The efficacy and safety of tocilizumab were previously demonstrated in the RADIATE trial [6
]. Efficacy was similar regardless of the previous number of TNFis failed. In the present analysis of these data from the RADIATE trial, treatment with 8
mg/kg tocilizumab resulted in statistically significant and clinically meaningful improvements in PROs, including pain, PtGA, physical function (HAQ-DI), HRQOL and FACIT-Fatigue.
Over 24 weeks, tocilizumab-treated patients reported statistically significant and clinically meaningful improvements in SF-36 PCS and HAQ-DI scores compared with controls. These results are important because improvements in SF-36 PCS and HAQ-DI scores in patients with RA are associated with improved work productivity, reduced long-term disability, reduced health care utilization and costs and reduced mortality [24–30
]. Improvements in SF-36 scores were further contextualized using spydergrams, which pictorially present all eight SF-36 domains in relation to treatment goals (e.g. age-/gender-matched normative values). The use of spydergrams also facilitates interpretation of improvements between treatment groups. The marked impact of RA on HRQOL is evident from the large separation in all eight domain scores at baseline between the trial population and age- and gender-matched US population norms as a benchmark for comparison.
Both tocilizumab doses resulted in improved HRQOL, but changes from baseline were numerically higher with 8
mg/kg than with 4
mg/kg at weeks 16 and 24. Treatment with 8
mg/kg resulted in more rapid improvements over time than 4
mg/kg; at week 24, mean changes from baseline with 4
mg/kg approached responses seen at week 16 with 8
mg/kg. Similarly, mean improvements from baseline in pain, PtGA, HAQ-DI and FACIT-Fatigue scores were greatest with 8
mg/kg, improving as early as week 4 and continuing through week 24 ().
Further clinically meaningful improvements in domain scores ranging from 1 to 5× MCID were observed between weeks 16 and 20 of treatment (). Some, particularly in the control group, can be attributed to non-responders receiving rescue therapy with 8
mg/kg at week 16. Because the primary analysis sets the values for rescue patients to missing, analyses beyond week 16 included only the responsive population. Given that the proportion of patients who received rescue treatment was greatest in the control group, analyses treating data after rescue as missing likely overestimate the response, especially in the control group. In the sensitivity analysis, LOCF imputation allowed inclusion of these rescue patients (non-responders) in the analyses. As in the original ITT analysis without imputation, responses in the tocilizumab groups remained higher than those in the control group.
A greater proportion of tocilizumab-treated patients than controls reported clinically meaningful improvements in each PRO measure and in at least two PROs. Not surprisingly, the proportions of tocilizumab-treated patients reporting improvements greater than or equal to MCID in individual PROs (~30–80% of patients; A) were similar to those reporting clinically meaningful improvements in a corresponding SF-36 domain score (~45–65%; B). This underscores the expected agreement between different PROs measuring related concepts (e.g. SF-36 PF or RP and HAQ-DI; SF-36 BP and patient pain; and SF-36 VT and FACIT-Fatigue). Tocilizumab patients were also more likely than controls to attain responses by ACR50 or DAS28 remission definitions and to report clinically meaningful improvements in an individual PRO. Together, these data demonstrate the importance of assessing both clinical response measures and PROs in randomized controlled trials to more completely assess treatment-associated improvements.
Overall, improvements in HRQOL associated with tocilizumab were in the range of those observed in clinical trials of other biologic agents in patients who had failed one or more TNFis [31–33
]. For example, the Abatacept Trial in the Treatment of Anti-tumor Necrosis Factor Inadequate Responders (ATTAIN) [32
], the Golimumab After Former Anti-TNF Therapy Evaluated in RA (GO-AFTER) study [33
] and the Randomized Evaluation of Long Term Efficacy of Rituximab in RA (REFLEX) [31
] trial demonstrated significant and clinically meaningful improvements in HRQOL outcomes. Over 6 months, ~45–65% of patients treated with a biologic agent compared with ~25–35% of placebo recipients experienced improvements greater than or equal to MCID in SF-36 PCS or HAQ-DI scores or both. In the present analyses, similar differences were evident between the tocilizumab and control treatment groups. At week 24, 50–65% of tocilizumab-treated patients compared with ~30% of controls reported improvements greater than or equal to MCID in SF-36 PCS or HAQ-DI scores.
Fatigue is frequently experienced by patients with RA and may be severe in >40% of patients [34
]. In the present study, treatment with both tocilizumab doses resulted in changes greater than or equal to MCID in FACIT-Fatigue score; improvements with 8
mg/kg were approximately twice those of controls. Similarly, with both tocilizumab doses, improvements in the SF-36 VT domain exceeded MCID, indicating that patients also had more pep and energy.
In conclusion, overall, results from this study demonstrate that tocilizumab-associated improvements in HRQOL occurred rapidly and were statistically significant and clinically meaningful despite long-standing active disease in patients who were inadequate responders to one or more TNFis. The proportions of patients reporting improvements greater than or equal to MCID in PROs were greater with 8
mg/kg than with 4
mg/kg tocilizumab. Thus tocilizumab may be considered a valuable therapeutic option that offers both clinical and HRQOL benefits to RA patients.