BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy. METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.
The purpose of this study is to summarize the safety and tolerability of abatacept during 6 months of combined treatment with one or more of the background non-biologic disease modifying anti-rheumatic drugs (DMARDs) approved for rheumatoid arthritis (RA) in subjects with active RA. Secondary objectives assessed the clinical efficacy of combination treatment, including disease activity, physical function, and quality of life outcomes.
OBJECTIVE: Rheumatoid arthritis (RA) patients who have inadequate response to anti-tumour necrosis factor (TNF) therapy currently have treatment options that are limited and less than optimal in their risk-to-benefit ratio. Abatacept provides a new generation of RA medications that has previously been demonstrated to have positive clinical outcomes with this population. The current study sought to demonstrate the efficacy of abatacept on quality of life (QoL) for RA patients with inadequate response to anti-TNF therapy. METHODS: Patients were entered into a double-blind, placebo-controlled, multicentre randomized clinical trial, with 258 patients randomized to abatacept + disease-modifying anti-rheumatic drugs (DMARDs) and 133 patients randomized to placebo + DMARDS. The QoL was measured with the Short Form Health Survey (SF-36), Health Assessment Questionnaire (HAQ) and fatigue visual analogue scale, and was analysed with basic (ANOVA, chi-square) and multigroup growth curve techniques to assess differential change over time. RESULTS: Treatment group QoL improved significantly more than placebo on the HAQ and fatigue indices, as well as seven of the eight SF-36 scales and SF-36 physical and mental summary scores. Improvement rate was faster for abatacept than for placebo on the QoL measures, and the improvements from abatacept related to normal levels of QoL on many domains. CONCLUSION: Clinically relevant benefits of abatacept over placebo are discussed regarding improving QoL. Importantly, the larger rate of change for abatacept over placebo provides clinicians with a medication that can lead to meaningful changes in a patient's life within a few weeks, even when the patient previously failed anti-TNF therapy.
OBJECTIVE: To determine the minimal clinically important differences (MCID) in the patient-reported outcomes of activity (0-30, number of days of limitation), fatigue (0 = none, 100 = complete), and sleep quality (0 = no problems, 100 = worst case) for patients with rheumatoid arthritis (RA).
METHODS: Two randomized controlled trials comparing abatacept to placebo in RA patients were considered: ATTAIN (n = 391) and AIM (n = 652). An internal anchor-based approach was used to derive the MCID using the Health Assessment Questionnaire, patient global assessment, and pain as anchors. Minimal important change in activity, fatigue, and sleep were determined by estimating mean changes in these outcomes in patients showing change in a narrow range about the MCID of the internal anchor. Correlation analysis was used to determine the consistency of the changes in the outcomes and anchors, and a Delphi process was used to determine the final MCID values.
RESULTS: For the 2 trials, consistent patterns of change for activity, fatigue, and sleep and the internal anchors were found with correlations in the range of 0.5, 0.7, and 0.4, respectively. The mean changes for activity, fatigue, and sleep in a narrow range about the MCID of the 3 internal anchors corresponding to the 2 trials were: 3.4 to 4.3 for activity; 6.7 to 17.0 for fatigue; and 4.1 to 7.3 for sleep. Following the Delphi process the MCID determined were 4 for activity, 10 for fatigue, and 6 for sleep.
CONCLUSION: These MCID for activity limitation, fatigue, and sleep problems can be used in designing clinical trials and providing benchmarks in assessing patient improvement.
OBJECTIVE: To evaluate the responsiveness of patient reported outcomes (PROs), including fatigue, sleep, activity limitation, and quality of life, in patients with rheumatoid arthritis (RA).
METHODS: Data were considered from a randomised controlled trial comparing abatacept (n = 258) with placebo (n = 133) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy (ATTAIN study). PROs assessed included SF-36, activity limitation, fatigue, and sleep. For each outcome the treatment difference, relative per cent improvement, standardised response mean (SRM), and relative efficiency for assessing an outcome's ability to detect a treatment effect relative to tender joint count (TJC) were calculated. A relative efficiency >1 suggests a measure that is more efficient than TJC in detecting treatment effect.
RESULTS: Moderate to large SRMs (>or=0.6) were observed for the PRO measures. In particular, SRMs (95% confidence interval) were: physician global, 0.72 (0.51 to 0.94); HAQ, 0.63 (0.42 to 0.85); SF-36 physical component score, 0.62 (0.40 to 0.83); SF-36 bodily pain, 0.68 (0.46 to 0.90); and fatigue, 0.59 (0.38 to 0.81). Relative efficiencies for physician global (1.6), SF-36 bodily pain domain (1.4), pain intensity (1.4), HAQ (1.2), SF-36 physical component score (1.2), fatigue (1.1), and patient global assessment (1.04) were all more responsive than TJC. The SF-36 mental component score (0.3), swollen joint count (0.6), activity limitation (0.8), sleep (0.7), and C reactive protein (0.9) were less responsive.
CONCLUSIONS: Using PROs for evaluating treatments for RA can detect improvements and will identify changes that are important to patients. In general, physical assessments are more responsive to an effective treatment than mental assessments.
Rheumatoid arthritis (RA) is a debilitating autoimmune disease that has traditionally been treated with disease-modifying anti-rheumatic drugs (DMARDs). In the European Union (EU), patients who fail to respond to traditional DMARDs may receive tumor necrosis factor-alpha (TNF-alpha) antagonists. However, approximately one-third of patients fail TNF-alpha antagonists due to adverse effects or lack of efficacy, and there are limited treatment options available to these patients. As knowledge of the underlying immunopathology of RA evolves, new strategies for inhibiting the inflammatory process have emerged. It is well known that activated T cells play a key role in orchestrating the immunopathological mechanisms of RA. Inhibiting the full activation of T cells is a rational strategy in the treatment of RA and represents a novel method of inhibiting disease activity, distinct from inflammatory cytokine blockade. Here, the safety and efficacy of abatacept, a selective T-cell co-stimulation modulator recently approved in the EU, is reviewed in patients with RA who have shown an inadequate response to TNF-alpha antagonists. In a randomized, placebo-controlled, double-blind, phase III trial of patients with an inadequate response to TNF-alpha antagonism, abatacept was effective in improving the signs and symptoms of RA, as well as patient-centered outcomes, such as fatigue, disability, and other mental and physical aspects of health-related quality of life. These improvements were sustained through 2 years during the open-label, long-term extension period. In this trial, abatacept demonstrated a safety and tolerability profile similar to placebo. Taken together, these data suggest that selective co-stimulation modulation with abatacept may be a viable option for patients who are refractory to both traditional therapies and TNF-alpha antagonists.
OBJECTIVE: To consider the feasibility of assessing multiple facets of independence in rheumatoid arthritis (RA) using a measure developed from existing items and examining its face validity, construct validity and responsiveness to change.
METHODS: The ATTAIN (Abatacept Trial in Treatment of Anti-tumor necrosis factor [TNF] Inadequate responders) database was used. Patients with RA were randomized 2:1, abatacept (n = 258) and placebo (n = 133). A multi-faceted scale to measure physical and psychosocial independence was constructed using items from the Health Assessment Questionnaire (HAQ) and Short Form 36 Health Survey (SF-36). Questions assessing activity limitations and need for outside caregiver help were also examined. Interviews with 20 RA patients assessed face validity.
RESULTS: Item Response Theory analysis yielded two traits - 'Psychosocial Independence', derived from the number of days with activity limitations plus the Role Emotional, Social Functioning and Role Physical subscale items from the SF-36; and 'Physical Independence', derived from 15 HAQ items assessing need for help from another. The two traits showed no significant differential item functioning for age or gender and demonstrated good face validity. Changes over 169 days on Psychosocial Independence were greater (mean 0.46 units, 95% confidence interval [CI]: 0.17-0.75) for the abatacept group than for placebo (p = 0.002). Changes in Physical Independence were greater (mean 0.59 units, 95% CI: 0.35-0.82) for the abatacept group than for placebo (p < 0.001).
CONCLUSIONS: The multi-faceted assessment of independence in RA based on items from commonly used instruments is feasible suggesting promise for evaluating independence in future clinical trials. This approach demonstrated good face and construct validity and responsiveness in RA patients who had previously failed anti-TNF therapy. However, we caution against an interpretation that these data suggest that abatacept improves independence because the component parts of this assessment came from instruments used in the ATTAIN trial where data had been previously analyzed.
OBJECTIVE: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis. METHODS: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years. RESULTS: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment. CONCLUSION: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease. TRIAL REGISTRATION NUMBER: NCT00124982.
OBJECTIVES: Quality of life (QoL) improvement is important to demonstrate in RA clinical trials, but can be abstract. More meaningful measures of QoL include medical expenditure and job loss, aspects that have marked importance for RA patients, physicians and society. We re-examined previous positive QoL findings for abatacept over placebo by converting existing QoL measures into estimated medical expenditure and estimated likelihood of job loss. METHODS: Two double-blind, placebo-controlled, multicentre randomized clinical trials were undertaken: one for MTX failure (n = 652) and one for more severe anti-TNF failure patients (n = 391). Based on derived scores using previously published formulae, measures of monthly medical expenditure, current inability to work and job loss at 6 months, 1 yr and 2 yrs were analysed. RESULTS: Abatacept led to greater reduction in medical expenditure over time in MTX failure ($152 lower) and anti-TNF failure patients ($122 lower) compared with placebo at end-point. Likewise, significantly more reduction in likelihood for current and future job loss was achieved with abatacept compared with placebo, which has 25-64% greater likelihood. CONCLUSIONS: QoL changes provided greater reduction in medical expenditure and likelihood of an inability to work. The strong effect sizes obtained for all significant analyses suggest that the results are clinically meaningful. Moreover, given the nature of the variables, results should also be meaningful for patients, physicians, employers and health care insurance entities. Limitations are discussed regarding using estimated outcomes rather than analysis of actual outcomes.
