Weinblatt 2007.

Methods	Multicenter, randomized, double‐blind, placebo‐controlled trial with an open‐label long‐term extension (LTE) phase, conducted at 40 centres in the US between 26 February 2001 and 13 October 2004.
Participants	Abatacept (N = 85): mean (SD) age = 49.8+/‐23.7, % female = 78; duration of RA in years (mean, SD) = 13+/‐10; Placebo (N = 36): mean (SD) age = 54.3+/‐28.7, % female = 72; duration of RA in years (mean, SD) = 12.8+/‐8.6 Eligible patients were > 18 years of age and met the ACR criteria for RA and were in functional class I, II or III. Patients must have received etanercept 25 mg twice weekly for > 3 months and have > 8 swollen joints (66‐joint count) and > 10 tender joints (68‐joint count). The original protocol definition of required C reactive protein (CRP) concentration at entry was > 2 mg/dl; however, owing to the effect of etanercept on normalising CRP levels, there was a high initial rate of screen failures. Therefore, the protocol was modified so that CRP elevation was not required for entry and the CRP threshold of > 2 mg/dl was never executed. Important exclusion criteria included active or latent infection, recent opportunist infection, tuberculosis requiring treatment within the previous 3 years, history of cancer within the previous 5 years or history of drug or alcohol misuse. Pregnant and nursing women were excluded.
Interventions	Abatacept (2 mg/kg) and etanercept (25 mg twice weekly) (N = 85) or placebo and etanercept (25 mg twice weekly) (N = 36). 2:1 ratio for randomisation. Etanercept (25 mg, twice weekly) was continued in all patients for the duration of the study. Abatacept was administered intravenously on days 1, 15, and 30, and every 4 weeks thereafter. MTX and other DMARDs were stopped at least 28 days before randomization, with the exception of leflunomide, which was stopped > 60 days before randomization. Low‐dose corticosteroids (10 mg/day) or NSAIDs were allowed, provided the dose remained stable during the study. Analgesics were also permitted at all times except (12 hours before a joint evaluation. Addition of hydroxychloroquine, sulfasalazine, leflunomide or MTX was allowed after 6 months of double‐blind treatment, as considered appropriate by the investigator according to the patient’s condition. Patients completing double‐blind treatment were eligible to enter the LTE. All patients entering the LTE were switched to receive abatacept at a fixed dose approximating 10 mg/kg (according to weight range). During the LTE, patients were permitted to increase, decrease or discontinue corticosteroids (to a maximum maintenance dose of 10 mg prednisone equivalent daily), etanercept (to a maximum of 25 mg twice weekly) and NSAIDs according to their condition.
Outcomes	Primary endpoint of the double‐blind phase was a modified ACR 20 (defined as >20% improvement in tender and swollen joints and > 20% improvement in 2 of the remaining four core measures (pain, physical function, modified Health Assessment Questionnaire, and patient and physician global assessments. CRP values were excluded from the definition) response rate at 6 months. The CRP values were excluded due to the normalizing effect of etanercept on CRP levels. The secondary endpoint of the double‐blind phase was the proportion of patients achieving a modified ACR 50 response at 6 months. The primary objective of the LTE was to assess the safety and tolerability of abatacept in combination with etanercept during long‐term administration in patients with active rheumatoid arthritis. Secondary efficacy measures included the modified ACR 50 and ACR 70 criteria at 6 months, standard ACR 20, ACR 50 and ACR 70 responses, and improvements in individual ACR criteria components
Notes	Study was funded and sponsored by Bristol‐Myers Squibb which was involved in the design of the study, the collection and analysis of the data, the writing of the report and the decision to submit the report.
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"; "the patients, investigators, infusion nurses and pharmacy and study personnel were blinded" (additional information from author)
Blinding? Physician assessed	Low risk	"Double"; "the patients, investigators, infusion nurses and pharmacy and study personnel were blinded" (additional information from author)
Incomplete outcome data addressed? Efficacy outcomes	High risk	68% in abatacept group and 61% in placebo group completed 12 months. Missing data was imputed appropriately. All withdrawals accounted for. "One additional patient was randomised but did not receive the study drug and was not included in any analyses." Judged a high risk of bias since drop‐out rate is > 80%.
Incomplete outcome data addressed? Safety outcomes	High risk	68% in abatacept group and 61% in placebo group completed 12 months. "One additional patient was randomised but did not receive the study drug and was not included in any analyses. Judged a high risk of bias since drop‐out rate is > 80%.
Free of selective reporting?	Low risk	"The original protocol definition of required C reactive protein (CRP) concentration at entry was > 2 mg/dl; however, owing to the effect of etanercept on normalising CRP levels, there was a high initial rate of screen failures. Therefore, the protocol was modified so that CRP elevation was not required for entry and the CRP threshold of > 2 mg/dl was never executed. The primary end point (ACR 20) was also modified early in the study to accommodate this finding." "Owing to the effect of etanercept on normalising CRP levels in this population, the primary and secondary end points were based on modified ACR 20 criteria, defined as >20% improvement in tender and swollen joints and >20% improvement in two of the remaining four core measures (pain, physical function, modified Health Assessment Questionnaire, and patient and physician global assessments). CRP values were excluded from the definition. Secondary efficacy measures included the modified ACR 50 and ACR 70 criteria at 6 months, standard ACR 20, ACR 50 and ACR 70 responses, and improvements in individual ACR criteria components." Judged a low risk of bias as the modification to the primary outcome occurred early in the study and was due to an unexpected finding that the drug being given in combination with abatacept had the effect of normalising CRP levels.
Free of other bias?	High risk	Funded by drug company. There is evidence that industry‐sponsored trials may overestimate the treatment effect (Bhandari 2004)

ACR = American College of Rheumatology 
 AE = adverse event 
 BMS = Bristol‐Myers Squibb 
 CRP = C reactive protein 
 DMARD = disease‐modifying anti‐rheumatic drugs 
 HAQ‐DI = Health Assessment Questionnaire Disability Index 
 IV = intravenous 
 LOCF = last observation carried forward 
 MTX = methotrexate 
 RA = rheumatoid arthritis 
 SAE = serious adverse event 
 SD = standard deviation 
 VAS = visual analogue scale 
 vs = versus 
 yrs = years