▶ An additional supplementary table is published online only. To view this ﬁle please visit the journal online at (http://ard. bmj.com) 1Kennedy Institute of Rheumatology Division, Imperial College, London, UK 2GlaxoSmithKline Clinical Development, Stockley Park, UK 3GlaxoSmithKline Clinical Development, Upper Merion, Pennsylvania, USA 4Genmab, Copenhagen, Denmark Correspondence to Professor Peter Taylor, Kennedy Institute of Rheumatology Division, Imperial College, London, UK; peter.c.taylor@imperial.ac.uk Accepted 17 July 2011 Published Online First 22 August 2011 Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522 Extended report Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial Peter C Taylor,1 Emilia Quattrocchi,2 Stephen Mallett,2 Regina Kurrasch,3 Jørgen Petersen,4 David J Chang3 ABSTRACT Objectives To evaluate the efﬁcacy and safety of intravenous ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, active rheumatoid arthritis (RA) patients despite methotrexate treatment. Methods In this double-blind, placebo-controlled, phase III study, active RA patients on stable methotrexate were randomly assigned to one course of two infusions of ofatumumab 700 mg (n=130) or placebo (n=130), 2 weeks apart. The primary endpoint was the ACR20 response at week 24. Secondary endpoints included ACR50/70, EULAR response, disease activity score based on 28 joints using C-reactive protein, adverse events (AE) and immunogenicity. Results At week 24, a greater proportion of patients on ofatumumab compared with placebo achieved an ACR20 response (50% vs 27%, p<0.001) and a good or moderate EULAR response (67% vs 41%, p<0.001). All other key secondary efﬁcacy endpoints were signiﬁcantly improved on ofatumumab. Efﬁcacy observed by 8 weeks was sustained throughout the study. The most common AE for ofatumumab versus placebo were rash (21% vs <1%) and urticaria (12% vs <1%), mostly occurring on the ﬁrst infusion day. Overall, ﬁrst-dose infusion reactions were 68% for ofatumumab and 6% for placebo, mostly mild to moderate; second-dose infusion reactions markedly declined (<1% and 0%). Serious AE were reported in 5% of ofatumumab versus 3% of placebo patients. Infection rates were 32% and 26% (serious infections <1% and 2%), respectively. One death (interstitial lung disease), unrelated to study drug, was reported on ofatumumab. No antidrug antibodies were detected in ofatumumab patients. Conclusions Ofatumumab signiﬁcantly improved all clinical outcomes in biological-naive, active RA patients with no detectable immunogenicity at week 24. No unexpected safety ﬁndings were identiﬁed. Trial Registry clinical trials.gov registration number NCT00611455 Ofatumumab (HuMax-CD20) is a human IgG1ĸ lytic monoclonal antibody (mAb) that speciﬁcally binds to the human CD20 antigen inducing potent B-cell lysis. The CD20 antigen is expressed only by B lymphocytes from the pre-B to the plasma- cytoid immunoblast stage. Ofatumumab recogn- ises a unique membrane-proximal epitope on the human CD20 molecule, distinct from the epitope recognised by rituximab1 or by other anti-CD20 mAb.2 3 The membrane proximity of this epitope probably accounts for the high efﬁciency of B-cell killing observed with ofatumumab in both in-vitro and in-vivo preclinical studies.4–7 In animal models, ofatumumab induced selec- tive and prolonged B-cell depletion primarily mediated by effective complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.8 9 Effective complement-dependent cytotoxicity may depend on the distance between the plasma membrane and the constant parts of the sensitising antibody thus enabling the efﬁcient and rapid engagement of complement activation.10 A phase I/II study of ofatumumab, administered as two intravenous infusions of 300, 700 or 1000 mg 2 weeks apart, in active rheumatoid arthritis (RA) patients with an inadequate response to disease- modifying antirheumatic drugs (DMARD), dem- onstrated signiﬁcant clinical beneﬁt and reasonable tolerability (improved after the implementation of premedication) at all doses investigated when com- pared with placebo, with the 700 mg dose consid- ered to be optimal.11 To characterise further the efﬁcacy and safety proﬁle of ofatumumab we conducted a placebo- controlled phase III trial in patients with active RA who had an inadequate response to methotrexate therapy and no previous biological treatment expo- sure. This trial was also designed to investigate the effects of ofatumumab on the extent and duration of B-cell depletion, biomarkers of clinical response, patient-reported outcomes and immunogenicity. METHODS Study design and objectives This was a multicentre, randomised, double- blind, placebo-controlled, parallel group, phase III trial. Patients were enrolled at 36 sites in west- ern Europe, eastern Europe, South America and Asia Paciﬁc. The trial is registered at clinicaltrials. gov number NCT00611455. The ﬁrst patient was enrolled in January 2008 and the last visit for the double-blind phase was in June 2009. The trial was conducted in accordance with good clinical practice and the Declaration of Helsinki. All par- ticipating sites received approval from national, regional, or investigational centre ethics committee 2119