Improvements in Fatigue in 1536 Patients with Rheumatoid Arthritis and Correlation with Other Treatment Outcomes: A Post Hoc Analysis of Three Randomized Controlled Trials of Abatacept

A post hoc analysis of three abatacept RCTs was conducted to evaluate the effect of treatment on fatigue and the correlation with pain, sleep, and DAS28 (CRP) outcomes. The trials were AGREE (Abatacept study to Gauge Remission and joint damage progression in MTX-naïve patients with Early Erosive RA; NCT00122382) in early RA [17], AIM (Abatacept in Inadequate responders to Methotrexate; NCT00048568) [18], and ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders; NCT00048581) in established RA [19]. In AGREE, patients were either MTX naïve or had previous exposure to MTX, ≤10 mg/week for ≤3 weeks [17]; in AIM, patients were MTX-IRs [18] (≥15 mg/week for ≥3 months, with a stable dose for 28 days before enrollment); and in ATTAIN, patients were inadequate responders to the TNF inhibitors etanercept, infliximab, or both after ≥3 months of treatment [19]. The RCTs selected included large patient populations and the same PROs at the same time points. The studies were conducted in accordance with the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice, and local regulations. An Institutional Review Board or Independent Ethics Committee approved the protocol and consent form at each study site. Informed consent was obtained from all patients for being included in the study. Study designs, patient populations, and primary efficacy and safety results have been reported previously [17‐19].

In all three trials, patients were randomized to receive either intravenous abatacept 10 mg/kg or placebo every 28 days. All patients received concomitant MTX in the AGREE and AIM trials, and patients continued concomitant DMARD medication at randomization in the ATTAIN trial.

Assessments were conducted at baseline and at days 29, 85, and 169. Fatigue and pain were assessed using visual analog scales (VAS; 0–100 mm), in which higher scores indicate worse symptoms. Sleep was assessed using the 12-item Medical Outcomes Study Sleep module (MOS-Sleep; score 0–100) in AIM and ATTAIN only. DAS28 (CRP) was evaluated at multiple time points including those when fatigue, pain, and sleep were assessed. Improvements in fatigue ≥minimum clinically important differences (MCID) from baseline to day 169 were cross-tabulated with those for other outcomes and with DAS28 (CRP) remission. MCIDs were defined as pain and fatigue VAS score changes from baseline ≤−10 mm [20], and sleep score change from baseline ≤−6 mm. DAS28 (CRP) remission was defined as DAS28 (CRP) <2.6.

Data from each RCT were analyzed separately. Mean changes from baseline in fatigue and pain at each time point were determined using an analysis of covariance model, with treatment as a factor and baseline value as a covariate. Agreement between reported improvements ≥MCID in fatigue with those in pain and sleep, and with attainment of DAS28 (CRP) remission were evaluated using agreement statistics (kappa) at baseline and at days 29, 85, and 169.

Patient demographics and clinical characteristics at baseline in the original RCTs (n = 1552) [17‐19] are shown in Table 1. Across the three trials, data for this post hoc analysis were available for a total of 1536 patients. Given the design of the trials, mean disease duration of RA for patients treated with abatacept varied from 6.2 months in AGREE to 8.5 and 12.2 years in AIM and ATTAIN, respectively.

Slightly higher mean fatigue and pain scores at baseline were observed in the patient population of ATTAIN compared with those of the patient populations of AGREE and AIM. Mean sleep scores at baseline were similar in AIM and ATTAIN, and DAS28 (CRP) scores were higher for patients in AIM than for patients in ATTAIN and AGREE (Table 1).

Changes from baseline in fatigue score were apparent by day 29 in each trial (Fig. 1a; Table 2). At day 169, improvements in fatigue ≥MCID with abatacept treatment were reported by ≥60% of patients in AGREE, AIM, and ATTAIN (Fig. 2a). Adjusted mean treatment differences for abatacept versus placebo at day 169 were highest in the ATTAIN patient population (Table 2).

Changes from baseline in pain scores were more pronounced in patients with early disease (AGREE) versus those seen in patients with longer disease duration (AIM and ATTAIN; Fig. 1b); a higher proportion of patients in AGREE versus AIM or ATTAIN reported improvements in pain ≥MCID with abatacept at day 169. Adjusted mean treatment differences for change from baseline in pain score for abatacept versus placebo at day 169 were highest in ATTAIN (Table 2).

Overall, most patients reporting improvements ≥MCID in fatigue with abatacept treatment at day 169 also did so for pain (62.9%; 532/846; Supplementary Fig. 1). Cross-tabulation indicated a greater proportion of patients who reported improvements in fatigue ≥MCID also reported improvements in pain ≥MCID at day 169 in AGREE (68.6%) versus AIM (62.6%) or ATTAIN (57.0%; Supplementary Fig. 1). Kappa statistics indicated that agreement between the proportions of patients with changes in fatigue and pain ≥MCID following abatacept treatment was low to moderate across the studies and time points (kappa range 0.30–0.51; Table 3).

In AIM and ATTAIN, most patients reported improvements in sleep ≥MCID with abatacept at day 169: 57.4% (241/420; 95% CI 52.7, 62.1) of patients in AIM and 58.6% (147/251; 95% CI 52.5, 64.7) of patients in ATTAIN. Agreement (kappa statistics) between the proportion of abatacept-treated patients with changes in fatigue and sleep ≥MCID at day 169 was low in both studies at all time points (kappa range 0.14–0.26; Table 3). Cross-tabulation indicated a corresponding 46.7 and 42.3% of patients in AIM and ATTAIN, respectively, who reported improvements in fatigue ≥MCID with abatacept also reported improvements in sleep ≥MCID at day 169.

Agreement (kappa statistics) between treatment-related improvements in fatigue ≥MCID and attainment of DAS28 (CRP) remission at day 169 was very small (0.12 [AGREE], 0.04 [AIM], and 0.06 [ATTAIN]; Table 3). Cross-tabulation indicated more patients in AGREE than in AIM or ATTAIN who reported improvement in fatigue ≥MCID also achieved DAS28 (CRP) remission at day 169 (26.8, 12.3, and 9.0% of patients in AGREE, AIM, and ATTAIN, respectively).