Kremer 2006.

Methods	1‐year, multicenter, multinational, randomized, double‐blind, placebo‐controlled study. Phase III. 2:1 abatacept to placebo ratio of random assignment.
Participants	Abatacept N = 433, age (mean, SD) 51.5 +/‐ 12.9, % female = 77.8, duration of RA in years (mean, SD) = 8.5 +/‐ 7.3 Placebo N = 219, age (mean, SD) 50.4 +/‐ 12.4, % female = 81.7, duration of RA in years (mean, SD) = 8.9 +/‐ 7.1 Eligible patients were at least 18 years of age, had RA for at least 1 year, and met the ARA criteria for RA. 2:1 randomization ratio. Abatacept N = 258 and placebo N = 133. RA was persistent and active despite MTX. All patients must have been treated with MTX for 3 months or longer, with a stable dose for 28 days before enrolment. Washout of all DMARDs at least 28 days before randomization. Concomitant medications: NSAIDs, corticosteroids with dosages equal to 10 mg of prednisone or less per day, stabilized for 25 days before randomization. Active disease at randomization. Exclusion: positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrolment
Interventions	Abatacept (10 mg/kg) (N = 258) + MTX or placebo + MTX (N = 133). Study medication given by 30‐minute intravenous infusion on days 1,15, and 29 and then every 28 days up to and including day 337. No premedication was required. All patients received MTX, 15 mg or more per week, although MTX at 10 mg per week was acceptable if the patient had a history of toxicity
Outcomes	Three primary: ACR 20 response at 6 months The proportion of patients in each group with clinically significant improvement (>= 0.3 unit) in the HAQ‐DI score at 1 year The radiographic progression of joint erosions (assessed by comparing changes from baseline in the Genant‐modified Sharp score) at 1 year Secondary: ACR 50 and ACR 70 at 6 months and all ACR responses at 1 year DAS28 HAQ‐DI Health related quality of life (SF‐36) Adverse events
Notes	AIM ‐ Abatacept in Inadequate Responders to Methotrexate study. This trial is also reported in Russell 2007. This trial was sponsored by Bristol‐Myers Squibb. The funding source helped design the study in consultation with the authors and provided statistical support for data analysis. Interpretation of the data was aided by the funding biostatisticians, with input from the authors. The funding source was not involved in the decision to submit the article for publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	"'central randomization"
Allocation concealment?	Low risk	"'central randomization'"
Blinding? Patient assessed	Low risk	"Double"; stated patient and "investigators were blinded to treatment group assignment throughout the 1‐year study."
Blinding? Physician assessed	Low risk	"Physicians blinded to treatment group assignment performed assessments at enrolment and at every visit before treatment administration"
Incomplete outcome data addressed? Efficacy outcomes	High risk	89% of treatment group and 74% of placebo group completed the 1 year study. All withdrawals accounted for except for four patients that were randomized but not treated (Figure 1). "We performed all efficacy and safety analyses on a modified intention‐to‐treat population, defined as all randomly assigned patients who received at least 1 dose of study medication." However, "Nine abatacept‐treated patients and 5 placebo recipients from 1 site were excluded from all efficacy analyses before unblinding due to nonadherence but were included in all safety analyses." Judged a high risk of bias due to exclusion of patients from efficacy analysis.
Incomplete outcome data addressed? Safety outcomes	Low risk	89% of treatment group and 74% of placebo group completed the 1 year study. All withdrawals accounted for except for 4 patients that were randomized but not treated. "We performed all efficacy and safety analyses on a modified intention‐to‐treat population, defined as all randomly assigned patients who received at least 1 dose of study medication."
Free of selective reporting?	Low risk	"Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20% improvement in American College of Rheumatology (ACR) response criteria (ACR 20) at 6 months, the proportion of patients in each group with clinically significant improvement (0.3 unit) in the Health Assessment Questionnaire Disability Index (HAQ‐DI) score at 1 year, and the radiographic progression of joint erosions (assessed by comparing changes from baseline in the Genant‐modified Sharp score) at 1 year."
Free of other bias?	High risk	Funded by drug company. There is evidence that industry‐sponsored trials may overestimate the treatment effect (Bhandari 2004)