Assessments The primary efficacy endpoint was the DAS28 response rate on Day 28 in Part A and Day 56 in Parts B and C. Secondary endpoints were ACR and European League Against Rheumatism response rates, together with Outcome our website Measure in Rheumatology core component measures, tender painful count, swollen joint count, Patients Assessment of Arthritis Pain , Patients and Physicians Global Assessments of Arthritis, Health Assessment Questionnaire Disability Index and Multi dimensional Assessment of Fatigue. Laboratory efficacy mea sures included CRP and ESR. Safety assessments including adverse events, vital signs, electrocardiograms and clinical laboratory tests were carried out at each study visit. Pharmacokinetics and pharmacodynamics PD biomarkers after single and repeat IV doses included, but were not limited to, serum OSM and GSK315234A OSM complexes.

Immunogenicity was measured by hu man anti GSK315234A antibodies. Sample size estimation and sensitivity In Part A, the use of a non linear mixed effects proce dure required simulation Inhibitors,Modulators,Libraries techniques to estimate power for a given sample size and expected magnitude of effect. Trial simulations of the Bayesian adaptive PK PD design using a nonlinear PK PD model were conducted using typical parameter estimates that six cohorts of eight pa tients Inhibitors,Modulators,Libraries each would provide power in excess of 95% to detect a PK PD maximum effect value of 66% inhibition from baseline. The probability of a false positive under the null hypothesis was approximately 5%. When the number of cohorts was increased to eight, the power in creased marginally accompanied by a steeper cumulative distribution curve.

When the magnitude of response was 33%, the power reduced to 80%. If the response to GSK315234 had a slower onset but similar sized re sponse to adalimumab, the power for the PK PD analysis was 80%. Overall, a sample size of 48 or 64 would provide Inhibitors,Modulators,Libraries at least 80% power assu ming a similar response to adalimumab. In Part B, a maximum of 54 patients was planned for enrollment. A treatment difference of 0. 95 between the selected dose Inhibitors,Modulators,Libraries and placebo in DAS28 scores 56 days post dose could be detected with approximately 90% power based on preliminary estimates of between subject vari ability of DAS28 scores seen in the interim analysis of Part A. This assumes a standard deviation of 1. 15 in the GSK315234 dose group and 1.

25 in the placebo dose group, a two Inhibitors,Modulators,Libraries sided test and an overall alpha of 5%. In Part C, no statistical techniques were used to deter mine the sample size. Statistical analysis plan A repeated measure analysis using a mixed effect pathway signaling model was used, including treatment, visit, and treatment by visit interaction as fixed effects and patient as a random effect to analyse the primary efficacy endpoint. Other effects such as baseline, baseline by visit, country, gen der, age and baseline OSM level were fitted into the model when deemed necessary.