(≤3 months of ﬁrst study dose or planned during study), leﬂunomide (≤1 year of screening) or any non-approved investigational biologi- cal agent. Trial design This multinational study consisted of three periods followed by a long-term extension (LTE) (ﬁgure 1). The study was conducted in accordance with the Declaration of Helsinki and was consis- tent with International Conference on Harmonization of Good Clinical Practice.12 Period I (Introduction) was an open-label (OL) 12-week period ending on day 85. On day 1, patients received a single intravenous dose of abatacept (~10 mg/kg based on weight range; the ‘loading dose’), followed 30 min later by SC abata- cept 125 mg. The single intravenous loading dose was given to ensure target therapeutic trough concentrations were achieved as quickly as possible. Thereafter, SC abatacept 125 mg was delivered at weekly intervals for the remainder of the 12-week period. Disease activity was assessed at day 78. Patients who had achieved an improvement in DAS28 (reduction of ≥0.6 from baseline; one times the measurement error and statistically con- sidered a change) were randomised into period II; patients with DAS28 reduction <0.6 could directly enter the LTE. Period II (Withdrawal) was a 12-week double-blind, placebo- controlled period ending on day 169, in which patients were randomised 2:1 to SC placebo or SC abatacept 125 mg/week. Patients could prematurely enter period III if RA symptoms per- sisted or worsened after symptomatic treatment in this period. This 12-week withdrawal period was determined to be sufﬁ- cient for assessing development of immunogenicity because, at this time, serum concentrations of abatacept would be too low to interfere with the assay, and any immunosuppressive effect of abatacept that may interfere with immunogenicity would have ceased. Clinical and epidemiological research Period III (Reintroduction) was an OL 12-week period end- ing on day 253. To enter period III, patients had to have been treated in (but not necessarily completed) period II. In all patients regardless of randomisation group, OL SC abatacept 125 mg was self-administered weekly throughout period III. Patients who received SC placebo during period II were randomised (1:1) to receive either an intravenous placebo or intravenous abatacept loading dose (approximately 30 min before SC abatacept dosing at the beginning of period III (day 169)) to determine whether the administration of the intravenous abatacept loading dose affected immunogenicity upon reintroduction. Patients ran- domised to SC abatacept during period II received intravenous placebo loading on day 169 to maintain blinding. A 4-week washout period was required for azathioprine, gold, etanercept or anakinra and an 8-week washout period was required for adalimumab or inﬂiximab. Patients receiving sul- fasalazine, chloroquine or hydroxychloroquine had to discon- tinue at screening. Throughout the trial, low-dose (≤10 mg/day prednisone equivalent) oral corticosteroids were permitted but had to be stable for 25 of the 28 days before entry. Additionally, up to two high-dose corticosteroid courses were permitted during period II and one course during periods I and III (excluding 28 days before disease activity assessment at day 78 in period I). Biological and DMARD therapies other than MTX were not permitted. The MTX dose had to be stable (at least 10 mg/ week) prior to study entry; increases in MTX dose were not permitted during the study, although decreases were allowed for toxicity. Immunogenicity assessments Blood samples were collected prior to intravenous infusions on days 1 and 169 and prior to SC injections on days 57, 78, 85, 113, 141, 197, 225 and 253. For the primary measure of Figure 1 Study design. *Most frequent reason for not being treated was no longer meeting entry criteria. †Patients who discontinued during period II (Withdrawal phase) due to lack of efﬁcacy could enter period III (Reintroduction phase) prematurely. IV, intravenous; LTE, long-term extension; MTX, methotrexate; SC, subcutaneous. Ann Rheum Dis 2012;71:38–44. doi:10.1136/annrheumdis-2011-200344 39