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Abstract
Objective To evaluate the effect of secukinumab on patient-reported outcomes (PROs) in subjects with active psoriatic arthritis (PsA) in the FUTURE 1 study.
Methods Subjects were randomised 1:1:1 to receive intravenous (i.v.) secukinumab 10 mg/kg at weeks 0, 2 and 4 followed by subcutaneous secukinumab 150 or 75 mg every 4 weeks or matching placebo until week 24.
Results At week 24, subjects receiving secukinumab i.v.→150 mg or i.v.→75 mg reported greater least squares mean changes from baseline than those receiving placebo in patient global assessment of disease activity (−20.6 and −20.0 vs −7.4, respectively), patient assessment of pain (−20.8 and −20.4 vs −6.7), psoriatic arthritis quality of life (−3.5 and −3.2 vs −0.4), Dermatology Life Quality Index (−8.8 and −7.9 vs 0.7); p<0.0001 vs placebo for both secukinumab groups for above PROs and Functional Assessment of Chronic Illness Therapy-Fatigue (6.74 (p<0.05 vs placebo) and 6.03 vs 4.00); all of which well exceeded minimum clinically important differences.
Conclusions In subjects with PsA, secukinumab treatment resulted in clinically meaningful improvements in global disease activity, pain, generic and disease-specific measures of health-related quality of life and fatigue.
Trial registration number NCT01392326; Results.
- Psoriatic Arthritis
- Treatment
- Quality Indicators
- Patient perspective
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Introduction
Psoriatic arthritis (PsA) is associated with reduced physical and psychosocial health-related quality of life (HRQoL).1 Hence, it is important to understand the effect of any treatment for PsA on HRQoL and patient-reported outcomes (PROs), as the functional effect of an illness and its therapy based on the patient's own perception are as important as improvements in the physical signs and symptoms of the disease.2 ,3
Secukinumab, a high-affinity, fully human monoclonal IgG1κ antibody that selectively binds and neutralises interleukin-17A,4–6 has proven efficacy in the treatment of moderate-to-severe plaque psoriasis and PsA.7 ,8
FUTURE 1 is a 2 year, phase III study designed to assess the long-term efficacy and safety of secukinumab in subjects with PsA. Efficacy and safety data through week 52 have been reported previously.9 Here, we present the effect of secukinumab treatment over 24 and 52 weeks on PROs.
Methods
Study population
Detailed inclusion and exclusion criteria are reported previously.9 Briefly, subjects ≥18 years of age, fulfilling the classification criteria for psoriatic arthritis10 with active disease, defined by ≥3 tender joints of 78 and ≥3 swollen joints of 76, despite treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs or tumour necrosis factor inhibitors were enrolled.
Study design
The detailed study design is reported previously.9 Eligible subjects were randomised (1:1:1) to receive intravenous (i.v.) secukinumab 10 mg/kg at baseline, weeks 2 and 4, followed by subcutaneous (s.c.) secukinumab 150 or 75 mg every 4 weeks from week 8 (i.v.→150 mg or i.v.→75 mg) or matching placebo. Placebo non-responders (<20% improvement from baseline in both tender and swollen joint counts) at week 16 and subjects remaining on placebo at week 24 were re-randomised (1:1) to receive secukinumab 150 or 75 mg s.c. every 4 weeks.
The PROs assessed in this study are defined in online supplementary table S1. The mean change from baseline in PROs, and the proportion of subjects reporting improvements meeting or exceeding the minimum clinically important differences (MCIDs) for health assessment questionnaire disability index scores (HAQ-DI responders) and Short Form-36 Health Survey physical component summary scores (SF-36 PCS responders) at weeks 24 and 52, were assessed (for MCIDs see online supplementary table S1). In addition, the SF-6D (model 1) utility scores were assessed (see online supplementary text).
Supplemental material
The details of the statistical analysis of PROs are provided as online supplementary text. All PROs were analysed in the full analysis set that comprised all randomised subjects to whom study treatment had been assigned.
Results
Of the 606 randomised subjects, 515 (85.0%) completed 52 weeks of the trial. Baseline demographics9 and HRQoL scores were similar across treatment groups (table 1). Approximately 60% (n=123) of subjects randomised to placebo treatment were non-responders at week 16 and had to be rescued.
Change from baseline at weeks 24 and 52 in PROs by treatment groups (full analysis set)
Patient-reported outcomes
Least squares mean changes from baseline in patient global assessment of disease activity (PtGA, table 1) and patient assessment of PsA pain by visual analogue scale (figure 1C) were higher in both secukinumab dose groups compared with placebo at all points up to week 24 (p<0.0001 at all-time points). Scores improved further at week 52 with both secukinumab doses (table 1).
Mean change from baseline in (A) FACIT-F and (B) subject's assessment of PsA pain (VAS) through week 52 (full analysis set). *p<0.0001; †p<0.001; §p<0.01; ‡p<0.05 versus placebo. LSM (±SE) change data up to week 24 are from mixed-effect repeated measures model analysis; observed data are shown from week 28 to 52. FACIT-F was an exploratory assessment and nominal p values are provided unadjusted for multiplicity. BL, baseline; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; i.v., intravenous; LSM, least squares mean; PsA, psoriatic arthritis; s.c., subcutaneous; VAS, visual analogue scale.
The HAQ-DI scores and SF-36 PCS scores improved significantly versus placebo at week 24, and improvements were sustained with both secukinumab dose groups up to week 52.9 The SF-36 mental component summary scores improved from baseline at week 24 with both secukinumab dose groups versus placebo; further improvements with both dose groups were observed at week 52 (table 1).
At week 24, 83/202 (41.1%) subjects receiving secukinumab i.v.→150 mg and 80/202 (39.6%) subjects receiving secukinumab i.v.→75 mg were HAQ-DI responders versus 25/202 (12.4%) subjects receiving placebo. Corresponding OR (95% CIs) were 5.24 (3.14 to 8.72) in the secukinumab i.v.→150 mg group and 4.94 (2.96 to 8.23) in the secukinumab i.v.→75 mg group (both p<0.0001 vs placebo). The proportion of subjects classed as HAQ-DI responders improved further at week 52 (99/174 (56.9%) subjects receiving secukinumab i.v.→150 mg and 95/172 (55.2%) subjects receiving secukinumab i.v.→75 mg).
At week 24, 102/202 (50.5%) subjects receiving secukinumab i.v.→150 mg and 104/202 (51.5%) subjects receiving secukinumab i.v.→75 mg were SF-36 PCS responders versus 39/202 (19.3%) subjects receiving placebo. Corresponding OR (95% CIs) were 4.65 (2.95 to 7.33) in the secukinumab i.v.→150 mg group and 4.90 (3.11 to 7.74) in the secukinumab i.v.→75 mg group (both p<0.0001 vs placebo). The proportion of subjects classed as SF-36 PCS responders improved further at week 52 (131/183 (71.6%) with secukinumab i.v.→150 mg and 116/178 (65.2%) with i.v.→75 mg).
In all treatment groups, SF-36 domain scores were lower across all eight domains at baseline and week 24 compared with US population normative values age and gender (A/G)-matched to this protocol population11 (figure 2). Clinically meaningful changes (≥MCID) were observed across all eight SF-36 domain scores with the three treatment groups at week 24, after rescue of placebo non-responders at week 16 (table 1). Subjects in the two secukinumab groups reported larger mean improvements across all eight domains compared with placebo responders. Importantly, improvements in vitality and mental health domains approached normative values observed in the A/G-matched population.11 These mean changes from baseline in SF-36 domain scores were sustained or increased further with the two secukinumab doses at week 52 (table 1).
Comparison of the SF-36 domain scores in subjects with PsA versus A/G-matched normative population. Increase in the score indicates improvement. The SF-36 domain scores at BL and week 24 versus A/G-matched norms in subjects receiving secukinumab i.v.→150 mg, secukinumab i.v.→75 mg or placebo. Gridlines represent changes of 10 points each (two times the MCID of five points). Axis of each polygon represents different domains. A/G, age and gender; BL, baseline; BP, bodily pain; GH, general health; i.v., intravenous; MCID, minimum clinically important difference; MH, mental health; PF, physical functioning; PsA, psoriatic arthritis; RE, role emotional; RP, role physical; s.c., subcutaneous; SF, social functioning; SF-36, Short Form-36 Health Survey; VT, vitality.
Similarly, both doses of secukinumab resulted in improvements from baseline in PsA quality of life, Work Productivity and Activity Impairment-General Health, Dermatology Life Quality Index (table 1), Functional Assessment of Chronic Illness Therapy-Fatigue (figure 1B) and EuroQoL 5-Dimension Health Status Questionnaire (see online supplementary figure S1a) scores at week 24 compared with placebo. Continued or additional improvements in these scores were observed with secukinumab at week 52 (table 1, figure 1B and see online supplementary figure S1a). In the employed subjects, the decrease from baseline at week 24 in the percentage work time missed and work impairment due to health was higher with both secukinumab doses versus placebo (table 1). SF-6D utility scores results are described in online supplementary text and shown in online supplementary figure S1b.
Discussion
The primary results of the FUTURE 1 study showed that secukinumab was efficacious in subjects with PsA.9 Here, we show that treatment with secukinumab for 24 weeks also resulted in clinically meaningful improvements compared with placebo across multiple PROs. Reported improvements were sustained or further improved through 52 weeks of secukinumab therapy. The i.v.→150 mg dose of secukinumab resulted in consistently better PRO improvements than the i.v.→75 mg dose, indicating a dose–response.
Subjects in the FUTURE 1 study had impaired physical function, work productivity and HRQoL at baseline, consistent with observations in other studies of subjects with arthritic conditions.3 ,12–17 Compared with the general population,3 ,15 the impact of PsA on HRQoL and ability to perform daily activities1 ,12–14 ,16 ,17 results in an average loss of 2–6 times more household work days and 2–4 times more workplace days (among those employed).18 Thus, therapies that improve these aspects of disease have the potential to reduce the broad burden of PsA and also reduce its impact on work productivity.
The SF-36 domain scores at baseline in this study were lower than those observed in an A/G-matched normative population, consistent with previous reports.3 ,13 Treatment with both doses of secukinumab resulted in clinically meaningful improvements in SF-36 PCS,9 mental component summary and all domain scores at week 24, indicating improvements in social and emotional well-being, as well as pain, fatigue and physical function. Improvements in each of the individual domain scores with secukinumab i.v.→150 mg dose were nearly double those observed with placebo responders (placebo non-responders were switched to secukinumab at week 16), despite mean changes in placebo responders also exceeding MCID. Compared with subjects with psoriasis, PsA populations generally have lower scores in the physical domains of SF-36 and report largest improvement with treatment in these domains.15 In this study, subjects reported improvements in the physical and mental domains of SF-36 with secukinumab treatment.
A limitation of this study is that although all PRO assessments were prespecified, they were not included in the predefined hierarchical testing procedure (except for HAQ-DI and SF-36 PCS) and were not adequately protected from increases in type I error due to multiplicity of testing. However, the improvements observed during the study across the PRO measures assessing several disease dimensions reflect the clinically meaningful impact of secukinumab on PsA. All of the generic and disease-specific instruments used to assess the PROs in this study are validated as reliable instruments in subjects with PsA, and recommended by Outcome Measures in Rheumatology (OMERACT) for use in randomised controlled trials.2 ,19–22
In summary, secukinumab demonstrated clinically meaningful and sustained improvements in PROs, including global disease activity, pain, physical function, fatigue and generic and disease-specific measures of HRQoL in subjects with active PsA. Further studies should address predictors of good PRO response to treatment and links between disease activity and PROs in PsA.
Acknowledgments
The authors would like to thank the subjects and the investigators who participated in the study. We would like to thank John Gallagher, medical consultant for Novartis Pharma AG, Basel, Switzerland. The draft of manuscript was written by Lakshmi Venkatraman, Novartis Healthcare, Hyderabad, India, as requested by the authors.
References
Footnotes
Handling editor Tore K Kvien
Parts of the patient-reported outcome data from the FUTURE 1 trial were previously presented at the American College of Rheumatology (ACR) annual meeting, 15–19 November 2014, Boston, Massachusetts, USA
Contributors All authors had access to the data, contributed to its interpretation and collaborated in the development of the manuscript. All authors critically reviewed and provided feedback on subsequent versions. All authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and fidelity of this report to the study protocol.
Funding The study was sponsored by Novartis Pharma AG, Basel, Switzerland and designed by the scientific steering committee and Novartis personnel. Medical writing support was funded by Novartis.
Competing interests VS has received consulting fees from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Genentech/Roche, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. PM has received research grants, consultation fees and/or speaking fees from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. LG has received lecture/consultancy honoraria from Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer, Roche and UCB. FvdB has received speaker or consultancy fees from Abbvie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. JZ, LP and SM are employees of Novartis.
Ethics approval The study protocol was approved by the institutional review board or ethics committees at each centre.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The study protocol can be made available on request.