Methods
Study Design and Patient Population
ACTION was a non-interventional, international, multicenter, prospective, observational cohort study to evaluate patient retention and the effectiveness of intravenous abatacept treatment in patients with RA in Europe and Canada. Patients were enrolled prospectively between May 2008 and January 2011, either on, or within 3 months of, initiating treatment with abatacept according to the Summary of Product Characteristics (SmPC) in Europe and the Product Monograph in Canada. Patients already on treatment with the study drug (169/1114 [15.2%]) were included only if baseline data were available and could be collected retrospectively.
In all participating countries, abatacept was required to have market authorization and a reimbursement policy to ensure that eligible patients had access to the drug. No product was provided to physicians or patients by the study sponsor. This observational study did not interfere with a physician's routine clinical practice. Moreover, the decision to treat a patient with abatacept was made before their enrollment in the study. By using a process of random selection from a comprehensive list of rheumatologists, the investigators in each country were geographically balanced and representative of rheumatologists who treat patients with biologics.
Enrolled patients provided informed written consent, were over 18 years of age, of either gender, with an established diagnosis of moderate-to-severe RA as defined by the American College of Rheumatology revised criteria 1987. Any patients already enrolled in an interventional RA clinical trial were excluded. The study protocol and patient enrollment were approved by ethics committees and regulatory agencies in accordance with each country's requirements. The central ethics committee that first approved the study on 31 January 2008 was the Munich, Bavaria, Germany ethics committee. For each country, local ethics committee approvals were also obtained, as required by local regulations.
The ACTION study was conducted in accordance with the Declaration of Helsinki and was consistent with the International Conference on Harmonization Good Clinical Practice Guidelines and Good Epidemiological Practice Guidelines.
Each patient was followed for up to 2 years or, if the patient discontinued abatacept treatment before the 2-year endpoint, for up to 6 months after abatacept discontinuation. Follow-up visits were approximately every 3 months. No formal assessment was performed to define reasons for prior treatment failure, other than those reported by the treating physician.
Effectiveness Assessments
Clinical characteristics and effectiveness are reported for patients with data available at baseline and Month 6, assessed no later than 8 days after the first abatacept infusion. Previous studies have demonstrated that abatacept may have an impact on efficacy measures as early as 7 days from the first infusion. Patients who had their clinical assessment more than 8 days after their first abatacept infusion were not included in the effectiveness analysis. Disease activity was evaluated using the 28-item Disease Activity Score (DAS28), based either on erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) according to physician's choice, and Clinical Disease Activity Index (CDAI). Although investigators could report disease activity outcomes using the DAS28 and/or CDAI scores, in practice a majority of investigators reported only DAS28 scores; in addition, the CDAI score was calculated from core components collected for each patient. A sensitivity analysis was conducted on data from patients for whom both DAS28 and CDAI assessments were available and showed that the effectiveness outcomes at Month 6 in these patients were similar to those in the overall population. For DAS28, patients were classified as being in high (>5.1), moderate (>3.2 and ≤5.1), or low disease activity state (LDAS; ≤3.2), or remission (<2.6). LDAS was defined as a CDAI score ≤10, and remission was defined as a CDAI score ≤2.8. European League Against Rheumatism (EULAR) response was defined as good/moderate or no response and was based on DAS28 (ESR) or DAS28 (CRP). Physical function was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI). HAQ response was defined as a mean change from baseline in HAQ score of ≥0.3 units; a clinically meaningful change in physical function was defined as a mean change from baseline in HAQ score of ≥0.22 units.
Safety Assessments
Safety was evaluated in accordance with local regulations and registered with the drug manufacturer's global pharmacovigilance department. Related treatment-emergent adverse events (AEs) were assessed by the treating physician and reported to the pharmacovigilance department. The relationship between the study drug and serious AE (SAE) was judged by the treating physician. A SAE was defined as an AE that was fatal or life-threatening, required or extended patient hospitalization (except pregnancy), resulted in persistent or significant disability or incapacity, induced a congenital anomaly or birth defect, or was considered an important medical event. All deaths were reported whether they were treatment-related or not. Safety was presented for the entire enrolled population, regardless of prior or concomitant treatment.
Statistical Analyses
The patient population was stratified by prior line of treatment into two subgroups: patients who were either biologic-naïve prior to initiating abatacept ('first-line'), or patients who had previously received and failed at least one biologic agent ('second-line'); this second group included patients initiating abatacept as a second- or further-line of treatment. Additional subgroup analyses of abatacept effectiveness and retention rates were performed for second-line patients stratified according to the number of prior anti-TNF agents failed (1 versus ≥2), the reason for discontinuing their previous biologic agent (primary/secondary inefficacy or safety and tolerability), or treatment pattern at abatacept initiation (monotherapy or in combination with conventional DMARDs). Baseline characteristics and demographics are presented using descriptive statistics for patients who received at least one infusion of abatacept and had data related to abatacept exposure. Retention on abatacept, defined as consecutive time on treatment, was analyzed using a Kaplan–Meier product limit estimator and is presented at Month 6 with 95% CIs. Patient discontinuation from abatacept treatment was recorded by the physician at any follow-up visit. In cases of abatacept discontinuation, exposure to abatacept was defined as the time between the date of the first abatacept infusion and the date of the last abatacept infusion, plus 30 days. Patients for whom data were not available at 6 months or who did not report abatacept discontinuation were censored at the date of the last available data. Effectiveness analyses were 'as-observed' for patients on treatment for whom data were available at each time point. These data were presented as proportions with 95% CIs, mean values, or changes with accompanying standard deviations (SDs) or 95% CIs.