Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)
Identifieur interne : 000E59 ( Istex/Corpus ); précédent : 000E58; suivant : 000E60Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)
Auteurs : Andrea Rubbert-Roth ; Paul P. Tak ; Cristiano Zerbini ; Jean-Luc Tremblay ; Luis Carreo ; Gillian Armstrong ; Neil Collinson ; Tim M. ShawSource :
- Rheumatology [ 1462-0324 ] ; 2010-09.
Abstract
Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. Methods. Patients with active RA despite stable MTX (1025 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 500 and 2 500 mg; 2 500 and 2 1000 mg (dose escalation); and 2 1000 and 2 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48. Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 500 mg (n 134) or dose escalation (n 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 1000 mg group (n 93) were consistently higher, with significantly more patients achieving EULAR responses (P 0.0495). At Week 48, rituximab 2 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 500 to 2 1000 mg did not appear to be associated with improved outcomes compared with continual 2 500 mg. All RTX regimens demonstrated comparable safety. Conclusions. RTX 2 500 and 2 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.
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DOI: 10.1093/rheumatology/keq116
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Tak</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Zerbini, Cristiano" sort="Zerbini, Cristiano" uniqKey="Zerbini C" first="Cristiano" last="Zerbini">Cristiano Zerbini</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Tremblay, Jean Luc" sort="Tremblay, Jean Luc" uniqKey="Tremblay J" first="Jean-Luc" last="Tremblay">Jean-Luc Tremblay</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Carreo, Luis" sort="Carreo, Luis" uniqKey="Carreo L" first="Luis" last="Carreo">Luis Carreo</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Armstrong, Gillian" sort="Armstrong, Gillian" uniqKey="Armstrong G" first="Gillian" last="Armstrong">Gillian Armstrong</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Collinson, Neil" sort="Collinson, Neil" uniqKey="Collinson N" first="Neil" last="Collinson">Neil Collinson</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Tim M" sort="Shaw, Tim M" uniqKey="Shaw T" first="Tim M." last="Shaw">Tim M. Shaw</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F3E04FFFC59BD82D9911877032D2391E29D4913E</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/rheumatology/keq116</idno><idno type="url">https://api.istex.fr/document/F3E04FFFC59BD82D9911877032D2391E29D4913E/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000E59</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)</title><author><name sortKey="Rubbert Roth, Andrea" sort="Rubbert Roth, Andrea" uniqKey="Rubbert Roth A" first="Andrea" last="Rubbert-Roth">Andrea Rubbert-Roth</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: andrea.rubbert@medizin.uni-koeln.de</mods:affiliation></affiliation></author><author><name sortKey="Tak, Paul P" sort="Tak, Paul P" uniqKey="Tak P" first="Paul P." last="Tak">Paul P. Tak</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Zerbini, Cristiano" sort="Zerbini, Cristiano" uniqKey="Zerbini C" first="Cristiano" last="Zerbini">Cristiano Zerbini</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Tremblay, Jean Luc" sort="Tremblay, Jean Luc" uniqKey="Tremblay J" first="Jean-Luc" last="Tremblay">Jean-Luc Tremblay</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Carreo, Luis" sort="Carreo, Luis" uniqKey="Carreo L" first="Luis" last="Carreo">Luis Carreo</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Armstrong, Gillian" sort="Armstrong, Gillian" uniqKey="Armstrong G" first="Gillian" last="Armstrong">Gillian Armstrong</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Collinson, Neil" sort="Collinson, Neil" uniqKey="Collinson N" first="Neil" last="Collinson">Neil Collinson</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author><author><name sortKey="Shaw, Tim M" sort="Shaw, Tim M" uniqKey="Shaw T" first="Tim M." last="Shaw">Tim M. Shaw</name><affiliation><mods:affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Rheumatology</title><idno type="ISSN">1462-0324</idno><idno type="eISSN">1462-0332</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-09">2010-09</date><biblScope unit="volume">49</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1683">1683</biblScope><biblScope unit="page" to="1693">1693</biblScope></imprint><idno type="ISSN">1462-0324</idno></series><idno type="istex">F3E04FFFC59BD82D9911877032D2391E29D4913E</idno><idno type="DOI">10.1093/rheumatology/keq116</idno><idno type="ArticleID">keq116</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1462-0324</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. Methods. Patients with active RA despite stable MTX (1025 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 500 and 2 500 mg; 2 500 and 2 1000 mg (dose escalation); and 2 1000 and 2 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48. Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 500 mg (n 134) or dose escalation (n 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 1000 mg group (n 93) were consistently higher, with significantly more patients achieving EULAR responses (P 0.0495). At Week 48, rituximab 2 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 500 to 2 1000 mg did not appear to be associated with improved outcomes compared with continual 2 500 mg. All RTX regimens demonstrated comparable safety. Conclusions. RTX 2 500 and 2 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Andrea Rubbert-Roth</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string><json:string>E-mail: andrea.rubbert@medizin.uni-koeln.de</json:string></affiliations></json:item><json:item><name>Paul P. Tak</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Cristiano Zerbini</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Jean-Luc Tremblay</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Luis Carreo</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Gillian Armstrong</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Neil Collinson</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item><json:item><name>Tim M. Shaw</name><affiliations><json:string>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Clinical Science</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Rituximab</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Rheumatoid arthritis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Repeat treatment</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>B-cell depletion</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Phase III</value></json:item></subject><articleId><json:string>keq116</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. Methods. Patients with active RA despite stable MTX (1025 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 500 and 2 500 mg; 2 500 and 2 1000 mg (dose escalation); and 2 1000 and 2 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48. Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 500 mg (n 134) or dose escalation (n 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 1000 mg group (n 93) were consistently higher, with significantly more patients achieving EULAR responses (P 0.0495). At Week 48, rituximab 2 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 500 to 2 1000 mg did not appear to be associated with improved outcomes compared with continual 2 500 mg. All RTX regimens demonstrated comparable safety. Conclusions. RTX 2 500 and 2 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48. Trial registration. 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Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></availability><date>2010-05-12</date></publicationStmt><notesStmt><note>See Appendix 1 for the MIRROR Trial Group investigators.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)</title><author xml:id="author-1" corresp="yes"><persName><forename type="first">Andrea</forename><surname>Rubbert-Roth</surname></persName><email>andrea.rubbert@medizin.uni-koeln.de</email><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-2"><persName><forename type="first">Paul P.</forename><surname>Tak</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-3"><persName><forename type="first">Cristiano</forename><surname>Zerbini</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-4"><persName><forename type="first">Jean-Luc</forename><surname>Tremblay</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-5"><persName><forename type="first">Luis</forename><surname>Carreo</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-6"><persName><forename type="first">Gillian</forename><surname>Armstrong</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-7"><persName><forename type="first">Neil</forename><surname>Collinson</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author><author xml:id="author-8"><persName><forename type="first">Tim M.</forename><surname>Shaw</surname></persName><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation></author></analytic><monogr><title level="j">Rheumatology</title><idno type="pISSN">1462-0324</idno><idno type="eISSN">1462-0332</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-09"></date><biblScope unit="volume">49</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1683">1683</biblScope><biblScope unit="page" to="1693">1693</biblScope></imprint></monogr><idno type="istex">F3E04FFFC59BD82D9911877032D2391E29D4913E</idno><idno type="DOI">10.1093/rheumatology/keq116</idno><idno type="ArticleID">keq116</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-05-12</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. Methods. Patients with active RA despite stable MTX (1025 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 500 and 2 500 mg; 2 500 and 2 1000 mg (dose escalation); and 2 1000 and 2 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48. Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 500 mg (n 134) or dose escalation (n 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 1000 mg group (n 93) were consistently higher, with significantly more patients achieving EULAR responses (P 0.0495). At Week 48, rituximab 2 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 500 to 2 1000 mg did not appear to be associated with improved outcomes compared with continual 2 500 mg. All RTX regimens demonstrated comparable safety. Conclusions. RTX 2 500 and 2 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Clinical Science</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Rituximab</term></item><item><term>Rheumatoid arthritis</term></item><item><term>Repeat treatment</term></item><item><term>B-cell depletion</term></item><item><term>Phase III</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-05-12">Created</change><change when="2010-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/F3E04FFFC59BD82D9911877032D2391E29D4913E/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">rheumatology</journal-id><journal-id journal-id-type="publisher-id">brheum</journal-id><journal-title>Rheumatology</journal-title><issn pub-type="ppub">1462-0324</issn><issn pub-type="epub">1462-0332</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/rheumatology/keq116</article-id><article-id pub-id-type="publisher-id">keq116</article-id><article-categories><subj-group><subject>Clinical Science</subject></subj-group></article-categories><title-group><article-title>Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Rubbert-Roth</surname><given-names>Andrea</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tak</surname><given-names>Paul P.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zerbini</surname><given-names>Cristiano</given-names></name><xref ref-type="aff" rid="AFF1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tremblay</surname><given-names>Jean-Luc</given-names></name><xref ref-type="aff" rid="AFF1"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Carreño</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="AFF1"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Armstrong</surname><given-names>Gillian</given-names></name><xref ref-type="aff" rid="AFF1"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Collinson</surname><given-names>Neil</given-names></name><xref ref-type="aff" rid="AFF1"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Tim M.</given-names></name><xref ref-type="aff" rid="AFF1"><sup>6</sup></xref></contrib><on-behalf-of>on behalf of the MIRROR Trial Investigators</on-behalf-of><xref ref-type="fn" rid="FN1">*</xref></contrib-group><aff id="AFF1"><sup>1</sup>Department of Internal Medicine, University of Cologne, Cologne, Germany, <sup>2</sup>Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, <sup>3</sup>Department of Rheumatology, Hospital Heliópolis, São Paulo, Brazil, <sup>4</sup>Department of Rheumatology, Centre Hospitalier Régional de Trois-Rivières, Trois-Rivières, QC, Canada, <sup>5</sup>Department of Rheumatology, Hospital Gregorio Marañón, Madrid, Spain and <sup>6</sup>Roche Products Ltd, Welwyn Garden City, UK.</aff><author-notes><corresp>Correspondence to: Andrea Rubbert-Roth, Klinikum der Universität zu Köln, Klinik für Innere Medizin I, Josef-Stelzmann-Strasse 9, 50931 Köln, Germany. E-mail: <email>andrea.rubbert@medizin.uni-koeln.de</email></corresp><fn id="FN1"><p>*See <xref ref-type="app" rid="APP1">Appendix 1</xref> for the MIRROR Trial Group investigators.</p></fn></author-notes><pub-date pub-type="ppub"><month>9</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>12</day><month>5</month><year>2010</year></pub-date><volume>49</volume><issue>9</issue><fpage>1683</fpage><lpage>1693</lpage><history><date date-type="received"><day>1</day><month>10</month><year>2009</year></date><date date-type="rev-recd"><day>15</day><month>3</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.5"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license></permissions><abstract><p><bold>Objective.</bold> To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA.</p><p><bold>Methods.</bold> Patients with active RA despite stable MTX (10–25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 × 500 and 2 × 500 mg; 2 × 500 and 2 × 1000 mg (dose escalation); and 2 × 1000 and 2 × 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48.</p><p><bold>Results.</bold> At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 × 500 mg (<italic>n</italic> = 134) or dose escalation (<italic>n</italic> = 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 × 1000 mg group (<italic>n</italic> = 93) were consistently higher, with significantly more patients achieving EULAR responses (<italic>P</italic> = 0.0495). At Week 48, rituximab 2 × 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 × 500 to 2 × 1000 mg did not appear to be associated with improved outcomes compared with continual 2 × 500 mg. All RTX regimens demonstrated comparable safety.</p><p><bold>Conclusions.</bold> RTX 2 × 500 and 2 × 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 × 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48.</p><p><bold>Trial registration.</bold> ClinicalTrials.gov, <ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov/">http://clinicaltrials.gov/</ext-link>, NCT00422383.</p></abstract><kwd-group><kwd>Rituximab</kwd><kwd>Rheumatoid arthritis</kwd><kwd>Repeat treatment</kwd><kwd>B-cell depletion</kwd><kwd>Phase III</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Andrea</namePart><namePart type="family">Rubbert-Roth</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><affiliation>E-mail: andrea.rubbert@medizin.uni-koeln.de</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul P.</namePart><namePart type="family">Tak</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cristiano</namePart><namePart type="family">Zerbini</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jean-Luc</namePart><namePart type="family">Tremblay</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Luis</namePart><namePart type="family">Carreo</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gillian</namePart><namePart type="family">Armstrong</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Neil</namePart><namePart type="family">Collinson</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tim M.</namePart><namePart type="family">Shaw</namePart><affiliation>Department of Internal Medicine, University of Cologne, Cologne, Germany, Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, Department of Rheumatology, Hospital Helipolis, So Paulo, Brazil, Department of Rheumatology, Centre Hospitalier Rgional de Trois-Rivires, Trois-Rivires, QC, Canada, Department of Rheumatology, Hospital Gregorio Maran, Madrid, Spain and Roche Products Ltd, Welwyn Garden City, UK.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Clinical Science</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-09</dateIssued><dateCreated encoding="w3cdtf">2010-05-12</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Objective. To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA. Methods. Patients with active RA despite stable MTX (1025 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 500 and 2 500 mg; 2 500 and 2 1000 mg (dose escalation); and 2 1000 and 2 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48. Results. At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 500 mg (n 134) or dose escalation (n 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 1000 mg group (n 93) were consistently higher, with significantly more patients achieving EULAR responses (P 0.0495). At Week 48, rituximab 2 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 500 to 2 1000 mg did not appear to be associated with improved outcomes compared with continual 2 500 mg. All RTX regimens demonstrated comparable safety. Conclusions. RTX 2 500 and 2 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00422383.</abstract><note type="footnotes">See Appendix 1 for the MIRROR Trial Group investigators.</note><subject><genre>keywords</genre><topic>Rituximab</topic><topic>Rheumatoid arthritis</topic><topic>Repeat treatment</topic><topic>B-cell depletion</topic><topic>Phase III</topic></subject><relatedItem type="host"><titleInfo><title>Rheumatology</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">1462-0324</identifier><identifier type="eISSN">1462-0332</identifier><identifier type="PublisherID">brheum</identifier><identifier type="PublisherID-hwp">rheumatology</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>49</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>1683</start><end>1693</end></extent></part></relatedItem><identifier type="istex">F3E04FFFC59BD82D9911877032D2391E29D4913E</identifier><identifier type="DOI">10.1093/rheumatology/keq116</identifier><identifier type="ArticleID">keq116</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. 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