Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate

Abstract

Objectives: This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo. The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score (based on erythrocyte sedimentation rates; DAS28 (ESR)) for the abatacept vs placebo groups at day 197.

Methods: Patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) were randomised 3:3:2 to abatacept ( approximately 10 mg/kg every 4 weeks, n = 156), infliximab (3 mg/kg every 8 weeks, n = 165), or placebo (every 4 weeks, n = 110) and background MTX. Safety and efficacy were assessed throughout the study.

Results: Similar patient demographics and clinical characteristics were present at baseline between groups, with mean scores of approximately 1.7 for HAQ-DI and 6.8 for DAS28 (ESR). At 6 months, mean changes in DAS28 (ESR) were significantly greater for abatacept vs placebo (-2.53 vs -1.48, p<0.001) and infliximab vs placebo (-2.25 vs -1.48, p<0.001). For abatacept vs infliximab treatment at day 365, reductions in the DAS28 (ESR) were -2.88 vs -2.25. At day 365, the following response rates were observed for abatacept and infliximab, respectively: American College of Rheumatology (ACR) 20, 72.4 and 55.8%; ACR 50, 45.5 and 36.4%; ACR 70, 26.3 and 20.6%; low disease activity score (LDAS), 35.3 and 22.4%; DAS28-defined remission, 18.7 and 12.2%; good European League Against Rheumatism (EULAR) responses, 32.0 and 18.5%; and Health Assessment Questionnaire Disability Index (HAQ-DI), 57.7 and 52.7%. Mean changes in physical component summary (PCS) were 9.5 and 7.6, and mental component summary (MCS) were 6.0 and 4.0, for abatacept and infliximab, respectively. Over 1 year, adverse events (AEs) (89.1 vs 93.3%), serious AEs (SAEs) (9.6 vs 18.2%), serious infections (1.9 vs 8.5%) and discontinuations due to AEs (3.2 vs 7.3%) and SAEs (2.6 vs 3.6%) were lower with abatacept than infliximab.

Conclusions: In this study, abatacept and infliximab (3 mg/kg every 8 weeks) demonstrated similar efficacy. Overall, abatacept had a relatively more acceptable safety and tolerability profile, with fewer SAEs, serious infections, acute infusional events and discontinuations due to AEs than the infliximab group.

Trial registration number: NCT00095147.

Figure 1. Patient disposition over 1 year. The ATTEST trial was a 12-month global trial conducted at 86 sites in the US (20 sites), Europe (18 sites (5 in Poland, 4 in Spain, 4 in Sweden, 2 in Russia, 2 in Denmark and 1 in Switzerland)), Canada (11 sites), Australia (6 sites), Mexico (10 sites), Argentina (5 sites), Brazil (8 sites), Peru (5 sites) and South Africa (3 sites). Patients were randomised in a 3:3:2 ratio to 6 months of abatacept (approximating 10 mg/kg), infliximab (3 mg/kg), or placebo treatment. During days 198–365, efficacy and safety data are not presented for the placebo group following reallocation to abatacept.

Figure 2. Disease Activity Score 28 (DAS28) based on erythrocyte sedimentation rates (ESR). A. DAS28 (ESR) mean changes from baseline at days 197 and 365. Error bars represent standard error of the mean. B. European League Against Rheumatism (EULAR) good responses, low DAS (LDAS; DAS28 ⩽3.2) and DAS28 (ESR)-defined remission at day 197 and at day 365. Data are presented for the intent-to-treat population with a last-observation carried forward analysis for mean changes in DAS28 (ESR), LDAS and DAS28 (ESR)-defined remission. Good EULAR responses were presented for the intent-to-treat population with patients who discontinued the study prematurely considered as non-responders subsequent to the time of discontinuation. Error bars show standard error of the mean. *Adjustment based on covariance with treatment as factor and baseline as covariant.

Figure 3. American College of Rheumatology (ACR) responses over 1 year. Proportion of patients with ACR 20, 50 and 70 responses was assessed on each visit day. Data are presented for the intent-to-treat population with a last-observation carried forward analysis. *Infliximab was administered on days 1, 15, 43, 85 and then every 56 days thereafter. Abatacept dosing occured at each visit day presentation following the assesment of efficacy.

Figure 4. Health-related quality of life. A. Mean change in physical and mental component summary (PCS and MCS, respectively) scores and the individual subscales of the Short Form-36 (SF-36) from day 1 to day 197. B. Mean change in PCS and MCS scores and the individual subscales of the SF-36 from day 1 to day 365; Data are presented for the intent-to-to treat population with a last observation carried forward analysis.