximab in Combination with Leflunomide: Results from a Multicenter Randomized Placebo Controlled Investigator Initiated Clinical Trial in Active Rheumatoid Arthritis (Amara-Study

Frank Behrens1, Tanja Rossmanith2, Michaela Koehm3, Rieke Alten4, Martin Aringer5, GR Burmester6, Eugen Feist7, Klaus Krüger8, Ulf Müller-Ladner9, Andrea Rubbert-Roth10, Siegfried Wassenberg11, Hans-Peter Tony12, Herbert Kellner13, Marina Backhaus14 and Harald Burkhardt1, 1Division of Rheumatology and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University, Frankfurt, Germany, 2Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Frankfurt, Germany, 3Division of Rheumatology and Fraunhofer IME-Project-Group Translational Medicine and Pharmacology, Goethe University, Frankfurt/Main, Germany, 4Schlosspark-Klinik University Medicine, Berlin, Germany, 5Abteilung für Rheumatologie, Dresden, Germany, 6Charité – University Medicine Berlin, Berlin, Germany, 7Charité-Universitätsmedizin Berlin, Berlin, Germany, 8Praxiszentrum St. Bonifatius, München, Germany, 9Justus-Liebig-University Giessen, Department of Internal Medicine and Rheumatology, Kerckhoff-Klinik, Bad Nauheim, Germany, Bad-Nauheim, Germany, 10Division Rheuamatology, University Köln, Köln, Germany, 11Rheumazentrum, Ratingen, Germany, 12Rheumatology/Immunology, Medical Clinic II, University Clinic Wuerzburg, Würzburg, Germany, 13Rheumatology Patient Care, Munchen, Germany, 14Rheumatology, Park-Klinik Weissensee, Berlin, Germany

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Disease Activity, Rheumatoid arthritis (RA), rituximab and treatment options

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Session Information

Date: Sunday, November 13, 2016

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy I: Treatment Strategies

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Use of biologicals such as Rituximab (RTX) in Rheumatoid Arthritis (RA) is effective and often only licensed in combination with Methotrexate (MTX). In cases of contraindications to or intolerances of MTX, other cDMARDs are frequently used in routine care without data from RCTs. In addition, in daily practice different strategies for retreatment with RTX are used. The objective of this study was to demonstrate safety and efficacy of RTX in combination with Leflunomide (LEF) and compare effectiveness of therapy for different dosages of RTX as retreatment at week 24 in a multicenter randomized placebo (PLA) controlled clinical trial in Germany.

Methods: A total of 189 patients with active RA (DAS28 > 3.2 and at least 3 SJC and 3 TJC) despite stable LEF treatment were screened for a 52-weeks randomized double-blind placebo controlled multicenter clinical trial, separated into two parts: in part I, patients were randomized to receive either two times 1000mg RTX i.v. followed by two times 1000 (RTX-RTXhigh) or 500 mg (RTX-RTXlow) at week 24 or PLA, followed by a second course of RTX of either two times 1000 (PLA-RTXhigh) or 500 mg(PLA-RTXlow) at week 24 in part II. The primary endpoint of part II of the study for the retreatment was change in DAS28 at week 52. Adult patients who had inadequate response to more than one antiTNF or failed more than three cDMARDs were excluded. Disease activity as well as patient reported outcomes were measured at each visit until week 52. For safety evaluation, frequency and severity of adverse events were documented.

Results: Of 189 screened patients 148 were randomized. The mean age was 56 years; the mean body weight 76 kg and 74% were female. The disease activity (DAS28) at baseline was 5.57 for RTX and 5.54 in the PLA group. All baseline-characteristics were well balanced between the treatment groups. A superior response for ACR 20 and 50 of RTX vs PLA was seen at week 16 in Part I with 51.6% vs 23.4% (p<0.05) and 31.2% vs 14.9% (p<0.05). For retreatment in part II in patients treated with RTX (2x1000mg) (n=60) at baseline no differences were seen for both groups (RTX-RTXhigh and RTX-RTXlow) with a change in DAS 28 to week 52 of -2.46 and -2.42 respectively. In patients who initially responded to placebo and therefore entered Part II (n=24) a clear difference for two times 1000 mg (PLA-RTXhigh) vs two times 500 mg (PLA-RTX low) could be detected with changes in DAS28 to week 52 of -2.68 and -2.32 respectively. A total of 372 adverse events (AE) were observed during the one-year study period, only 14 were classified as severe (10 in RTX and 4 in PLA). 43 serious adverse events were reported, 28 of them in the RTX treatment group during the placebo controlled period.

Conclusion: Here we report for the first time data of a RCT of combination of RTX with LEF. The treatment with RTX in combination with LEF demonstrated significant efficacy compared to PLA in part I. Retreatment with two times 500mg RTX after standard first course of RTX (two times 1000mg) is comparable to two times 1000mg while clear differences were seen after PLA-treatment. This illustrates the importance of two times 1000mg as initial therapy while retreatment with the lower dose seems equally effective after regular induction therapy. The combination of RTX and LEF demonstrated a reasonable safety profile.


Disclosure: F. Behrens, AbbVie Deutschland, Roche, Janssen, 5,Chugai, 8; T. Rossmanith, Pfizer, Roche Janssen, 2; M. Koehm, Pfizer, Janssen, 2; R. Alten, Roche Pharmaceuticals, 5; M. Aringer, Roche, Chugai, 3,Roche, Chugai, 8; G. Burmester, UCB, 2,AbbVie, 5,BMS, 5,Hexal, 5,Janssen Pharmaceutica Product, L.P., 5,Lilly, 5,MSD, 5,MadImmune, 5,Novartis Pharmaceutical Corporation, 5,Pfizer Inc, 5,Roche Pharmaceuticals, 5,AbbVie, 8,BMS, 8,Hexal, 8,MSD, 8,Novartis Pharmaceutical Corporation, 8,Pfizer Inc, 8,Roche Pharmaceuticals, 8; E. Feist, None; K. Krüger, AbbVie, BMS, Celgene,Janssen Biologics, Pfizer, Roche, Sanofi-Aventis, 5; U. Müller-Ladner, Boehringer Ingelheim, 9; A. Rubbert-Roth, Roche Pharmaceuticals, 5; S. Wassenberg, AbbVie, Celgene, Janssen, Chugai, Lilly, Pfizer, MSD and UCB, 5,AbbVie, Celgene, Janssen, Chugai, Lilly, Pfizer, MSD and UCB, 8; H. P. Tony, Abbvie, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Roche, Takeda, UCB, 5,Abbvie, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Roche, Takeda, UCB, 8; H. Kellner, Roche Pharmaceuticals, 5; M. Backhaus, Roche Pharmaceuticals, 5; H. Burkhardt, AbbVie Deutschland, BMS, Chugai, Janssen, Pfizer, UCB, 5,Pfizer Inc, 2.

To cite this abstract in AMA style:

Behrens F, Rossmanith T, Koehm M, Alten R, Aringer M, Burmester G, Feist E, Krüger K, Müller-Ladner U, Rubbert-Roth A, Wassenberg S, Tony HP, Kellner H, Backhaus M, Burkhardt H. Effectiveness of Different Dosages of Retreatment of Rituximab in Combination with Leflunomide: Results from a Multicenter Randomized Placebo Controlled Investigator Initiated Clinical Trial in Active Rheumatoid Arthritis (Amara-Study [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/effectiveness-of-different-dosages-of-retreatment-of-rituximab-in-combination-with-leflunomide-results-from-a-multicenter-randomized-placebo-controlled-investigator-initiated-clinical-trial-in-active/. Accessed .
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