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Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trialIain B McInnes, Frank Behrens, Philip J Mease, Arthur Kavanaugh, Christopher Ritchlin, Peter Nash, Jordi Gratacós Masmitja, Philippe Goupille, Tatiana Korotaeva, Alice B Gottlieb, Ruvie Martin, Kevin Ding, Pascale Pellet, Shephard Mpofu, Luminita Pricop, on behalf of EXCEED Study GroupLancet 2020; 395: 1496–505

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1496 www.thelancet.com Vol 395 May 9, 2020

Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trialIain B McInnes, Frank Behrens, Philip J Mease, Arthur Kavanaugh, Christopher Ritchlin, Peter Nash, Jordi Gratacós Masmitja, Philippe Goupille, Tatiana Korotaeva, Alice B Gottlieb, Ruvie Martin, Kevin Ding, Pascale Pellet, Shephard Mpofu, Luminita Pricop, on behalf of EXCEED Study Group

SummaryBackground Head-to-head trials in psoriatic arthritis are helpful in guiding clinical decision making. The EXCEED study evaluated the efficacy and safety of secukinumab versus adalimumab as first-line biological monotherapy for 52 weeks in patients with active psoriatic arthritis, with a musculoskeletal primary endpoint of American College of Rheumatology (ACR) 20 response.

Methods This parallel-group, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries) trial enrolled patients aged at least 18 years with active psoriatic arthritis. Eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalimumab. Patients, investigators, site personnel, and those doing the assessments (except independent study drug administrators) were masked to study assignment. 300 mg secukinumab was administered subcutaneously at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48 as a pre-filled syringe. Adalimumab was administered every 2 weeks from baseline until week 50 as 40 mg per 0·4 mL citrate free subcutaneous injection. The primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Patients were analysed according to the treatment to which they were randomly assigned. Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. The trial is registered at ClinicalTrials.gov, NCT02745080.

Findings Between April 3, 2017 and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study, of whom 691 (81%) received the last study treatment at week 50. 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group achieved an ACR20 response at week 52 versus 62% of patients in the adalimumab group (OR 1·30, 95% CI 0·98–1·72; p=0·0719). The safety profiles of secukinumab and adalimumab were consistent with previous reports. Seven (2%) of 426 patients in the secukinumab group and six (1%) of 427 patients in the adalimumab group had serious infections. One death was reported in the secukinumab group due to colon cancer and was assessed as not related to the study drug by the investigator.

Interpretation Secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than adalimumab. This study provides comparative data on two biological agents with different mechanisms of action, which could help guide clinical decision making in the management of patients with psoriatic arthritis.

Funding Novartis Pharma.

Copyright © 2020 Elsevier Ltd. All rights reserved.

IntroductionPsoriatic arthritis is clinically heterogeneous, comprising musculoskeletal and dermatological manifestations that might involve arthritis, spondylitis, enthesitis, dactylitis, and psoriasis of skin and nails, and is associated with impaired physical function and poor quality of life.1 Non-steroidal anti-inflammatory drugs (NSAIDs) are typically the first choice in treating psoriatic arthritis symptoms, but have associated safety issues of cardio-vascular risk and gastrointestinal toxicity; therefore,

physicians initiate conventional synthetic disease-modi-fying anti-rheumatic drugs (csDMARDs), preferably methotrexate, early in patients with poor prognostic factors and relevant skin involvement to modify under-lying musculoskeletal and skin inflammation.2,3

Several biological disease modifying anti-rheumatic drugs (bDMARDs) targeting inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs.3,4 Adalimumab, a human monoclonal antibody against tumour necrosis

Lancet 2020; 395: 1496–505

See Comment page 1463

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary

and Life Sciences, University of Glasgow, Glasgow, UK

(I B McInnes FRCP); Rheumatology University

Hospital and Fraunhofer Institute for Molecular Biology

and Applied Ecology, Branch for Translational Medicine and Pharmacology and Fraunhofer

Cluster of Excellence for Immune-Mediated Diseases,

Goethe University, Frankfurt, Germany (F Behrens MD); Swedish Medical Centre,

Providence St Joseph Health and University of Washington,

Seattle, WA, USA (P J Mease MD); Rheumatology, Allergy, Immunology Division,

University of California San Diego, School of Medicine,

La Jolla, CA, USA (A Kavanaugh MD); Allergy,

Immunology and Rheumatology Division, University of Rochester,

Rochester, NY, USA (C Ritchlin MD); Department of

Medicine, Griffith University, Brisbane, QLD, Australia

(P Nash FRACP); Rheumatology Department, University

Hospital Parc Taulí, Sabadell, Universitat Autònoma de

Barcelona, Spain (J G Masmitja PhD); Department

of Rheumatology and INSERM-CIC1415, University

Hospital of Tours, EA 7501 GICC, University of

Tours, Tours, France (P Goupille MD); Research

Institute of Rheumatology n.a. V A Nasonova, Moscow, Russia (T Korotaeva PhD); Department

of Dermatology, Icahn School of Medicine at Mount Sinai,

New York, NY, USA (A B Gottlieb PhD); Novartis

Pharmaceuticals, East Hanover, NJ, USA (R Martin PhD,

K Ding MSc, L Pricop MD); and Novartis Pharma, Basel,

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Switzerland (P Pellet PhD, S Mpofu FRCP)

Correspondence to: Dr Iain B McInnes, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland, UK iain.mcinnes@glasgow.ac.uk

factor (TNF), is widely used as a first line bDMARD in the treatment of patients with psoriatic arthritis as mono-therapy or an add-on to methotrexate.5 Secukinumab, a human monoclonal antibody that directly inhibits IL-17A, has shown substantial improvement in the key clinical domains of psoriatic arthritis, including signs and symp-toms, radiographic progression, physical functioning, and quality of life.6–8 In the treatment of patients with moderate to severe psoriasis and plaque psoriasis, secukinumab has shown greater efficacy versus a TNF inhibitor (etanercept) and an IL-12/23 inhibitor (ustekinumab).9–11

Both adalimumab and secukinumab are approved for treatment of patients with active psoriatic arthritis with or without the use of concomitant methotrexate.5,6,12 More than 40% of patients treated with methotrexate discon-tinue treatment or are non-compliant because of poor tolerability or toxicity, or cannot receive methotrexate because of liver abnormalities related to psoriatic arthritis or concomitant alcohol abuse.13–15 The European League Against Rheumatism (EULAR) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations differ. EULAR proposes a treatment algorithm, whereas GRAPPA proposes an evidence-based clinical domain approach that includes biologicals with novel mechanisms of action.3,16 However, there is a paucity of trials to determine which biological treatment should be the initial treatment in patients with psoriatic arthritis upon csDMARD failure or intolerance.

The advent of biological therapies with selective mecha-nisms of action that are approved and widely used in clinical practice has prompted indirect comparison approaches to guide therapy, but these comparisons have metho dological limitations.17

Head-to-head trials have shown that IL-17A inhibitors have higher efficacy in treatment of patients with moderate to severe psoriasis and on the skin manifes-tations of patients with psoriatic arthritis. However, comparative data are lacking on the efficacy of these drugs on musculo skeletal manifestations of psoriatic arthritis and are urgently required. The aim of the EXCEED study was to investigate whether secukinumab 300 mg monotherapy was superior to adalimumab 40 mg monotherapy as first-line bDMARD treatment, thus testing the musculoskeletal endpoint of the American College of Rheumatology (ACR) 20 response as the primary objective in a fully blinded manner. Safety of secukinumab and adalimumab was also assessed.

MethodsStudy design and participantsEXCEED is a randomised, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries; appendix p 19), parallel-group, 52-week study that evaluated secukinumab monotherapy and adalimumab mono-therapy in patients with active psoriatic arthritis who were naive to biological therapy for psoriatic arthritis and

Research in context

Evidence before this studyMany patients with psoriatic arthritis who have active psoriasis and musculoskeletal symptoms show inadequate clinical responses to conventional synthetic disease-modifying antirheumatic agents (csDMARDs), including methotrexate, in all manifestations of psoriatic arthritis, including arthritis, spondylitis, enthesitis, dactylitis, and psoriasis. Several biological disease-modifying anti-rheumatic drugs (bDMARDs) that target different inflammatory cytokines are recommended for patients with psoriatic arthritis with inadequate response to csDMARDs. Adalimumab, a human monoclonal antibody against tumour necrosis factor (TNF), is widely used as a first-line bDMARD in the treatment of patients with psoriatic arthritis in monotherapy or in combination with methotrexate. We searched PubMed using the terms “psoriatic arthritis”, “biologic”, and “head-to-head” for English language articles published from inception up to Jan 13, 2020, with no limitation or restriction for year of publication or article type. The search results yielded 30 articles, of which nine used matching adjusted indirect comparisons to compare two biologicals, 20 were review articles, and one was a head-to-head comparison of two biologicals in psoriatic arthritis. However, matching adjusted indirect comparisons have an inherent limitation of the methodology used and might lead to different conclusions; therefore, prospective head-to-head trials in psoriatic arthritis are needed to help guide physicians in

clinical decision making. A 2020 head-to-head, open label, 24-week trial compared the efficacy and safety of two biologicals—adalimumab and ixekizumab (an IL-17A inhibitor)—in psoriatic arthritis and supported that ixekizumab was superior to adalimumab in achieving combined American College of Rheumatology 50 (ACR50) and Psoriasis Area and Severity Index 100 responses at week 24.

Added value of this studyTo our knowledge, EXCEED is the first fully blinded head-to-head trial to evaluate the efficacy and safety of secukinumab (an IL-17A inhibitor) versus adalimumab (an anti-TNF agent) as first-line biological monotherapy in patients with active psoriatic arthritis with a musculoskeletal primary endpoint of ACR20 at week 52. The efficacy data in this study suggest that secukinumab was at least as efficacious as adalimumab in improving musculoskeletal endpoints, provided better responses on skin endpoints, and had a higher retention rate at week 52. No new safety signals were reported for secukinumab and adalimumab.

Implications of all the available evidenceThis study presents a considerable volume of comparative efficacy and safety data on two biologicals with different mechanisms of action in the treatment of patients with psoriatic arthritis.

See Online for appendix

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psoriasis, and who were intolerant or had an inadequate response to csDMARDs.

Patients fulfilling all the following criteria were included in the study: aged at least 18 years of age, fulfilled the Classification Criteria for Psoriatic Arthritis,18 had active psoriatic arthritis (defined as ≥3 swollen joints and ≥3 tender joints), had active plaque psoriasis with at least one plaque of at least 2 cm diameter or nail changes consistent with psoriasis or documented history of plaque psoriasis, were naive to treatment with biologicals, had previously been treated with csDMARDs (including but not limited to methotrexate) with an inadequate response or had stopped treatment due to safety or tolerability problems, and had a previous inadequate response to NSAIDs for at least 4 weeks before randomisation.

Patients had to stop any csDMARD, including metho-trexate, before randomisation, with a washout period of 4 weeks for all csDMARDs or 8 weeks for leflunomide. Patients who were receiving concomitant corticosteroids were required to be on a stable dose of 10 mg/day or less of prednisone or equivalent for at least 2 weeks before randomisation and remain on a stable dose up to week 52 (appendix p 13).

Key exclusion criteria were pregnancy, evidence of ongoing infection or malignancy, previous exposure to any biologicals or opioids, ongoing use of oral or topical retinoids, photochemotherapy, phototherapy, or topical skin treatment. For detailed information on the exclusion criteria, please refer to the appendix (p 14).

All clinical studies were done in compliance with the Declaration of Helsinki, International Council for Harmonization Guidelines for Good Clinical Practice, and local country regulations. All patients provided written informed consent to participate in the respective studies. The institutional review board at each participating centre approved the protocol.

Randomisation and maskingAfter a screening period of up to 8 weeks, eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalim-umab. The interactive response technology assigned a randomisation number to the patient (randomisation block size was 4), which linked the patient to a treatment group and specified a unique medication number. The randomisation scheme for patients was reviewed and approved by a member of the Novartis randomisation office.

To maintain allocation concealment, all groups received placebo injections to ensure a consistent number of injections at each visit. Study treatments were admin-istered by suitably qualified independent study drug administrators, who were not masked and had no responsibility for any aspect of patient assessment or follow-up. Before administration of study treatment, unmasked site personnel were required to use physical barriers (curtains, blindfolds, or similar measures) to prevent patients from seeing their study treatment to preserve the masking. Patients, investigators, site personnel, and those performing the assessments (except independent study drug administrators) were masked to the study assignment (appendix p 16).

ProceduresSecukinumab 300 mg was administered at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48. Adalimumab 40 mg was administered every 2 weeks from baseline until week 50 (appendix p 19). Secukinumab was administered with a pre-filled syringe and adalim-umab as 40 mg in 0·4 mL citrate free subcutaneous injection. Additional information about the assessments undertaken during the trial is provided in the appendix (p 17). Key efficacy (assessed by primary endpoint, key secondary endpoints, and other relevant exploratory endpoints), safety, and tolerability (assessed by adverse events, laboratory values, injection site reaction, and immunogenicity) assessments were done at screening, baseline, week 2, week 4, and every 4 weeks until week 52 (primary endpoint). 337 (40%) of 853 patients had at least one protocol deviation in the study, of whom

Figure 1: Trial profileFor the secukinumab group, six patients who discontinued treatment but stayed in the study up to week 52 are not included in the 55 patients who discontinued the study. For the adalimumab group, 12 patients who discontinued treatment but stayed in the study up to week 52 are not included in the 89 patients who discontinued the study. *Patients might have had multiple reasons for being a screen failure but are only counted for the first major reason in one of the three categories of screen failures

426 assigned to secukinumab

371 completed week 52

61 discontinued study treatment at week 50

55 discontinued the study before week 5222 patient or guardian decision13 adverse events11 lack of efficacy

3 lost to follow-up3 physician decision3 protocol deviation

214 excluded before randomisation174 screen failures*

94 did not meet diagnosis criteria for active psoriaticarthritis

42 had clinically significant safety exclusion criteria38 other

33 patient or guardian decision4 physician decision2 adverse events1 technical problems

427 assigned to adalimumab

1067 patients assessed for eligibility

853 randomly assigned

338 completed week 52

101 discontinued study treatment at week 50

89 discontinued the study before week 5241 patient or guardian decision23 lack of efficacy21 adverse events

3 lost to follow-up1 protocol deviation

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172 (40%) of 426 were in the secukinumab group and 165 (39%) of 427 were in the adalimumab group. Major reasons for protocol deviations were use of prohibited concomitant medi cation and other deviations from Good Clinical Practice guidelines. Other reasons for protocol deviations included unmet selection criteria and treatment deviation. For further details of protocol deviations, see the appendix (p 24).

OutcomesThe primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Key secondary endpoints in order of the statistical hierarchy were Psoriasis Area and Severity Index (PASI) 90 response, ACR50 response, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score, and resolution of enthesitis (based on Leeds Enthesitis Index [LEI] criteria) at week 52.

Prespecified exploratory endpoints assessed at week 52 were clinically relevant musculoskeletal and skin endpoints, which included the proportion of patients achieving a combined ACR50 and PASI 100 response, PASI 75 or 100 response, absolute PASI score of 3 or less, ACR70 response, psoriatic arthritis response criteria response, resolution of dactylitis, resolution of enthesitis (based on Spondyloarthritis Research Consortium of Canada [SPARCC] criteria), proportion of patients achieving Psoriatic Arthritis Disease Activity Score (PASDAS) low disease activity and remission, Disease Activity in Psoriatic Arthritis (DAPSA) low disease activity and remission, minimal disease activity, and very low disease activity response and quality-of-life questionnaires (HAQ-DI). Additional prespecified efficacy analyses in the subset of patients with psoriasis with body surface area greater than 10% or PASI of at least 10 were also done.

Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. MedDRA version 22.0 was used for reporting adverse events.

Statistical analysisThe study was powered based on the planned analysis of patients achieving an ACR20 response at week 52. An ACR20 response rate of 50% for the TNF inhibitor-naive population without methotrexate use (monotherapy) was assumed for adalimumab based on observed week 48 response rate reported in a previous study.19 The response to secukinumab was estimated to be 62% based on ACR20 response in the TNF inhibitor-naive monotherapy population from phase 3 studies.6 With 425 patients per treatment group, we anticipated that there would be approximately 94% power to detect a treatment difference of around 12% (odds ratio [OR] 1·63) in ACR20 response rates at two-sided α=0·05 between secukinumab and adalimumab in the evaluation of the primary efficacy hypothesis at week 52.

Secukinumab 300 mg (n=426)

Adalimumab 40 mg (n=427)

Total (n=853)

Age (years) 48·5 (12·38) 49·5 (12·44) 49·0 (12·41)

Sex

Male 208 (49%) 229 (54%) 437 (51%)

Female 218 (51%) 198 (46%) 416 (49%)

Weight (kg) 83·5 (19·12) 84·1 (18·33) 83·8 (18·72)

Body-mass index (kg/m²) 28·8 (6·03) 28·9 (5·55) 28·8 (5·79)

Race

White 402 (94%) 391 (92%) 793 (93%)

Asian 16 (4%) 20 (5%) 36 (4%)

Other or unknown 8 (2%) 16 (4%) 24 (3%)

No smoking status at baseline 333 (78%) 351 (82%) 684 (80%)

Systemic glucocorticoids use at randomisation 61 (14%) 58 (14%) 119 (14%)

Time since first diagnosis of psoriatic arthritis (years)

5·1 (7·60) 5·7 (7·29) 5·4 (7·45)

Baseline PASI score 10·6 (9·00) 10·0 (8·15) 10·3 (8·60)

Patients with psoriasis (BSA ≥3%) 215 (50%) 202 (47%) 417 (49%)

Patients with psoriasis (BSA >10% or PASI ≥10) 110 (26%) 101 (24%) 211 (25%)

Adjusted tender joint total score for psoriatic arthritis (78 joints)

19·4 (13·86) 20·6 (14·81) 20·0 (14·35)

Adjusted swollen joint total score for psoriatic arthritis (76 joints)

9·7 (7·30) 10·2 (7·86) 10·0 (7·58)

Patient’s global assessment (0–100) 64·0 (19·67) 61·9 (20·75) 62·9 (20·23)

Physician’s global assessment (0–100) 60·0 (17·12) 61·4 (15·92) 60·7 (16·54)

Psoriatic arthritis pain (0–100) 58·6 (23·49) 57·9 (22·42) 58·3 (22·95)

Health Assessment Questionnaire-Disability Index 1·3 (0·64) 1·2 (0·64) 1·3 (0·64)

CRP ≥10 mg/L 131 (31%) 128 (30%) 259 (30%)

Disease Activity Score 28-CRP 4·7 (1·00) 4·7 (0·94) 4·7 (0·97)

Presence of enthesitis (Leeds Enthesitis Index) 234 (55%) 264 (62%) 498 (58%)

Presence of enthesitis (Spondyloarthritis Research Consortium of Canada)

301 (71%) 330 (77%) 631 (74%)

Presence of dactylitis 130 (31%) 137 (32%) 267 (31%)

Data are mean (SD) or n (%). BSA=body surface area. CRP=C-reactive protein. PASI=Psoriasis Area Severity Index.

Table 1: Baseline and disease characteristics of patients

Figure 2: ACR20 response rate through week 52 (multiple imputation)Unadjusted p values versus adalimumab are presented. Data were analysed using logistic regression. Patients who discontinued study treatment before or at week 50 or took csDMARDs after week 36 were considered non-responders for the visits after discontinuation or taking csDMARDs. Multiple imputation was used for all other missing data. csDMARD=conventional synthetic disease-modifying anti-rheumatic drugs. OR=odds ratio.

0 4 8 12 16 20 24 28 32 36 40 44 48 520

10

20

30

40

50

60

70

80

Resp

onde

rs (%

)

Time (weeks)

29

48

6063 66 68

7167 66 68 68 68 70 67

32

50 59 6266 63 64 64 63 61 62 62 65

62

At week 52, OR 1·30 (95% CI 0·98–1·72); p=0·0719Secukinumab 300 mg (n=426)Adalimumab 40 mg (n=427)

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The full analysis set used for efficacy analysis comprised all patients who were randomly assigned to study treatment. As per the intention-to-treat principle, patients were analysed according to the treatment to which they were randomly assigned. Psoriasis-related endpoints used the psoriasis subset, which included all patients in the full analysis set who had at least 3% of their body surface area affected by psoriasis at baseline. Enthesitis-related endpoints used the enthesitis subset, which included all patients in the full analysis set who had enthesitis based on LEI (as a key secondary endpoint) and based on SPARCC criteria (as an exploratory endpoint) at baseline.

We used a sequential hierarchical testing method to maintain the familywise type 1 error rate at 5% across the primary and ranked secondary endpoints. If the primary efficacy analysis was significant, secondary analyses were planned to be completed in the following sequence: ACR20, PASI 90, ACR50, HAQ-DI, and resolution of enthesitis. The inferential testing procedure only con-tinued if the previous test was rejected at the two-sided 5% level. Subgroup analysis was tested independently from the hierarchical testing strategy.

The primary efficacy endpoint was defined as meeting the following three conditions: achieving an ACR20 response, with no permanent study treatment (secukinumab or adalimumab) discontinuation before or at week 50 (the last dosing visit), and no concomitant use of csDMARDs (including methotrexate) after week 36 (regardless of the time initiation of csDMARDs). A patient meeting all these conditions was regarded as a responder, otherwise they were considered non-responders. All secondary and exploratory binary end-points were defined in the same way as the primary endpoint.

For analyses of binary endpoints, we computed ORs, 95% CIs, and p values for comparisons of secukinumab versus adalimumab from a logistic regression model, with treatment as a factor and baseline weight as a covariate.

For the primary endpoint and other binary endpoints, if a patient discontinued study treatment prematurely or took csDMARDs after week 36 they were considered a non-responder. If a patient neither discontinued study treatment prematurely nor took csDMARDs after week 36 but had all or some components missing that precluded the calculation of ACR20 response (eg, missed visits, electronic device malfunction, or site error), then missing data for these components were handled by multiple imputation. This method imputes missing data based on a patient’s own observed data and observed data from similar patients in similar conditions. As a sensi tivity analysis, non-responder imputation was specified to assess the effect of missing data. Non-responder impu-tation is a highly conservative method that assumes non-response for all missing data.

We evaluated between-group differences in continuous endpoints using a mixed-effect model repeated measures

Secukinumab 300 mg

Adalimumab 40 mg

Odds ratio (95% CI)

p value (unadjusted)*

Primary endpoint

ACR20 67% (426) 62% (427) 1·30 (0·98 to 1·72) 0·0719

Prespecified sensitivity analysis using non-responder imputation

ACR20 67% (426) 59% (427) 1·38 (1·04 to 1·83) 0·0239

Key secondary endpoints

PASI 90 65% (215) 43% (202) 2·49 (1·67 to 3·71) <0·0001

ACR50 49% (426) 45% (427) 1·18 (0·90 to 1·55) 0·2251

HAQ-DI score, change from baseline, mean (SE) [n]

–0·58 (0·03) [363]

–0·56 (0·03) [318]

–0·02† (–0·10 to 0·05) 0·5465

Resolution of enthesitis (based on Leeds Enthesitis Index)

61% (234) 54% (264) 1·30 (0·91 to 1·87) 0·1498

Combined endpoint

ACR50 plus PASI100‡ 31% (215) 19% (202) 1·85 (1·17 to 2·92) 0·0087

Exploratory endpoints

Psoriatic arthritis endpoints

Minimal disease activity (78/76 joints)

43% (426) 38% (427) 1·22 (0·93 to 1·61) 0·1498

Very low disease activity (78/76 joints)

18% (426) 17% (427) 1·10 (0·77 to 1·57) 0·6107

DAS28 CRP low disease activity

69% (426) 61% (427) 1·45 (1·09 to 1·95) 0·0118

DAPSA low disease activity and remission

62% (426) 53% (427) 1·41 (1·06 to 1·87) 0·0178

DAPSA-based remission 25% (426) 24% (427) 1·04 (0·76 to 1·42) 0·8252

DAS28 CRP-based remission 53% (426) 48% (427) 1·20 (0·91 to 1·59) 0·1922

ACR70 33% (426) 29% (427) 1·17 (0·87 to 1·57) 0·2950

Resolution of dactylitis 75% (130) 70% (137) 1·29 (0·75 to 2·22) 0·3560

Resolution of enthesitis (based on Spondyloarthritis Research Consortium of Canada)

53% (301) 50% (330) 1·11 (0·81 to 1·52) 0·5117

PASDAS-based remission 22% (425) 18% (427) 1·27 (0·90 to 1·79) 0·1708

PASDAS-based low disease activity and remission

51% (425) 44% (427) 1·31 (0·99 to 1·73) 0·0557

Psoriatic Artiritis Response Criteria

80% (426) 70% (427) 1·71 (1·24 to 2·34) 0·0009

Skin endpoints§

PASI 75 79% (215) 61% (202) 2·33 (1·50 to 3·60) 0·0002

PASI 100 46% (215) 30% (202) 2·01 (1·34 to 3·03) 0·0007

Absolute PASI score ≤3 79% (215) 65% (202) 2·06 (1·32 to 3·22) 0·0015

Quality-of-life endpoints

HAQ-DI ≥0·3 55% (426) 51% (427) 1·13 (0·85 to 1·49) 0·3984

HAQ-DI ≥0·35 55% (426) 51% (427) 1·13 (0·86 to 1·49) 0·3945

Data % (N), unless otherwise indicated. Binary variables, including the primary endpoint, were analysed using logistic regression. Patients who discontinued study treatment before or at week 50 or took csDMARDs after week 36 were considered non-responders for the visits after discontinuation or taking csDMARDs. Multiple imputation was used for all other missing data. The primary endpoint of ACR20, as part of the prespecified sensitivity analysis, was analysed using non-responder imputation for all other missing data. Continuous variables were analysed using mixed-effect model repeated measures. ACR=American College of Rheumatology. PASI=Psoriasis Area Severity Index. HAQ-DI=Health Assessment Questionnaire-Disability Index. DAS28=disease activity score based on 28 joint count. CRP=C-reactive protein. DAPSA=Disease Activity in Psoriatic Arthritis. PASDAS=Psoriatic Arthritis Disease Activity Score. csDMARDS=conventional synthetic disease-modifiying antirheumatic drugs. *Versus adalimumab. †Between-treatment difference in mean change from baseline for HAQ-DI is presented and n is the number of patients having values both at baseline and week 52. ‡Proportion of ACR50 responders among patients with psoriasis who have ≥3% body surface area affected at baseline and have achieved PASI 100 response. §PASI 75 and 100 responses and absolute PASI scores ≤3 are calculated in patients with psoriaris who have ≥3% body surface area affected at baseline.

Table 2: Efficacy and health outcomes at week 52 in full analysis set

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approach, with missing data assumed to be missing at random. Treatment and assessment visit were included in the model as factors. Weight and baseline values of the endpoints were included in the model as continuous covariates. Treatment by analysis visit and baseline score by analysis visit were interaction terms, and an unstructured covariance structure was assumed.

For continuous efficacy endpoints, data for patients who discontinued study treatment before week 50 or took csDMARDs after week 36 were set to missing for the visits after discontinuation or taking csDMARDs.

Safety endpoints were assessed for all patients who received at least one dose of study drug and were summarised descriptively for data reported up to and including each patient’s week 52 visit at the time of the week 52 database lock (Oct 21, 2019).

Analyses were done with SAS version 9.4. The trial is registered at ClinicalTrials.gov, NCT02745080.

Role of the funding sourceThe study was designed by the funder, Novartis, in collaboration with the authors. Data were collected in accordance with Good Clinical Practice guidelines by the study investigators and were analysed by the funder. All authors contributed to interpretation of the data and had access to the full datasets. Statistical analyses were done by statisticians employed by the funder and were reviewed by all authors. Agreements between the funder and the inves tigators included provisions relating to confidentiality of the study data. Writing support for the manuscript was provided by a medical writer from Novartis, India, and funded by the funder. All authors vouch for the accuracy and completeness of the data and analyses, as well as for the fidelity of this report to the trial protocol, which is available from the funder. All authors had the final responsibility for the decision to submit the manuscript for publication.

ResultsBetween April 3, 2017, and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study (figure 1), of whom 691 (81%) received the last study treatment at week 50 (appendix p 20). 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. Major reasons for disconti nuation of treatment were adverse events (15 [4%] of 426 patients in the secukinumab group vs 30 [7%] of 427 patients in the adalimumab group), lack of efficacy (15 [4%] of 426 patients in the secukinumab group vs 32 [7%] of 427 patients in the adalimumab group), and patient or guardian decision (23 [5%] of 426 patients in the secukinumab group vs 35 [8%] of 427 patients in the adalimumab group). A Kaplan-Meier curve for time to study treatment discontinuation is shown in the appendix (p 21), indicating a higher proportion of patients

being retained for a longer duration on secukinumab versus adalimumab until the last dosing visit at week 50 (p=0·0005).

Baseline demographics and disease characteristics were similar across the secukinumab and adalimumab groups, except for the proportion of female patients and patients with enthesitis as defined by LEI (table 1).

Figure 3: Key secondary endpoints up to week 52Patients who discontinued study treatment before or at week 50 or took csDMARDs after week 36 were considered non-responders for the visits after discontinuation or taking csDMARDs. Multiple imputation was used for all other missing data for binary variables (PASI 90, ACR50, and resolution of enthesitis based on LEI). Unadjusted p values are presented versus adalimumab. (A) PASI 90 response. PASI reported only in patients with at least 3% body surface area affected with psoriasis at baseline. (B) ACR50 response. (C) Mean change from baseline in Health Assessment Quality-Disability Index score Least squares means are from mixed-effect model repeated measures with treatment group, analysis visit as factors, weight, and baseline score as covariates, and treatment by analysis visit, and baseline score by analysis visit as interaction terms. (D) Resolution of enthesitis is reported in number of patients with available enthesitis data at baseline (LEI criteria). csDMARD=conventional synthetic disease-modifying anti-rheumatic drugs. OR=odds ratio. PASI=psoriasis area severity index. ACR=American College of Rheumatology. LEI=Leeds Enthesitis Index.

0 4 8 12 16 20 24 28 32 36 40 44 48 520

10

20

30

40

50

60

70

80

D

Resp

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rs o

f ent

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is (%

)

–0·7

–0·6

–0·5

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–0·2

–0·1

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C

Mea

n ch

ange

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bas

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Time (weeks)

Secukinumab 300 mg (n=215)Adalimumab 40 mg (n=202)

Secukinumab 300 mg (n=426)Adalimumab 40 mg (n=427)

Secukinumab 300 mg (n=426)Adalimumab 40 mg (n=427)

Secukinumab 300 mg (n=234)Adalimumab 40 mg (n=264)

5

19

42

5458

63 6265 65

25

15

2937

42 42 42 43

At week 52, OR 2·49 (95% CI 1·67 to 3·71); p<0·0001

7

16

2832

3842 43 41 43 44 44

4749 49

8

19

3134

36 39 40 41 3943 43 45 44 45

At week 52, OR 1·18 (95% CI 0·90 to 1·55); p=0·2251

–0·22

–0·34–0·41

–0·45–0·50 –0·50 –0·50

–0·53–0·55 –0·55–0·55 –0·56

–0·60

–0·56

–0·25

–0·36–0·43

–0·47–0·50 –0·52

–0·54

–0·51 –0·52 –0·53 –0·54 –0·55 –0·56

–0·58

At week 52, between treatment difference in least squares mean: –0·02 (95% CI –0·10 to 0·05); p=0·5465

21

31 3945 46

5156 57

61

19

29

4147 48

44

52 54 54

At week 52, OR 1·30 (95% CI 0·91 to 1·87); p=0·1498

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357 (84%) of 426 patients in the secukinumab group and 371 (87%) of 427 patients in the adalimumab group were previously exposed to methotrexate.

The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group has an ACR20 response at week 52 versus 62% in the adalimumab group (OR 1·30, 95% CI 0·98–1·72; p=0·0719; figure 2, table 2). Three patients in the secukinumab group and ten patients in adalimumab group with partial or all missing values of the ACR components at baseline or week 52 (not because of treatment or study discontinuation) had values imputed

using multiple imputation. In the prespecified sensiti-vity analysis using non-responder imputation, these 13 patients were imputed as non-responders and ACR20 response at week 52 was reported in 285 (67%) of 426 patients in the secukinumab group and 254 (59%) of 427 patients in the adalimumab group (OR 1·38, 95% CI 1·04–1·83; p=0·0239; table 2).

As the superiority of secukinumab versus adalimumab was not established for the primary endpoint, key secondary endpoints in the hierarchy were not formally tested for statistical significance. Therefore, we present unadjusted p values (without adjusting for multiplicity) and ORs with 95% CIs for key secondary endpoints (table 2; figure 3).

In prespecified exploratory analyses, a higher propor-tion of patients in the secukinumab group versus the adalimumab group achieved combined joint and skin response (simultaneous ACR50 and PASI 100 response), specific skin outcomes (PASI 75 response, PASI 100 response, absolute PASI score ≤3), low disease activity score (disease activity score based on 28 joint count C-reactive protein low disease activity, DAPSA-based low disease and remission, PASDAS-based low disease activity and remission, and Psoriatic Arthritis Response Criteria responses (table 2).

Overall, 211 (25%) of 853 patients had psoriasis with body surface area greater than 10% or PASI of at least 10. In this subset of patients, ACR20 and PASI 90 responses with secukinumab versus adalimumab were seen in 76% versus 68% of patients and 69% versus 42% of patients, respectively. The data for efficacy outcomes reported in this subset of patients were consistent with the overall study population (appendix p 22).

The safety profiles of secukinumab and adalimumab were consistent with previous reports.6,20 Over the entire treatment period, the mean exposure to secukinumab was 351·7 days (SD 77·9) and to adalimumab was 332·9 days (94·2). Treatment-emergent adverse events occurred in 330 (77%) of 426 patients in the secukinumab group and 338 (79%) of 427 patients in the adalimumab group (table 3).

Major adverse cardiovascular events were reported in two (<1%) patients in the secukinumab group (a male patient with a pre-existing medical history of diabetes, hypertension, and dyslipidaemia, and ongoing ischaemic heart disease with previous stent insertion had acute myocardial infarction and a male patient, a current smoker with a pre-existing medical history of hyper-tension, had a myocardial infarction). One patient in the adalimumab group had acute cardiac failure that required hospitalisation. Inflammatory bowel disease (IBD) was reported in two patients in the secukinumab group—one patient was diagnosed with both ulcerative colitis and Crohn’s disease and the other had ulcerative colitis. Both IBD cases were flares in patients with a pre-existing medical history of IBD. Two cases of malignancy were reported in the secukinumab group—one patient

Secukinumab 300 mg (n=426)

Adalimumab 40 mg (n=427)

Duration of exposure (days) 351·7 (77·9) 332·9 (94·2)

Number of patients with any adverse event 330 (77%) 338 (79%)

Number of patients with serious or other clinically significant events

Death* (n) 1 0

Non-fatal serious adverse events 32 (8%) 28 (7%)

Discontinued study treatment because of adverse event 17 (4%) 32 (7%)

Adverse events of special interest

Infections and infestations (system organ class) 237 (56%) 234 (55%)

Serious infections 7 (2%) 6 (1%)

Candida infections (high-level term) 16 (4%) 7 (2%)

Viral infectious disorders (high-level group term) 66 (15%) 65 (15%)

Injection-site reactions (high-level term) 17 (4%) 47 (11%)

Hypersensitivity (standardised MedDRA query; narrow) 39 (9%) 60 (14%)

Major adverse cardiac event (Novartis MedDRA query) 2 (<1%) 0

Inflammatory bowel disease (Novartis MedDRA query; narrow term)†

2 (<1%) 0

Crohn’s disease (preferred term) 1† (<1%) 0

Ulcerative colitis (preferred term) 2† (<1%) 0

Malignancies 2 (<1%) 3 (1%)

Most frequent treatment-emergent adverse events

Nasopharyngitis 81 (19%) 80 (19%)

Upper respiratory tract infection 41 (10%) 49 (11%)

Headache 35 (8%) 32 (7%)

Diarrhoea 31 (7%) 35 (8%)

Hypertension 27 (6%) 23 (5%)

Oropharyngeal pain 25 (6%) 15 (4%)

Psoriasis 24 (6%) 25 (6%)

Arthralgia 23 (5%) 29 (7%)

Psoriatic arthropathy 20 (5%) 26 (6%)

Back pain 14 (3%) 31 (7%)

Bronchitis 14 (3%) 23 (5%)

Rash 8 (2%) 21 (5%)

Injection site reactions 4 (1%) 28 (7%)

Data are mean (SD) or n (%), unless otherwise indicated. n is the number of patients with events. MedDRA=Medical Dictionary for Regulatory Activities. *A 53-year-old man entered the study without any reported medical history or active medical conditions. On study day 85, this patient had severe abdominal pain considered a serious adverse event, which led to discontinuation of secukinumab and the study (last dose study day 70; total of six 300 mg doses). The patient was subsequently diagnosed with colon cancer, and died on study day 146. This event was assessed as not related to study drug by the investigator. †One patient was diagnosed with both Crohn’s disease and ulcerative colitis.

Table 3: Safety summary at week 52 in safety set

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had colon cancer (day 85) and the other was diagnosed with plasma cell myeloma (day 201). Three cases of malignancy were reported in the adalim umab group, a synovial sarcoma (day 361), intraductal papillary carcinoma of the pancreas (day 85), and non-Hodgkin lymphoma (day 222). All cases of malignancy led to treatment discontinuation.

One death was reported in the secukinumab group. The patient had severe abdominal pain and discontinued the study on day 85 after receiving six doses of secukinumab. The patient died after study discontinuation on day 146 due to colon cancer assessed as not related to study drug by the investigator.

DiscussionWith increased availability of approved medicines that have distinct mechanisms of action, head-to-head trials can be useful to help guide clinical decision making in the management of psoriatic arthritis after csDMARD (including methotrexate) failure, intolerance, or contra-indication.3,21 To our knowledge, EXCEED is the first head-to-head, double-blind, randomised trial to compare secukinumab and adalimumab, and tested a musculo-skeletal primary endpoint of ACR20 response in psoriatic arthritis. This trial addresses an important gap in knowledge that informs the initiation of biological treatment in patients with psoriatic arthritis in the context of biological monotherapy. Pooled FUTURE 2–5 studies show that secukinumab 300 mg provides greater efficacy than does secukinumab 150 mg or placebo and long-term maintenance of response in biological-naive patients irrespective of concomitant methotrexate use; hence, we used secukinumab 300 mg in this study.22 The results of the pre-specified sensitivity analysis also showed higher ACR20 response rates at week 52 versus adalimumab.

Baseline demographics and disease characteristics were generally similar between the secukinumab group and adalimumab group; however, the proportion of female patients was higher in the secukinumab group than in the adalimumab group. Several reports have shown that female patients have lower treatment response rates in psoriatic arthritis than do male patients.23

It is becoming increasingly clear that different tissue compartments in psoriatic arthritis might not be driven by identical pathogenetic pathways. A cutaneous psoriasis study showed superiority of IL-17A inhibition with secukinumab compared with etanercept, a TNF inhibitor, in a head-to-head trial.9

A 2020 open-label, head-to-head study of the IL-17A inhibitor ixekizumab versus adalimumab reported that ixekizumab was superior in achievement of simultaneous improvement of joint and skin disease (combined ACR50 and PASI 100 response) in patients with psoriatic arthritis and inadequate response to csDMARDs.24 The current study has several important elements. It was fully blinded, minimising the potential bias and effect of knowledge of treatment allocation on reporting of outcomes. The study

included patients who more closely reflect patients with psoriatic arthritis who visit the rheumatology clinic, as the patients predominantly had articulatar symptoms. We investigated biological monotherapy, representing a common, clinically relevant scenario given either primary methotrexate intolerance or prevalence of metabolic syndrome and hepatosteatosis in psoriatic arthritis, both of which pose challenges for the use of methotrexate.13–15 Importantly, we evaluated musculoskeletal disease as the primary outcome, thereby removing the influence of cutaneous responses on interpretation of the results. Moreover, our primary outcome directly addresses a key research question in psoriatic arthritis management, namely whether IL-17A or TNF inhibition confer musculoskeletal advantage. However, we recognise that improvements in both musculoskeletal and skin manifestations are considered essential for optimising overall quality of life in psoriatic arthritis.25 Notably, secukinumab also showed a higher combined ACR50 and PASI 100 response, PASI 75 response, and PASI 100 responses compared with adalimumab in the current study. Overall, the data suggest that IL-17A inhibitors could offer a more robust proposition to manage the entirety of the clinical manifestations of patients with psoriatic arthritis.

EULAR recommends a treat-to-target approach for patients with psoriatic arthritis for achieving low disease activity or remission as an important goal of treatment, which has been shown to improve physician-reported and patient-reported outcomes in those with recent onset of psoriatic arthritis.26 The heterogeneous manifestations of psoriatic arthritis are captured in several composite definitions that encompass clin-ically important aspects, such as synovitis, psoriasis, enthesitis, pain, patient-assessed global disease activity, and physical function. One such composite definition, DAPSA, primarily focuses on peripheral arthritis, and does not include other psoriatic arthritis manifestations such as psoriasis, axial disease, nail disease, dactylitis, or enthesitis.27 Secukinumab showed numerically higher efficacy compared with adalimumab across musculoskeletal endpoints and composite indices including DAPSA low disease activity, PASDAS low disease activity, minimal disease activity, and Psoriatic Arthritis Response Criteria response. A higher propor-tion of patients treated with secukinumab versus adalimumab achieved the stringent outcome of DAPSA low disease activity and remission, suggesting that improvements with secukinumab were driven primarily by musculoskeletal outcomes.

There were fewer overall discontinuations with secukinumab compared with adalimumab during the study. Higher proportions of patients discontinued adalimumab because of loss of efficacy, adverse events, and acute injection site reactions. Injection site reactions (including injection site pain) were higher with citrate-free adalimumab formulation, as shown in previous

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studies in other indications.28 The rates of IBD and candidiasis reported in this study for secukinumab were consistent with previously reported data for IL-17A inhibitors.24,29 Overall, the safety profiles of both bDMARDs were consistent with those published in previous studies.6,20,29,30

Management of psoriatic arthritis in the clinical setting should be targeted at the disease domains (peripheral arthritis, axial disease, dactylitis, enthesitis, skin psoriasis, and nail psoriasis) that are active in, and important to, individual patients. Although there is evidence suggesting that IL-17A, IL-12/23p40, and IL-23p19 inhibitors have high efficacy in plaque psoriasis, the current study provides evidence for efficacy in musculoskeletal disease.

The monotherapy design of this study might limit the generalisation of its findings to the entire population, as concomitant methotrexate is widely used in psoriatic arthritis. Another limitation of this study is the lack of comparative data on inhibition of radiographic progres-sion. Given the different treatment discontinuation rates between secukinumab and adalimumab, the underlying assumption behind the mixed model repeated measures (ie, missing at random) warrants further investigation. The influence of sex on efficacy of treatment also needs further analysis.

In conclusion, secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than was adalimumab and provided numerically higher clinical responses across musculoskeletal endpoints, skin endpoints, and com-posite indices at week 52. The safety profiles of secukinumab and adalimumab were consistent with previous reports. This study presents a considerable volume of comparative efficacy and safety data on two biological agents with different mechanisms of action in the treatment of patients with psoriatic arthritis.ContributorsAll authors meet the International Committee of Medical Journal Editors criteria for authorship for this Article, take responsibility for the integrity of the work as a whole, were involved in drafting and critical review of the manuscript, and approved the final version for submission. All authors agree to be accountable for all aspects of the work and attest to the accuracy and integrity of the work. SM, LP, IBM, PJM, AK, CR, and PN designed and conceived the study. FB, PN, JGM, PG, TK, and ABG interpreted the data. PP and KD acquired and analysed the data. RM analysed the data.

Declaration of interestsIBM declares research grants, consultation fees, or speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB. FB declares research grants from Pfizer, Janssen, Chugai, Celgene, and Roche; consultation fees from Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, Merck Sharp & Dohme, Celgene, Roche, and Chugai; and investigator fees from Lilly. PJM reports grants or research support from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Galapagos, Genentech, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; consultancy for AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Galapagos, Celgene, Genentech, Gilead, Janssen, Lilly, Novartis, Pfizer, SUN Pharma, and UCB; and speakers bureau fees

from AbbVie, Amgen, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB. AK reports consultancy fees and grants or research support from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, and UCB. CR reports research grants from AbbVie, Amgen, and UCB and consultancy for AbbVie, Amgen, UCB, Novartis, Pfizer, Lilly, Janssen, and Bristol-Myers Squibb. PN reports research grants for clinical trials and honoraria for lectures and advice from Novartis, Abbvie, Roche, Pfizer, Bristol-Myers Squibb, Janssen, Celgene, UCB, Lilly, Merck Sharp & Dohme, Sanofi, and Gilead. JGM reports research grants, consultation fees, or speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, and Pfizer. PG reports research grants, consultation fees, or speaker honoraria from AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Lilly, Medac, Merck Sharp & Dohme, Nordic Pharma, Novartis, Pfizer, Sanofi, and UCB. TK reports research grants, consultation fees, or speaker honoraria from AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Novartis, Pfizer, BIOCAD, and UCB. ABG reports research grants from Janssen, Incyte, Novartis, XBiotech, UCB, and Boerhinger Ingelheim, and consulting fees from Janssen, Incyte, Novartis, XBiotech, UCB, Boerhinger Ingelheim, Celgene, Beiesdorf, Bristol-Myers Squibb, Abbvie, Lilly, SUN Pharma, and Avotres Therapeutics. RM, PP, SM, and LP are shareholders and employees of Novartis. KD is an employee of Novartis.

Data sharingThe datasets generated and analysed during the current study are not publicly available. Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved based on scientific merit. All data provided are anonymised to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. The data can be requested from the corresponding author of the manuscript. The protocol can be made available on request by contacting the corresponding author.

AcknowledgmentsWe thank the patients who participated in this study and the study investigators for their contributions. Suchita Dubey (Novartis) provided medical writing support and John Gallagher (Novartis) provided medical and editorial guidance. The study was funded by Novartis Pharma in accordance with Good Publication Practice guidelines. Patient consent was not required for the publication.

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27 Smolen JS, Schoels M, Aletaha D. Disease activity and response assessment in psoriatic arthritis using the disease activity index for psoriatic arthritis (DAPSA). A brief review. Clin Exp Rheumatol 2015; 33 (suppl 93): S48–50.

28 Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004; 50: 1400–11.

29 Deodhar A, Mease PJ, McInnes IB, et al. Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res Ther 2019; 21: 111

30 Mease P, van der Heijde D, Landewé R, et al. Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis 2018; 77: 890–97.

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

This online publication has been corrected. The corrected version first appeared at thelancet.com on May 28, 2020.

Supplement to: McInnes IB, Behrens F, Mease PJ, et al. Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trial. Lancet 2020; 395: 1496–505.

1

APPENDIX

Secukinumab versus Adalimumab Comparison for the Treatment of Active Psoriatic Arthritis (EXCEED): A

Randomised, Double-blind, Active-controlled Phase 3b Trial

Iain B McInnes1*, Frank Behrens2, Philip J Mease3, Arthur Kavanaugh4, Christopher Ritchlin5, Peter Nash6, Jordi

Gratacós Masmitja7, Philippe Goupille8, Tatiana Korotaeva9, Alice B Gottlieb10, Ruvie Martin11, Kevin Ding12,

Pascale Pellet13, Shephard Mpofu14, and Luminita Pricop15 on behalf of EXCEED Study

1University of Glasgow, Glasgow, United Kingdom 2Rheumatology University Hospital and Fraunhofer Institute for Molecular Biology and Applied Ecology IME,

Branch for Translational Medicine and Pharmacology TMP and Fraunhofer Cluster of Excellence for Immune-

Mediated Diseases CIMD, Goethe University, Frankfurt, Germany 3Swedish Medical Centre/Providence St. Joseph Health and University of Washington, Seattle, United States 4Rheumatology, Allergy, Immunology Division, University of California, San Diego, School of Medicine, La Jolla,

United States, La Jolla, United States 5Allergy/Immunology and Rheumatology Division, University of Rochester, Rochester, United States 6Department of Medicine, Griffith University, Brisbane, Australia 7Rheumatology Department, University Hospital Parc Taulí, Sabadell, UAB, Spain 8Department of Rheumatology and INSERM-CIC1415, University hospital of Tours, EA 7501 GICC, University of

Tours, Tours, France 9Research Institute of Rheumatology n.a. V.A. Nasonova, Moscow, Russia 10Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, United States 11Novartis Pharmaceuticals Corporation, East Hanover, United States 12Novartis Pharmaceuticals Corporation, East Hanover, United States 13Novartis Pharma AG, Basel, Switzerland

14Novartis Pharma AG, Basel, Switzerland 15Novartis Pharmaceuticals Corporation, East Hanover, United States

Corresponding author: Dr. (Prof.) Iain B McInnes

Director

Institute of Infection, Immunity and Inflammation

College of Medical, Veterinary and Life Sciences

University of Glasgow

Scotland, United Kingdom

Tel: + +44 141 330 8412

E-mail: Iain.McInnes@glasgow.ac.uk

2

1. List of Investigators

Investigator and

other important

participants

Position / Role Facility Name

Address

Country

Country No. of

Patients

Enrolled

Dr. Jane Zochling Principal

Investigator

Southern Clinical Research Pty Ltd

Hobart, TAS,

Australia, 7000

Australia 12

Dr. Peter Nash Principal

Investigator

Rheumatology Research Unit Sunshine

Coast

Maroochydore, QLD,

Australia, 4558

Australia 8

Dr. Paul Bird Principal

Investigator

Optimus Clinical Research

Kogarah, NSW,

Australia, 2217

Australia 3

Prof Andrew Ostor Principal

Investigator

Emeritus Research

Camberwell, VIC,

Australia, 3145

Australia 10

Assoc. Prof

Nikolay Georgiev

Nikolov

Principal

Investigator

UMHAT Dr George Stranski

Pleven,

Bulgaria, 5800

Bulgaria 5

Dr. Boycho

Oparanov

Principal

Investigator

Military Medical Academy Sofia

Sofia, Bulgaria,

Bulgaria, 1606

Bulgaria 4

Prof. Rumen

Stoilov

Principal

Investigator

UMHAT Sveti Ivan Rilski EAD

Sofia,

Bulgaria, 1612

Bulgaria 3

Dr. Ivan Goranov Principal

Investigator

MHAT Plovdiv AD

Plovdiv,

Bulgaria, 4002

Bulgaria 8

Prof. Anastas

Batalov

Principal

Investigator

UMHAT Kaspela

Plovdiv,

Bulgaria, 4002

Bulgaria 7

Prof. Rasho

Rashkov

Principal

Investigator

UMHAT Sveti Ivan Rilski EAD

Sofia,

Bulgaria, 1612

Bulgaria 1

Dr. Timothy

McCarthy

Principal

Investigator

Manitoba Clinic

Winnipeg, MB,

Canada, R3A 1M1

Canada 3

Dr Frederic Morin Principal

Investigator

Centre de Recherche Musculo-

Squelettique

Trois-Rivieres, QC,

Canada, G8Z 1Y2

Canada 8

Dr Milton Baker Principal

Investigator

PerCuro Clinical Research Ltd

Victoria, BC,

Canada, V8V 3M9

Canada 3

Dr. Eva

Dokoupilova

Principal

Investigator

Medical Plus s.r. o.

Uherske Hradiste,

Czech Republic, 686 01

Czech Republic 26

Dr. Dagmar

Galatikova

Principal

Investigator

Revmatologie Bruntal s.r. o.

Bruntal,

Czech Republic, 792 01

Czech Republic 11

Dr. Rudolf Horvath Principal

Investigator

FN Motol

Praha 5,

Czech Republic, 150 06

Czech Republic 15

3

MD Herman F

Mann

Principal

Investigator

Revmatologicky ustav

Praha 2,

Czech Republic, 128 50

Czech Republic 22

Dr Petr Vitek Principal

Investigator

PV MEDICAL s r o

Zlin,

Czech Republic, 760 01

Czech Republic 6

Dr. Lars Erik

Kristensen

Principal

Investigator

HS Frederiksberg Hospital, Parker

institute

Frederiksberg,

Denmark, DK-2000

Denmark 17

Dr. Triin Savi Principal

Investigator

East Tallinn Central Hospital

Magdalena Policlinic

Tallinn,

Estonia, 11312

Estonia 6

Dr. Mart Kull Principal

Investigator

Meditrials OU

Tartu,

Estonia, 50406

Estonia 11

Dr. Ene Ojassalu Principal

Investigator

North Estonia Medical Centre

Foundation

Tallinn,

Estonia, 13419

Estonia 11

Dr. Pentti Jarvinen Principal

Investigator

Kiljavan laaketutkimus

Hyvinkaa,

Finland, 05800

Finland 12

MD. Aulikki

Kononoff

Principal

Investigator

Pihlajalinna Ite Kuopio

Kuopio,

Finland, 70100

Finland 2

Pr Philippe

Goupille

Principal

Investigator

CHRU - Hospital Trousseau

Chambray les Tours,

France, 37170

France 4

Dr. Gregoire

Lambert De

Cursay

Principal

Investigator

Centre Hospitalier Dubois

Brive-la-Gaillarde,

France, 19100

France 1

Dr. Emmanuelle

Dernis

Principal

Investigator

Centre Hospitalier du Mans

Le Mans,

France, 72037

France 3

Dr. Slim Lassoued Principal

Investigator

Centre Hospitalier Jean Rougie

Cahors,

France, 46000

France 2

Dr. Elisabeth Solau

Gervais

Principal

Investigator

CHU Hospital Jean Bernard

Poitiers,

France, 86000

France 1

Dr Eric

Lespessailles

Principal

Investigator

CHR ORLEANS

Orleans,

France, 45067

France 2

Dr. Pascal Richette Principal

Investigator

Centre hospitalier Lariboisiere

Paris,

France, 75010

France 1

Prof. Dr. med.

Juergen Braun

Principal

Investigator

Rheumazentrum Ruhrgebiet St Josefs

Krankenhaus

Herne,

Germany, 44649

Germany 1

Dr. med. Jan

Brandt Juergens

Principal

Investigator

Rheumatologische Schwerpunktpraxis

Dr Jan Brandt-Juergens

Germany 10

4

Berlin,

Germany, 12161

Prof. Dr. med.

Gerd Ruediger

Burmester

Principal

Investigator

Universitaetsmedizin Charite

Berlin,

Germany, 10117

Germany 2

Dr. med. Georg P.

Dahmen

Principal

Investigator

Praxis fur Klinische Studien Dr. med.

Georg Dahmen

Hamburg,

Germany, 22415

Germany 9

Mr. Andrei

Khariouzov

Principal

Investigator

Klinische Forschung Berlin Mitte

GmbH

Berlin,

Germany, 10117

Germany 2

Prof. Dr. med.

Ruediger Moericke

Principal

Investigator

Institut fuer Praeventive Medizin &

Klinische Forschung GbR

Magdeburg,

Germany, 39110

Germany 3

Prof. Dr. med.

Gunther Neeck

Principal

Investigator

Rheumazentrum Bad Doberan

Bad Doberan,

Germany, 18209

Germany 3

Prof. Dr. med.

Denis Poddubnyy

Principal

Investigator

Universitaetsmedizin Charite, Campus

Mitte, Med. Klinik I

Berlin,

Germany, 12200

Germany 1

Dr. med. Florian

Schuch

Principal

Investigator

Rheumatologische Schwerpunktpraxis

Erlangen

Erlangen,

Germany, 91056

Germany 9

Ms. Charlotte von

Engelhardt

Principal

Investigator

Klinische Forschung Schwerin gGmbH

Schwerin,

Germany, 19055

Germany 6

Prof. Dr. med.

Thilo Gambichler

Principal

Investigator

St. Josef Hospital,Hauttumorzentrum,

Ruhr- Universität Bochum

Bochum,

Germany, 44791

Germany 7

Dr. med. Georg

Gauler

Principal

Investigator

Rheumapraxis an der Hase

Osnabruck,

Germany, 49074

Germany 1

Dr. med. Rieke

Alten

Principal

Investigator

Schlosspark Klinik, Innere Medizin II,

Rheumatologie

Berlin,

Germany, 14059

Germany 2

Prof. Dr. med. Ulf

Wagner

Principal

Investigator

Universitaetsklinikum Leipzig AoR,

Klinik für Gastroenterologie

Leipzig,

Germany, 04103

Germany 9

Prof. Dimitrios

Boumpas

Principal

Investigator

University General Hospital ATTIKON

Chaidari Athens, Greece,

Greece, 12462

Greece 9

Prof Dr Dimitrios

Vassilopoulos

Principal

Investigator

General Hospital of Athens Ippokrateio

Athens, Greece,

Greece, 11527

Greece 3

Prof. Petros

Sfikakis

Principal

Investigator

General Hospital of Athens Laiko

Athens, Greece,

Greece, 115 27

Greece 5

5

Prof. Athanasios G

Tzioufas

Principal

Investigator

General Hospital of Athens Laiko

Athens, Greece,

Greece, 115 27

Greece 2

Dr. Alexandros

Garyfallos

Principal

Investigator

General Hospital of Thessaloniki

IPPOKRATEIO

Thessaloniki, Greece,

Greece, 54642

Greece 5

Dr. Regina Cseuz Principal

Investigator

Revita Reumatologiai Rendelő

Budapest,

Hungary, 1027

Hungary 1

Dr. Edit Drescher Principal

Investigator

Vital Medical Center

Veszprem,

Hungary, 8200

Hungary 3

Dr. Marta Kiraly Principal

Investigator

Petz Aladár Megyei Oktató Kórház

Reumatológiai Osztály

Győr, Hungary,

Hungary, 9025

Hungary 3

Dr. Sandor Szanto Principal

Investigator

Debreceni Egyetem Klinikai Központ

Belgyógyászati Klinika, Re

Debrecen,

Hungary, 4032

Hungary 5

Dr Edit Toth Principal

Investigator

Pest Megyei Flór Ferenc Kórház,

Reumatológiai és Fizioterá

Kistarcsa,

Hungary, 2143

Hungary 4

Dr. Ilona Ujfalussy Principal

Investigator

Magyar Honvédség Egészségügyi

Központ, Reumatológiai Oszt

Budapest, -,

Hungary, 1062

Hungary 4

Dr. Peter Balint Principal

Investigator

Orszagos Reumatologiai es

Fizioterapias Intezet

Budapest,

Hungary, 1023

Hungary 2

Dr. Gerdur

Grondal

Principal

Investigator

Landspitali Haskolasjukrahus

Fossvogur

Reykjavik,

Iceland, 108

Iceland 5

Dr. Jyotsna Oak Principal

Investigator

Kokilaben Dhirubhai Ambani Hospital

nd Medical Research Inst

Mumbai, Maharashtra,

India, 400 053

India 5

Dr. Praveen Jadhav Principal

Investigator

Sujata Birla Hospital and Medical

Research Center

Nashik, Maharashtra,

India, 422 101

India 12

Dr. Sarath Chandra

Mouli Veeravali

Principal

Investigator

Krishna Institute of Medical Sciences

Ltd

Secunderabad, Telangana,

India, 500003

India 3

Prof Uma Kumar Principal

Investigator

All India Institute of Medical Science

New Delhi, New Delhi,

India, 110029

India 3

Prof. Merav Lidar Principal

Investigator

The Chaim Sheba Medical Center

Ramat Gan,

Israel, 5266202

Israel 4

6

Prof. Itzhak Rosner Principal

Investigator

Bnai Zion Medical Center

Haifa,

Israel, 3339419

Israel 1

Prof Yair Molad Principal

Investigator

Rabin Medical Center

Petach Tikva,

Israel, 49100

Israel 2

Prof. Ori Elkayam Principal

Investigator

Tel Aviv Sourasky Medical Center

Ichilov

Tel Aviv,

Israel, 64239

Israel 7

Prof Yair Levy Principal

Investigator

Meir Sapir Medical Center

Kfar Saba,

Israel, 4428164

Israel 6

Prof. Alexandra

Balbir Gurman

Principal

Investigator

Rambam Medical Center

Haifa,

Israel, 3525408

Israel 5

Dr Devy Zisman Principal

Investigator

Carmel Medical Center

Haifa,

Israel, 34362

Israel 6

Dr. Carlo Selmi Principal

Investigator

IRCCS Istituto Clinico Humanitas

ROZZANO, ITALY,

Italy

Italy 3

Dr. Luca Idolazzi Principal

Investigator

Ospedale Borgo Trento

Verona, VR,

Italy, 37126

Italy 8

Elisa Rossi Principal

Investigator

Azienda Osp.-Univ. Bologna -

Policlinico S.Orsola-Malpighi

Bologna, Italy,

Italy, 40138

Italy 9

Dr. Marta Mosca Principal

Investigator

Azienda Ospedaliero-Universitaria

Pisana "Santa Chiara"

Pisa,

Italy, 56126

Italy 3

Dr. Enrico Fusaro Principal

Investigator

AOU Citta della Salute e della Scienza

di Torino

Torino,

Italy, 10126

Italy 1

Dr. Gerolamo

Bianchi

Principal

Investigator

Stab Osp La Colletta Presidio Ospedal

Unico ASL 3 Genovese

Arenzano, GE,

Italy, 16011

Italy 1

Dr. Ju Ha Lee Principal

Investigator

Seoul St Marys Hospital

Seoul, Seocho gu,

Korea, Republic of, 06591

Korea, Republic

of

2

Dr. Sarmite

Saleniece

Principal

Investigator

Dr Saleniece private practice in

rheumatology

Valmiera,

Latvia, LV-4201

Latvia 2

Dr. Anna

Mihailova

Principal

Investigator

ORTO Clinic

Riga,

Latvia, LV-1005

Latvia 5

Dr Asta

Baranauskaite

Principal

Investigator

HoLUoHS Kaunas Clinics

Kaunas,

Lithuania, LT-50161

Lithuania 9

7

Ms Loreta

Bukauskiene

Principal

Investigator

Klaipeda University Hospital

Klaipeda, Lithuania,

Lithuania, LT-92288

Lithuania 13

Dr. Rasa Kausiene Principal

Investigator

Republican Siauliai Hospital

Siauliai,

Lithuania, LT-76231

Lithuania 12

Dr Harald E

Vonkeman

Principal

Investigator

Medische Spectrum Twente

Enschede,

Netherlands, 7512KZ

Netherlands 2

Dr. EN Griep Principal

Investigator

Antonius Ziekenhuis Sneek

Sneek,

Netherlands, 8601 ZK

Netherlands 6

Dr. Elzbieta Gigiel Principal

Investigator

NSZOZ Unica CR

Dopiewo,

Poland, 62 069

Poland 13

Dr Marzena

Olesinska

Principal

Investigator

Narodowy Instytut Geriatrii

Reumatologii i Rehabilitacji

Warszawa, Poland,

Poland, 02-637

Poland 6

Dr. Brygida

Kwiatkowska

Principal

Investigator

Narodowy Instytut Geriatrii

Reumatologii i Rehabilitacji

Warszawa, Poland,

Poland, 02-637

Poland 8

Prof Dr Marek

Brzosko

Principal

Investigator

SP Szpital Kliniczny nr 1 im, prof

Tadeusza Soko¿owskiego PU

Szczecin,

Poland, 71-252

Poland 3

Prof. Witold

Owczarek

Principal

Investigator

Wojskowy Instutyt Medyczny CSK

MON

Warszawa,

Poland, 04 141

Poland 5

Dra. Helena Santos Principal

Investigator

Instituto Portugues de Reumatologia

Lisboa,

Portugal, 1050-034

Portugal 3

Dra. Elsa Sousa Principal

Investigator

Centro Hospitalar Lisboa Norte

Lisboa,

Portugal, 1649-035

Portugal 3

Dra. Alexandra

Bernardo

Principal

Investigator

Centro Hospitalar de Sao Joao

Porto, Portugal,

Portugal, 4200 319

Portugal 1

Dr. Antonio

Marinho

Principal

Investigator

CHP Hospital Geral de Santo Antonio

Porto,

Portugal, 4099 001

Portugal 2

Dr Jose Costa Principal

Investigator

Unidade Local de Saude do Alto Douro

e Minho ULSAM

Ponte de Lima,

Portugal, 4990 041

Portugal 4

Prof. Natalia

Nikolaevna

Vezikova

Principal

Investigator

Baranovs Republican Hospital

Petrozavodsk,

Russia, 185019

Russia 7

Dr. Irina Andreeva Principal

Investigator

Smolensk State Medical Academy of

Roszdrav

Smolensk,

Russia, 214019

Russia 12

8

Dr. Galina

Vasilievna

Shestakova

Principal

Investigator

Nizhny Novgorod City hospital no 13

of Avtozavodsky region

Nizhny Novgorod,

Russia, 603018

Russia 15

Prof. Tatiana

Alekseevna

Raskina

Principal

Investigator

Kemerovo State Medical Academy

Kemerovo,

Russia, 650000

Russia 12

Prof. Nadezda

Vladimirovna

Izmozherova

Principal

Investigator

Ural State Medical University

Ekaterinburg,

Russia, 620149

Russia 10

Dr. Svetlana

Polyakova

Principal

Investigator

Medical Center Maximum zdorovia

Kemerovo,

Russia, 650066

Russia 6

Dr. Olga Borisovna

Ershova

Principal

Investigator

Clinical Hospital for Emergency

Medical Care na N V Solovy

Yaroslavl,

Russia, 150003

Russia 9

Dr. Evgenia

Isaakovna Shmidt

Principal

Investigator

City clinical hospital 1 n a N I Pirogov

Moscow,

Russia, 119049

Russia 5

Dr Tatiana

Korotaeva

Principal

Investigator

Institute of Rheumatology of Russian

Academy

Moscow,

Russia, 115522

Russia 11

Prof. Alexander

Alexianosovich

Kastanayan

Principal

Investigator

Rostov on Don State Med University

Rostov on Don,

Russia, 344022

Russia 12

Dr. Maria

Oetterova

Principal

Investigator

ARTROMAC no

Kosice, Slovakia,

Slovakia (Slovak Republic), 04011

Slovakia (Slovak

Republic)

5

Dr. Livia Bruskova Principal

Investigator

Reumacentrum s r o

Partizanske, Slovakia,

Slovakia (Slovak Republic), 95801

Slovakia (Slovak

Republic)

6

Dr. Eva Ladicka Principal

Investigator

LERAM s.r.o., Reumatologicka

ambulancia

Topolcany, Slovakia,

Slovakia (Slovak Republic), 95501

Slovakia (Slovak

Republic)

6

Dr. Emoke Stenova Principal

Investigator

I.interná klinika

Bratislava, Slovakia,

Slovakia (Slovak Republic), 81369

Slovakia (Slovak

Republic)

4

Dr. Alberto Alonso Principal

Investigator

Hospital de Cruces

Baracaldo, Bizkaia,

Spain, 48903

Spain 7

Dr. Jordi Gratacos Principal

Investigator

Corporacio Sanitaria Parc Tauli

Sabadell

Sabadell, Barcelona,

Spain, 08208

Spain 10

Dr. Juan de Dios

Canete Crespillo

Principal

Investigator

Hospital Clinic l Provincial De

Barcelona

Barcelona, Cataluna,

Spain, 08036

Spain 1

Dr. Lourdes Mateo

Soria

Principal

Investigator

Hospital Germans Trias i Pujol

Badalona, Barcelona,

Spain, 08916

Spain 4

9

Dr. Jesus

Rodriguez Moreno

Principal

Investigator

Hospital De Bellvitge

L Hospitalet de Llobregat, Barcelona,

Spain, 08907

Spain 2

Dra. Sagrario

Bustabad

Principal

Investigator

Hospital Universitario General de

Canarias

La Laguna, Santa Cruz de Tenerife,

Spain, 38320

Spain 4

Dr. Eugenio

Chamizo Carmona

Principal

Investigator

Hospital de Merida

Merida, Badajoz,

Spain, 06800

Spain 3

Dr. Jose Luis

Pablos

Principal

Investigator

Hospital 12 de Octubre

Madrid,

Spain, 28041

Spain 3

Dr. Francisco

Javier Blanco

Principal

Investigator

Hospital Universitario A Coruna

La Coruna, Galicia,

Spain, 15006

Spain 4

Dr. Ricardo Blanco Principal

Investigator

Hospital Universitario Marques de

Valdecilla e IDIVAL

Santander, Cantabria,

Spain, 39008

Spain 6

Dr. Mari Luz

Garcia Vivar

Principal

Investigator

Hospital Universitario de Basurto

Bilbao Bizkaia, Pais Vasco,

Spain, 48013

Spain 9

Dr. Antonio Mera Principal

Investigator

Hospital Clinico Universitario de

Santiago

Santiago de Compostela, Galicia,

Spain, 15706

Spain 7

Dra Maria Dolores

Lopez Montilla

Principal

Investigator

Hospital Reina Sofia

Cordoba, Andalucia,

Spain, 14004

Spain 10

Dr. Jose Andres

Roman

Principal

Investigator

Hospital Universitario i Politecnico La

Fe

Valencia, Comunidad Valenciana,

Spain, 46026

Spain 5

Dr. Ana Laiz

Alonso

Principal

Investigator

Hospital de la Santa Creu i Sant Pau

Barcelona, Espana,

Spain, 08026

Spain 4

Dr. Jose Luis

Marenco

Principal

Investigator

Hospital Univ Nuestra Sra de Valme

Sevilla,

Spain, 41014

Spain 4

Dr. Juan Povedano Principal

Investigator

Hospital Universitario Virgen del

Rocio

Sevilla,

Spain, 41013

Spain 1

Dr. Juan Jose

Alegre Sancho

Principal

Investigator

Hospital Doctor Peset

Valencia, Comunidad Valenciana,

Spain, 46017

Spain 3

Dr. Antonio

Fernandez Nebro

Principal

Investigator

Hospital Civil de Malaga Carlos Haya

Malaga, Andalucia,

Spain, 29009

Spain 3

Dr. Raul Veiga

Cabello

Principal

Investigator

Hospital Universitario de Fuenlabrada

Madrid,

Spain, 28942

Spain 4

10

Dr. Hector Chinoy Principal

Investigator

Salford Royal NHS Foundation Trust

Salford, Manchester,

United Kingdom, M6 8HD

United Kingdom 4

Dr. Sophia Khan Principal

Investigator

Solihull Hospital

Solihull,

United Kingdom, B91 2JL

United Kingdom 2

Dr. Hasan Inmam

Sayed Tahir

Principal

Investigator

Whipps Cross Hospital

Leytonstone, London,

United Kingdom, E11 1NR

United Kingdom 9

Dr Ben Thompson Principal

Investigator

Freeman Hospital

Newcastle Upon Tyne,

United Kingdom, NE7 7DN

United Kingdom 2

Dr. Bruce Kirkham Principal

Investigator

Guys Hospital and St Thomas NHS

Trust

London,

United Kingdom, SE1 9RT

United Kingdom 4

Dr Nick Viner Principal

Investigator

Derriford Hospital

Plymouth,

United Kingdom, PL6 8DH

United Kingdom 3

Dr. Kirsten

Mackay

Principal

Investigator

Torbay and South Devon NHS

Foundation Trust

Torquay, Devon,

United Kingdom, TQ2 7AA

United Kingdom 2

Dr. Nick Barkham Principal

Investigator

New Cross Hospital

Wolverhampton,

United Kingdom, WV10 0QP

United Kingdom 3

Dr. Jonathan

Packham

Principal

Investigator

Haywood Hospital

Stoke on Trent, Staffordshire,

United Kingdom, ST6 7AG

United Kingdom 5

Dr Thomas P G

Sheeran

Principal

Investigator

Cannock Chase Hospital

Cannock, Staffordshire,

United Kingdom, WS11 5XY

United Kingdom 17

Dr. Neil McKay Principal

Investigator

Western General Hospital PPDS

Edinburgh,

United Kingdom, EH4 2XU

United Kingdom 8

Dr. Yusuf Patel Principal

Investigator

Hull Royal Infirmary

Hull,

United Kingdom, HU3 2JZ

United Kingdom 3

Dr. Easwaradhas

Gladston Chelliah

Principal

Investigator

Wigan and Leigh NHS Foundation

Trust

Wigan,

United Kingdom, WN6 9EP

United Kingdom 2

Dr. Animesh Singh Principal

Investigator

Royal Free Hospital

London,

United Kingdom, NW3 3QG

United Kingdom 7

Dr. Stefan Siebert Principal

Investigator

Glasgow Clinical Research Facility

Glasgow,

United Kingdom, G31 2ER

United Kingdom 3

Dr Alan J Kivitz Principal

Investigator

Altoona Center for Clinical Research

Duncansville, PA,

United States, 16635

United States 3

Dr. Tina Bunch Principal

Investigator

Austin Regional Clinic Rheumatology

Austin, TX,

United States, 78731

United States 4

11

Dr. Bonita Libman Principal

Investigator

The University of Vermont Medical

Center

Burlington, VT,

United States, 05401

United States 1

Dr. Angela Moore Principal

Investigator

Arlington Research Center Inc

Arlington, TX,

United States, 76011

United States 4

Dr. Atul K K.

Singhal

Principal

Investigator

Southwest Rheumatology Research

LLC

Mesquite, TX,

United States, 75150

United States 2

Dr. Shirley Pang Principal

Investigator

St Joseph Heritage Healthcare

Fullerton, CA,

United States, 92835

United States 1

Dr. Kathryn Dao Principal

Investigator

Arthritis Care & Research Center

Dallas, TX,

United States, 75231

United States 2

Dr. John H Tu Principal

Investigator

Skinsearch of Rochester Inc

Rochester, NY,

United States, 14623

United States 1

Dr. Jeffrey B

Butler

Principal

Investigator

Arthritis Northwest PLLC

Spokane, WA,

United States, 99204

United States 2

Dr. Charles

Ludivico

Principal

Investigator

East Penn Rheumatology Associates

Bethlehem, PA,

United States, 18015

United States 1

Dr. Asad Fraser Principal

Investigator

Graves Gilbert Clinic

Bowling Green, KY,

United States, 42101

United States 1

Dr. Philip J Mease Principal

Investigator

Seattle Rheumatology Associates

Seattle, WA,

United States, 98122

United States 2

Dr. Melvin

Churchill

Principal

Investigator

Physician Research Collaboration

Lincoln, NE,

United States, 68516

United States 4

Dr. Kurt Oelke Principal

Investigator

Rheumatic Disease Center

Glendale, WI,

United States, 53217

United States 4

Dr. William R.

Palmer

Principal

Investigator

Westroads Clinical Research, Inc

Omaha, NE,

United States, 68114

United States 1

Dr. Vivian Laquer Principal

Investigator

Tien Q Nguyen MD Inc

Fountain Valley, CA,

United States, 92708

United States 4

Dr. Roshan Kotha Principal

Investigator

Purushotham Akther and Roshan Kotha

MD Inc

La Mesa, CA,

United States, 91942

United States 2

Dr. Chad Ronholm Principal

Investigator

Clayton Medical Associates

St. Louis, MO,

United States, 63117

United States 2

Dr. Eric Lee Principal

Investigator

Inland Rheumatology Clinical Trials

Inc

Upland, CA,

United States, 91786

United States 2

12

2. Changes to the Study Protocol

Important changes to the study protocol after commencement of the trial (no patients were randomised at this stage)

included: inclusion of additional follow-up visit, update in wording of exclusion criteria per guidelines for

contraception use after the last dose of study treatment for women of childbearing potential, extension of the

interruption requirement if the patient received a live vaccine underwent an update (to extend the recommended time

before starting a new biologic as elimination of adalimumab may take up to 4 months).

Amendment 2 happened to clarify the estimand to align with the study objectives, which were comparing efficacy of

secukinumab monotherapy with adalimumab monotherapy. Non-parametric regression1 model was not essential to

the final analysis but could be performed and sensitivity analyses was to be conducted to examine the effect of taking

concomitant treatment of methotrexate (MTX) and/or other conventional synthetic disease modifying antirheumatic

drugs (csDMARDs) along with study drug.

None of the changes were made due to safety concerns, had an impact on the conduct of the trial, or altered the

treatment of study patients. The changes occurred while the sponsor remained blinded to study data.

3. Patient Inclusion Exclusion Criteria

Inclusion criteria

Patients eligible for inclusion in this study had to fulfill all of the following criteria:

• Male or non-pregnant, non-lactating female patients at least 18 years of age.

• Diagnosis of psoriatic arthritis (PsA) as classified by ClASsification of Psoriatic ARthritis (CASPAR)

criteria2 and with symptoms for at least 6 months and with active PsA at baseline defined as ≥3 tender joints

out of 78 and ≥3 swollen joints out of 76 (dactylitis of a digit, counts as one joint each).

• Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies negative at screening.

• Diagnosis of active plaque psoriasis, with at least one psoriatic plaque of ≥2 cm diameter or nail changes

consistent with psoriasis or documented history of plaque psoriasis.

• Patients with PsA who took non-steroidal anti-inflammatory drugs (NSAIDs) for at least 4 weeks prior to

randomization with inadequate control of symptoms or at least one dose if stopped due to intolerance to

NSAIDs.

• Patients who regularly received NSAIDs as part of their PsA therapy were required to be on a stable dose for

at least 2 weeks before study randomization and remained on a stable dose up to Week 52.

• Patients who received corticosteroids were required to be on a stable dose of ≤10 mg/day prednisone or

equivalent for at least 2 weeks before randomization and remained on a stable dose up to Week 52.

• Patients who were previously treated with a csDMARD, including but not limited to MTX, with an

inadequate response to therapy, or had stopped treatment due to safety/tolerability problems after at least one

administration of the csDMARD.

13

• Patients who received a csDMARD were allowed to enter the study only after csDMARD discontinuation

and appropriate wash-out e.g. 4 weeks prior to randomization visit except for leflunomide, which had to be

discontinued for 8 weeks prior to randomization unless a cholestyramine wash-out was performed.

Exclusion criteria

Patients fulfilling any of the following criteria were not eligible for inclusion in this study.

• Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception

and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG)

laboratory test.

• Women of childbearing potential, defined as all women physiologically capable of becoming pregnant,

unless they were using effective methods of contraception during dosing of study treatment and minimum 16

weeks or longer if local label required it after the last dose (e.g. 20 weeks for secukinumab, 5 months for

adalimumab in Europe). Effective contraception methods included:

o Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic

abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were

not acceptable methods of contraception.

o Female sterilization (had surgical bilateral oophorectomy with or without hysterectomy), total

hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of

oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow

up hormone level assessment.

o Male sterilization (at least 6 months prior to screening); for female patients on the study, the

vasectomized male partner should be the sole partner for that subject.

o Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).

o Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception

or other forms of hormonal contraception that had comparable efficacy (failure rate <1%), for

example hormone vaginal ring or transdermal hormone contraception or placement of an

intrauterine device (IUD) or intrauterine system (IUS). In case of use of oral contraception, women

who had been stable on the same pill for a minimum of 3 months before taking investigational drug.

Women were considered post-menopausal and not of child bearing potential if they had at least 12 months of natural

(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms)

or had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six

weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman had been confirmed

by follow up hormone level assessment was she considered not of childbearing potential.

• Chest X-ray or chest magnetic resonance imaging (MRI) with evidence of ongoing infectious or malignant

process obtained within 3 months prior to screening and evaluated by a qualified physician.

• Previous exposure to any biologic drugs for PsA and PSO, including but not limited to TNFα inhibitors,

secukinumab or other biologic drugs targeting IL-17 or IL-17 receptor.

14

• Patients who received high-potency opioid analgesics, including but not limited to, methadone,

hydromorphone, and morphine.

• Ongoing use of prohibited psoriasis treatments/medications (e.g., topical corticosteroids or ultraviolet (UV)

therapy at randomisation). The following wash out periods need to be observed:

o Oral or topical retinoids: 4 weeks.

o Photochemotherapy (e.g., PUVA): 4 weeks.

o Phototherapy (UVA or UVB): 2 weeks.

o Topical skin treatments (except in face, eyes, scalp and genital area during screening; only

corticosteroids with mild to moderate potency): 2 weeks.

• Previous treatment with any cell-depleting therapies, including but not limited to anti-CD20 or investigational

agents (e.g., alemtuzumab (Campath®), anti-CD4, anti-CD5, anti-CD3, and anti-CD19).

• Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days until the expected

pharmacodynamic effect had returned to baseline, whichever is longer.

• History of hypersensitivity to any of the study drugs or excipients or to drugs of similar chemical classes.

• Any intramuscular or intravenous corticosteroid treatment within 4 weeks before randomization.

• Any therapy by intra-articular injections (e.g., corticosteroid) within 4 weeks before randomization.

• Active ongoing inflammatory diseases other than PsA that had confound the evaluation of the benefit of

secukinumab therapy.

• Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or

gastrointestinal conditions which in the opinion of the investigator immunocompromised the patient and/or

placed the patient at unacceptable risk for participation in an immunomodulatory therapy.

• Significant medical problems or diseases, including but not limited to the following: uncontrolled

hypertension (≥160/95 mmHg), congestive heart failure (New York Heart Association status of class III or

IV) and uncontrolled diabetes.

• History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests

(LFTs) such as aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine

aminotransferase/ serum glutamic pyruvictransaminase (ALT/SGPT), alkaline phosphatase or serum

bilirubin. The investigator was guided by the following criteria:

o Any single parameter not exceeding 2 x upper limit of normal (ULN). A single parameter elevated

up to and including 2 x ULN was re-checked once more as soon as possible and in all cases, at least

prior to enrollment/randomization, to rule out any possible lab error.

o If the total bilirubin concentration was increased above 2 x ULN, total bilirubin was differentiated

into the direct and indirect reacting bilirubin.

• History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum creatinine level

exceeding 1.5 mg/dL (132.6 μmol/L).

• Screening total white blood cell (WBC) count <3,000/μL, or platelets <100,000/μL or neutrophils <1,500/μL

or hemoglobin <8.5 g/dL (85 g/L).

15

• Active systemic infections during the last two weeks (exception: common cold) prior to randomization.

• History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined

by either a positive purified protein derivative (PPD) skin test (the size of induration was measured after 48-

72 hours, and a positive result was defined as an induration of ≥ 5mm or according to local

practice/guidelines), or a positive QuantiFERON TB-Gold test. Patients with a positive test were to

participate in the study if further work up (according to local practice/guidelines) established conclusively

that the patient has no evidence of active tuberculosis. If presence of latent tuberculosis was established then

treatment according to local country guidelines were initiated prior to enrollment.

• Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at screening or

randomization.

• History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ

system within the past 5 years (except for basal cell carcinoma or actinic keratoses that had been treated with

no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix or non-invasive malignant

colon polyps that had been removed).

• Current severe progressive or uncontrolled disease, which in the judgment of the clinical investigator

rendered the patient unsuitable for the trial.

• Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor tolerability or lack of

access to veins).

• Any medical or psychiatric condition, which in the investigator’s opinion precluded the patient from adhering

to the protocol or completing the study per protocol.

• Donation or loss of 400 mL or more of blood within 8 weeks before randomisation.

• History or evidence of ongoing alcohol or drug abuse, within the last six months before randomisation.

• Plans for administration of live vaccines during the study period or within 6 weeks preceding randomisation.

4. Randomisation and blinding

At baseline, all eligible patients were randomised via interactive response technology (IRT) to one of the two treatment

groups: (secukinumab 300 mg s.c. or adalimumab 40 mg s.c.). A designated Site-staff member other than the

investigator or study staff involved in safety and efficacy assessments or eCRF completion contacted IRT after

confirming that the patient fulfilled all the inclusion/exclusion criteria. The IRT assigned a randomisation number to

the patient, which was used to link the patient to a treatment arm and specified a unique medication number for the

first package of investigational treatment to be dispensed to the patient. The randomisation number was not to be

communicated to the investigator or study site staff involved in the conduct of efficacy assessments.

This was a double-blind randomised treatment trial. Patients, investigators, site personnel, and persons performing the

assessments (except for those described below) remained blinded to treatment assignment from the time of

randomisation until the database lock and analyses were completed, using the following methods: Randomisation data

are kept strictly confidential until the time of unblinding and were not be accessible by anyone else involved in the

study with the exception of the bioanalyst. Investigational treatment was to be dispensed by an unblinded pharmacist

(or other unblinded qualified site personnel) who was independent of those involved in the assessment of study

16

patients. In addition, the unblinded pharmacist (or other unblinded qualified site personnel) stored study medication

and kept medication records containing unblinded information in a separate area to which blinded staff did not have

access.

Study treatment was administered by “independent study drug administrator”- an unblinded suitably qualified

individual (nurse, physician, or other unblinded qualified site personnel) who was not responsible for any aspect of

patient assessment or follow-up. “Independent study drug administrator” could be the same person dispensing the

drug if suitably qualified to perform both activities. Prior to the administration, the unblinded site personnel put in

place suitable methods, e.g physical barriers such as curtains, blindfolds, or similar as agreed with the patient and

available to prevent patient seeing the appearance of their study treatment. The individual administering study

treatment and all study patients were advised to refrain from making any comments to study staff or to other patients

regarding the appearance of study treatments.

5. Outcomes

The efficacy outcome measures used in this study are standard measures used across all PsA trials:

• American College of Rheumatology (ACR) 20, 50 and 70 responses

• Swollen Joint Count (SJC)/Tender Joint Count (TJC)

• Patient’s global assessment of disease activity (VAS)

• Physician’s global assessment of disease activity (VAS)

• Patient’s assessment of PsA pain intensity (VAS)

• Health Assessment Questionnaire – Disability Index (HAQ-DI©)

• high sensitivity C-Reactive Protein (hsCRP) and Erythrocyte Sedimentation Rate (ESR)

• Psoriatic arthritis response criteria (PsARC) response

• Disease Activity Score (DAS28) and EULAR response criteria

• Psoriatic Arthritis Disease Activity Score (PASDAS)

• Patient’s global assessment of psoriasis and arthritis disease activity (VAS)

• Leeds Dactylitis Index (LDI)

• Leeds Enthesitis Index (LEI)

• Spondyloarthritis Research Consortium of Canada (SPARCC) index

• Psoriasis Area and Severity Index (PASI)

• Modified Composite Psoriatic Disease Activity Index (mCPDAI)

Safety Outcomes

Evaluation of adverse events/serious adverse events

• Physical examination

• Vital signs

• Height and weight

• QuantiFERON TB-Gold test or PPD skin test

17

• Electrocardiogram

• Local tolerability (injection site reactions)

• Laboratory evaluations (hematology, clinical chemistry, lipids)

• Pregnancy and assessment of fertility

• Tolerability of study treatment

• Immunogenicity

References.

1. Koch GG, Tangen CM, Jung JW, et al. Issues for covariance analysis of dichotomous and ordered categorical

data from randomized clinical trials and non-parametric strategies for addressing them. Stat Med 1998; 17:

1863-92.

2. Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new

criteria from a large international study. Arthritis Rheum 2006; 54(8): 2665-73.

18

SUPPLEMENTARY FIGURES AND TABLES

Figure S1. Study Design and Hierarchical Testing

n, number of patients

ACR, American college of rheumatology; BL, baseline; DMARD-IR, disease modifying anti-rheumatic drugs-inadequate responders; HAQ-DI, health

assessment quality-disability index; PASI, psoriasis activity severity index; s.c., subcutaneous; PsA, psoriatic arthritis

19

Figure S2. Patient Study Treatment Disposition up to Week 50

Wk, week

N, number of randomised patients; n, number of available patients

20

Figure S3. Kaplan Meier Time to Study Treatment Discontinuation Curve

p value versus adalimumab

21

Table S1. Efficacy in Patients with Psoriasis (BSA>10% or PASI ≥10)

Endpoints, data is presented as % response SEC 300 mg

(N = 110)

ADA 40 mg

(N = 101)

Odds Ratio 95% CI p-value*

ACR20 76 68 1·53 0·83, 2·83 0·1752

PASI 90 69 42 3·21 1·80, 5·71 <0·0001

ACR50 55 49 1·28 0·73, 2·22 0·3866

HAQ-DI (>=0.35) 57 55 1·2 0·67, 2·14 0·5321

Resolution of enthesitis (based on LEI) 75 66 1·54 0·85, 2·82 0·1571

ACR50 + PASI 100 28 18 1·92 0·97, 3·79 0·0604

DAS-28 CRP low disease activity 82 64 2·58 1·34, 4·97 0·0046

DAS28-CRP based remission 58 51 1·34 0·76, 2·38 0·3095

ACR70 31 29 1·14 0·62, 2·08 0·6734

Resolution of dactylitis 91 81 2·39 1·05, 5·45 0·0379

PASI 75 87 60 5·02 2·48, 10·19 <0·0001

PASI 100 39 24 2·15 1·17, 3·96 0·0136

*Unadjusted p values versus adalimumab

N, number of patients in with psoriasis with BSA>10% or PASI ≥10

ACR, American college of rheumatology; ADA, adalimumab; BSA, body surface area; CI, confidence interval; CRP, C-reactive protein; DAS28, disease activity

score based on 28 joint count; DAPSA, disease activity in psoriatic arthritis; HAQ-DI, health assessment questionnaire-disability index; LEI, Leeds enthesitis

index; MI, multiple imputation; PASI, psoriasis area severity index; SEC, secukinumab

22

Table S2. Details of Serious Infections

Secukinumab 300 mg (N = 426) Adalimumab (N = 427)

Infections and infestations, n 7 6

Appendicitis 1 0

Chronic sinusitis 1 0

Gastroenteritis salmonella 1 0

Influenza 1 0

Lower respiratory tract infection fungal 1 0

Pilonidal cyst 1 0

Tonsillitis 1 0

Bursitis infective 0 1

Diverticulitis 0 1

Labyrinthitis 0 1

Measles 0 1

Mycobacterial infection 0 1

Pneumonia 0 1

Preferred terms were sorted within primary system organ class in descending order of frequency in the Secukinumab 300 mg column

A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment

A patient with multiple adverse events within a primary system organ class is counted only once in the total row

MedDRA version 22.0 was used for reporting

23

Table S3 Details on Protocol Deviation

Secukinumab (N = 426) Adalimumab (N = 427)

Patients with at least one protocol deviation, n (%) 172 (40) 165 (39)

Protocol deviations, n (%)

Selection criteria not met 37 (9) 37 (9)

Patient not withdrawn as per protocol 0 0

Key procedures not performed as per protocol 0 0

Treatment deviation 3 (1) 4 (1) *Prohibited concomitant medication 84 (20) 95 (22)

Other GCP deviation 92 (22) 79 (19) *Not related to csDMARD use except 3 patients who took csDMARDs before Week 36 whilst on study treatment

24

Table S4 Absolute and relative frequencies for treatment emergent serious adverse events by primary system organ class and preferred term up to

Week 52

Secukinumab 300 mg

N=426

Adalimumab 40 mg

N=427

Primary system organ class

Preferred term n n

Any primary system organ class

-Total 32 28

Blood and lymphatic system disorders

-Total 2 0

Anaemia 1 0

Lymphadenopathy 1 0

Cardiac disorders

-Total 3 2

Acute myocardial infarction 1 0

Myocardial infarction 1 0

Pericarditis 1 0

Angina pectoris 0 1

Cardiac failure acute 0 1

Gastrointestinal disorders

-Total 4 3

Abdominal pain 1 0

Abdominal pain upper 1 0

Colitis ulcerative 1 0

Diarrhoea 1 0

Abdominal wall haematoma 0 1

Splenic artery aneurysm 0 1

Umbilical hernia 0 1

General disorders and administration site conditions

-Total 1 0

Chest pain 1 0

Hepatobiliary disorders

-Total 1 0

Cholecystitis 1 0

Infections and infestations

-Total 7 6

Appendicitis 1 0

25

Secukinumab 300 mg

N=426

Adalimumab 40 mg

N=427

Primary system organ class

Preferred term n n

Chronic sinusitis 1 0

Gastroenteritis salmonella 1 0

Influenza 1 0

Lower respiratory tract infection fungal 1 0

Pilonidal cyst 1 0

Tonsillitis 1 0

Bursitis infective 0 1

Diverticulitis 0 1

Labyrinthitis 0 1

Measles 0 1

Mycobacterial infection 0 1

Pneumonia 0 1

Injury, poisoning and procedural complications

-Total 6 4

Burns second degree 1 0

Concussion 1 0

Foot fracture 1 0

Joint dislocation 1 0

Post procedural haematoma 1 0

Post-traumatic neck syndrome 1 0

Skin laceration 1 0

Wound 1 0

Epicondylitis 0 1

Hand fracture 0 1

Tibia fracture 0 1

VIIIth nerve injury 0 1

Musculoskeletal and connective tissue disorders

-Total 4 3

Osteoarthritis 1 1

Cervical spinal stenosis 1 0

Intervertebral disc protrusion 1 0

Synovitis 1 0

Foot deformity 0 1

26

Secukinumab 300 mg

N=426

Adalimumab 40 mg

N=427

Primary system organ class

Preferred term n n

Psoriatic arthropathy 0 1

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

-Total 3 3

Colon cancer 1 0

Plasma cell myeloma 1 0

Uterine leiomyoma 1 0

Leiomyoma 0 1

Non-Hodgkin's lymphoma 0 1

Synovial sarcoma 0 1

Nervous system disorders

-Total 1 3

Syncope 1 0

Paraesthesia 0 1

Radiculopathy 0 1

Transient ischaemic attack 0 1

Psychiatric disorders

-Total 0 1

Alcohol abuse 0 1

Depression 0 1

Reproductive system and breast disorders

-Total 2 3

Endometrial hypertrophy 1 0

Ovarian cyst 1 0

Prostatitis 0 2

Uterine polyp 0 1

Respiratory, thoracic and mediastinal disorders

-Total 3 2

Pulmonary embolism 1 1

Dyspnoea 1 0

Epistaxis 1 0

Sleep apnoea syndrome 1 0

Alveolitis 0 1

27

Secukinumab 300 mg

N=426

Adalimumab 40 mg

N=427

Primary system organ class

Preferred term n n

Haemoptysis 0 1

Skin and subcutaneous tissue disorders

-Total 2 1

Drug reaction with eosinophilia and systemic symptoms 1 0

Skin ulcer 1 0

Perioral dermatitis 0 1

Vascular disorders

-Total 1 1

Peripheral arterial occlusive disease 1 0

Aortic aneurysm 0 1

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