Full details regarding patient inclusion and exclusion criteria and randomization for RAPID 1 were previously published 15. In brief, patients were aged 18 years or older with active RA (according to the 1987 ACR RA classification criteria 16) with an inadequate response to MTX therapy (≥ 10 mg weekly for ≥ 6 months with stable doses for ≥ 2 months prior to baseline). Patients were ineligible if they had previously failed to respond to treatment with a TNF inhibitor. All patients provided written informed consent.

RAPID 1 was a phase III, double-blind, randomized, placebo (PBO)-controlled, multicenter trial in which patients with active RA were randomized 2:2:1 to receive subcutaneous CZP (400 mg weeks 0, 2 and 4 followed by CZP 200 mg or 400 mg) plus MTX every other week, or PBO plus MTX. Patients not achieving ACR20 responses at weeks 12 and 14 were to be withdrawn from treatment per protocol at week 16. These patients, and those who completed RAPID 1, were eligible to enter an ongoing open-label extension study of CZP 400 mg plus MTX every other week. The study (NCT00152386) was conducted in accordance with the International Conference on Harmonisation E6 Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) and Declaration of Helsinki. All elements of the CONSORT checklist for reporting randomized clinical trials have been previously published in the primary RAPID 1 publication 15. Institutional review boards or ethics committees approved the protocol at each center, and all patients provided written consent.

All patient-reported outcomes assessed in the RAPID 1 trial were secondary endpoints. These PROs included evaluations of concepts such as HRQoL, fatigue and the patient-reported components of the ACR core set criteria (physical function, arthritis pain and patient's global assessment of disease activity). The PRO instruments assessed in RAPID 1 have been shown to provide valid and reliable data in prior RA research. They were properly implemented in the CZP trials in terms of patient and investigator training, timing of assessments, linguistic validations, and pre-specification of analysis in the statistical analysis plan. Psychometric properties of the data based on the endpoints of the patient-reported outcomes are consistent with prior evidence of the measurement properties for each instrument.

HRQoL was assessed using the Short-Form 36-Items (SF-36) health survey (Version 1.0 standard recall), which is a widely used generic HRQoL instrument with numerous studies documenting its validity and reliability as an accurate measure of generic health concepts in RA 4101718192021. SF-36 assesses eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health, scored from 0 to 100, with higher scores indicating better HRQoL 22. The Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores were obtained from normalized and z-transformed domain scores, with normative values of 50 and standard deviations of 10. Minimum clinically important differences (MCIDs) for the SF-36 domains are defined as a 5.0 or more point increase from baseline and a 2.5 or more point increase from baseline for PCS and MCS scores 23. Baseline SF-36 domain scores were compared with US population norms adjusted for the age and gender distribution of the trial population.

Fatigue (weariness, tiredness) over the past week was evaluated using the Fatigue Assessment Scale (FAS), a numeric rating scale (NRS) from 0 to 10 with higher scores indicating greater fatigue 24. The MCID for the FAS is 10% of the scale range, corresponding to a one-point change 25. Physical function was assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), evaluating eight activities of daily living 2627. HAQ-DI scores range from 0 to 3, with higher scores indicating lower levels of physical functioning. Improvements of 0.22 or more points from baseline represent the HAQ-DI MCID 28. Patient's arthritis pain and patient's global assessment of disease activity (PtGA) were evaluated using 0 to 100 mm visual analog scales (VAS), where higher scores indicate greater pain and disease activity. MCIDs for both pain VAS and PtGA are defined as 10 mm improvements from baseline 25282930.

The SF-36 was completed at baseline, week 12 and every 12 weeks thereafter until week 52 or withdrawal. All other patient-reported outcomes were assessed at baseline, weeks 1 and 2 and every 2 weeks until week 20, followed by every 4 weeks until week 52 or early withdrawal. Fatigue (FAS) was additionally assessed at weeks 5 and 9.

Analyses were conducted on the intent-to-treat (ITT) population, which included all randomized patients receiving at least 1 dose of study treatment. Changes from baseline in PRO scores were analyzed using Analysis of Covariance (ANCOVA) with region and treatment as factors, and baseline score as covariate (using last observation carried forward (LOCF) imputation of missing data). Sensitivity analyses were performed using the repeated measures direct likelihood method. The proportions of patients reporting improvements equal to or greater than the determined MCID for each PRO (post hoc analyses) were compared using repeated-measures logistic regression with region, treatment, time and treatment by time interaction as factors and baseline score as covariate. Response rates (i.e., proportions of patients with clinically meaningful improvements) in pain VAS, HAQ-DI, fatigue NRS, and SF-36 PCS and MCS were compared at week 52 to clinical response rates, defined as a decrease from baseline in DAS28 of 1.2 units or an ACR20 response, by cross tabulation. For analysis of response rates, patients with missing data after rescue medication intake or withdrawal were imputed with a conservative approach of non-responders.

A total of 982 patients were randomized in RAPID 1: 393 to CZP 200 mg plus MTX, 390 to CZP 400 mg plus MTX, and 199 to PBO plus MTX. Of these, 255 (64.9%), 274 (70.3%) and 43 (21.6%) completed 52 weeks of treatment, respectively 28. At baseline, 82% of patients were female, with mean age 52 years, 77% rheumatoid factor positive, mean disease duration 6.2 years, and having failed a mean of 1.4 disease-modifying antirheumatic drugs (DMARDs; excluding MTX). The burden of RA at baseline was significant, as evidenced by patient-reported global assessment of disease activity, pain, physical function, and fatigue scores (Table 1). In particular, SF-36 domain scores at baseline were markedly lower than age- and gender-matched US population norms, and SF-36 MCS and PCS scores reflected a significant psychological burden as well as physical impairments.

RA patients receiving CZP plus MTX reported statistically significant improvements in HRQoL compared with PBO plus MTX by the first post-baseline assessment (week 12; P < 0.001); improvements in all eight SF-36 domains (Table 2), PCS (Figure 1a), and MCS (Figure 1b) were sustained to week 52. In particular, mean changes from baseline at week 12 for the CZP 200 mg plus MTX, CZP 400 mg plus MTX, and PBO plus MTX groups were 5.6, 5.5 and 2.0 for the SF-36 MCS, respectively (Table 2; P < 0.001). Significantly more patients treated with CZP plus MTX than PBO plus MTX also reported improvements in SF-36 MCS equal to or greater than the MCID from weeks 12 to 52 (Table 2; P < 0.05).

Figure 2 shows the SF-36 domain scores for the CZP 200 mg and PBO groups compared with normative values from an age/gender-matched US population. Baseline domain scores reflect the largest decrements in the Role Emotional mental domain, and the physical domains of Role Physical and Physical Function (Figure 2). Improvements exceeding MCID were evident in all domains at week 12 and were sustained through week 52, with the Mental Health and Vitality domains approaching US population normative values.

Statistically significant and clinically meaningful reductions in fatigue were reported by more patients treated with CZP plus MTX than PBO plus MTX throughout the study (P < 0.001; Figure 3a). At week 1, mean changes from baseline in FAS were -1.3 and -1.2 for CZP 200 mg and 400 mg plus MTX, respectively, compared with -0.5 for the PBO plus MTX group (P < 0.001), and by the end of the study (week 52), mean changes from baseline were -2.6, -2.5 and -0.8, respectively (P < 0.001). Statistically more CZP plus MTX patients also reported reductions in fatigue equal to or greater than the MCID compared with PBO plus MTX (P < 0.001; Figure 4a). At week 52, 48.9% and 48.6% of CZP 200 mg- and 400 mg-treated patients reported fatigue reductions equal to or greater than the MCID compared with only 12.6% of PBO-treated patients (P < 0.001).

Rapid, statistically significant improvements in physical function, as assessed by HAQ-DI, were reported by patients treated with CZP plus MTX compared with PBO plus MTX (Figure 3b; P < 0.001). By the end of the study at week 52, mean scores were 1.1 for both CZP plus MTX treatment groups, respectively, compared with baseline scores of 1.7. Significantly more CZP plus MTX-treated patients than PBO plus MTX-treated patients reported HAQ-DI improvements equal to or greater than the MCID throughout the trial (P < 0.001). CZP-treated patients also reported statistically significant improvements in physical function that met or exceeded MCID as reported above for SF-36 PCS (Figure 1a) and Physical Functioning domain scores (Table 2).

CZP-treated patients reported significant improvements from baseline in pain VAS (Figure 3c) and patient's global assessment of disease activity (Figure 3d; P < 0.001), evident at week 1 and sustained through week 52. Significantly more CZP plus MTX-treated patients than PBO plus MTX-treated patients also reported clinically meaningful reductions in pain (Figure 4c) and improvements in global assessment of disease activity (Figure 4d) throughout the trial (P < 0.001). Results were similar regardless of CZP dose (200 mg or 400 mg).

Sensitivity analyses showed that improvements in all PROs were consistent with the LOCF results.

To explore the relation between the patient-reported outcomes and the physician-reported assessments of disease, PRO responses (as defined by improvements in physical function, pain, fatigue and SF-36 scores equal to or greater than the MCIDs) were compared with DAS28 responses (defined as a decrease from baseline of ≥ 1.2) and ACR20 response rates at week 52. In general, PRO responses were in agreement with clinical responses as determined by either improvements in RA signs and symptoms (ACR20 response rates) or decrease in disease activity (DAS28 scores; Table 3). As expected, classification of response according to physical function and pain was highly correlated with ACR20 response rates, with 88.8% and 93.6% of patients treated with CZP 200 mg plus MTX being classified the same by physical function/ACR20 and pain/ACR20, respectively. Correlations between fatigue and ACR20 responses were also high (90.0%) as were those between patient's global assessment of disease activity (98.0%), while changes in HRQoL (SF-36 PCS and MCS scores) had the lowest correlation with ACR20 responses (84.3% and 77.4%, respectively).

Results were similar for correlations between PRO responses and DAS28 responses, with SF-36 PCS and MCS scores showing the lowest correlations with DAS28 responses (82.4% and 77.6%, respectively) and physical function, fatigue, pain and global assessment of disease activity showing the highest correlations (88.0%, 90.6%, 92.8% and 93.6%, respectively).