Extended report or institutional review boards; each patient provided written informed consent. The trial included a 24-week double-blind, placebo-controlled period followed by a 120-week open-label extension and a safety follow-up. This paper summarises results from the completed, placebo-controlled, 24-week double-blind phase only. Eligible patients were randomly assigned (1:1) to receive two infusions of either ofatumumab 700 mg or placebo 2 weeks apart (one course), added to their stable background methotrexate dose. Randomisation was stratiﬁed by rheumatoid factor (RF) seropositivity/negativity and region. GlaxoSmithKline prepared a computer-generated randomisation schedule and randomisa- tion was handled centrally through an interactive voice response system. An unblinded pharmacist at each site prepared the infu- sions; ofatumumab and saline (placebo) infusions were indis- tinguishable. Other study personnel and patients were blinded to treatment allocation until the double-blind period was com- plete. Premedication with antihistamine (certirizine 10 mg or equivalent), oral paracetamol 1000 mg and intravenous meth- ylprednisolone 100 mg was administered 30 min to 2 h before each infusion. Patients who did not respond were allowed non- biological DMARD rescue treatment from week 16; however, the use of rescue treatment precluded subsequent entry into the open-label period. Breakthrough pain management such as analgesics, non-steroidal anti-inﬂammatory drugs and one intra- articular corticosteroid injection in one joint per 6-month period were allowed. The joint receiving an intra-articular injection was scored as both swollen and tender in joint count assess- ments during the following 12-week period. The primary objective was to evaluate the efﬁcacy of ofa- tumumab compared with placebo based on the proportion of patients achieving an American College of Rheumatology (ACR) 2012 response at week 24. Secondary endpoints included propor- tions of patients achieving ACR50, ACR70, European League Against Rheumatism (EULAR) good or moderate responses,13 and mean changes in the disease activity score based on 28 joints (DAS28) using C-reactive protein (CRP),14 health assess- ment questionnaire disability index (HAQ–DI),15 short-form health survey (SF-36v2) and functional assessment of chronic ill- ness therapy–fatigue version 4 (FACIT–F)16 at week 24. Patient population Male and non-pregnant, non-lactating female patients 18 years and older, diagnosed with active RA according to ACR 1987 criteria17 (RA functional class I, II or III) of 6 months or more duration were eligible to participate. Active RA was deﬁned as eight or more swollen and eight or more tender joint counts, based on 66/68 joint count; either CRP of 1.0 mg/dl or greater or erythrocyte sedimentation rate (ESR) of 22 mm/h or greater; and DAS28 based on ESR of 3.2 or greater. Patients were required to have an inadequate response to methotrexate and to be receiv- ing methotrexate 7.5–25 mg/week for at least 12 weeks, and at a stable dose for at least 4 weeks, before baseline. All patients underwent a washout period of at least 4 weeks for all DMARD (leﬂunomide ≥12 weeks or administration of cholestyramine treatment for washout according to the manufacturer’s instruc- tions) but maintained their concomitant stable methotrexate therapy, along with folic acid of 5 mg/week or greater. Oral corticosteroids (≤10 mg/day of prednisolone equivalent), non- steroidal anti-inﬂammatory drugs and one intra-articular injec- tion of corticosteroid (80 mg methylprednisolone or equivalent) in a single joint were permitted. Key exclusion criteria com- prised previous exposure to any biological and B-cell-depleting 2120 therapy, other autoimmune diseases, signiﬁcant concurrent, uncontrolled medical conditions, neutrophils less than 2×109/l, platelets less than 100×109/l, IgG less than 6.94 g/l (below lower limits of normal), and positive serology for HIV, hepatitis B or C infection. Patients were screened for JC virus using PCR for JC viral DNA (Quest Diagnostics, Van Nuys, CA, USA and Heston, Middlesex, UK) and were excluded if tested positive. Assessments Clinical assessments of disease activity were performed at baseline and every 4 weeks to week 24 and included an evalu- ation of the 68-joint tender joint count and 66-joint swollen joint count conducted by an independent assessor (blinded to patient-rated outcomes), patient’s pain assessment (visual ana- logue scale (VAS) 0–100 mm), patient’s and physician’s global assessment of disease activity (VAS 0–100 mm), HAQ-DI and levels of acute-phase reactants (ESR and CRP). From these data, ACR20, ACR50 and ACR70 response rates, mean change in DAS28–ESR and DAS28–CRP and EULAR response were deter- mined. FACIT-F and SF-36v2 were assessed at baseline, week 16 and week 24. Laboratory investigations included levels of peripheral B lymphocytes measured by ﬂuorescence-activated cell sorting analysis by the surrogate marker CD19, peripheral T lympho- cytes measured by CD3, CD4 and CD8 markers, immunoglob- ulins (IgA, IgM, IgG), RF and immunoglobulins to RF (IgM–RF, IgG–RF and IgA–RF), anticyclic citrullinated peptide antibodies (anti-CCP), acute phase serum amyloid A, interleukin 6 (IL-6) (all performed by Quest Diagnostics) and antibodies to ofatu- mumab measured using a validated electrochemiluminescence meso-scale discovery immunoassay. Positive samples from the binding antibody assay were tested in a neutralising antibody assay (Clinical Immunology, Biopharm R&D, GlaxoSmithKline, King of Prussia, PA, USA). Adverse events (AE) and serious adverse events (SAE) were collected throughout the study and coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12. Infusion-related events occurring during study drug infusion and up to 24 h after completion of the infusion (and likely to repre- sent clinical signs and symptoms characteristic of ofatumumab infusion reactions in patients with RA) were identiﬁed by a safety review team before unblinding. Low CD19 cell counts were not reported as AE and hospitalisation for completion of an infusion was not reported as a SAE. Infections were deter- mined using the MedDRA system organ class ‘infections and infestations’. Sample size estimation A sample size of 124 subjects per group was estimated to pro- vide at least 90% power to detect differences in the proportions of patients achieving an ACR20 response at week 24 between ofatumumab versus placebo, at a 5% level of signiﬁcance. This was based on a χ2 test comparing two binomial proportions. Statistical analysis For categorical endpoints, the efﬁcacy of ofatumumab ver- sus placebo was analysed using the Cochran Mantel Haenszel test, adjusting for baseline stratiﬁcation factors, RF status and geographical region (ie, eastern Europe, western Europe, South America, Asia Paciﬁc). For continuous endpoints efﬁcacy was analysed using analysis of covariance, adjusting for RF status, geographical region and baseline value. For categorical end- points, patients who took disallowed medication or withdrew Ann Rheum Dis 2011;70:2119–2125. doi:10.1136/ard.2011.151522