Efficacy of Secukinumab and Adalimumab in Patients With Psoriatic Arthritis and Concomitant Moderate-to-severe Plaque Psoriasis

Results From EXCEED, a Randomized, Double-blind Head-to-head Monotherapy Study

A.B. Gottlieb; J.F. Merola; K. Reich; F. Behrens; P. Nash; C.E.M. Griffiths; W. Bao; P. Pellet; L. Pricop; I.B. McInnes

Disclosures

The British Journal of Dermatology. 2021;185(6):1124-1134. 

In This Article

Materials and Methods

Study Design and Participants

EXCEED is a 52-week phase IIIb randomized, double-blind, multicentre (168 sites in 26 countries), active-controlled, parallel-group monotherapy study (trial registration number NCT02745080). The detailed study design and the patient inclusion and exclusion criteria have been previously reported.[17]

Briefly, patients aged ≥ 18 years fulfilling the PsA classification criteria,[18] who had active PsA (defined as at least three tender joints and at least three swollen joints) and active plaque psoriasis, with at least one plaque with a diameter ≥ 2 cm or documented history of plaque psoriasis or nail changes that were consistent with psoriasis were included. Other inclusion criteria included patients who had received previous treatment with csDMARDs (included but not limited to MTX) and had an inadequate response or discontinued treatment owing to safety/tolerability problems, and had an inadequate response to nonsteroidal anti-inflammatory drugs for ≥ 4 weeks prior to randomization. Before randomization, patients were required to stop any csDMARD (including MTX) with a washout period of 4 weeks and 8 weeks for csDMARDs and leflunomide, respectively. Patients on concomitant corticosteroids were required to remain on a stable dose of ≤ 10 mg per day of prednisone for ≥ 2 weeks before randomization up to week 52. Key exclusion criteria were as follows: indication of ongoing infection or malignancy, pregnancy, former exposure to any biologics for PsA or psoriasis, intake of high-potency opioids, and ongoing use of oral/topical retinoids or skin treatment, or photochemotherapy.

Eligible patients were randomized (1 : 1) to receive secukinumab 300 mg or adalimumab 40 mg after a screening period of up to 8 weeks. Secukinumab was administered using subcutaneous injections (via a prefilled syringe) at baseline, weeks 1–4, and then every 4 weeks until week 48. Adalimumab was also administered via subcutaneous injection as 40 mg/0·4 mL citrate-free every 2 weeks from baseline until week 50. To ensure a consistent number of injections and to maintain allocation concealment, all groups received placebo injections at each visit.

The institutional review board at each participating centre approved the protocol. Data were collected in accordance with Good Clinical Practice guidelines by the study investigators and were analysed by the sponsor.

Outcome Measures

The primary outcome in the EXCEED study was the proportion of patients with ≥ 20% improvement in the ACR response criteria (ACR 20) at week 52. The key secondary endpoints assessed at week 52 (in order of statistical hierarchy) were Psoriasis Area and Severity Index (PASI) 90 response, ACR 50 response, Health Assessment Questionnaire-Disability Index (HAQ-DI) score (mean change from baseline), and resolution of enthesitis [Leeds Enthesitis Index (LEI)].

In the present prespecified subgroup analyses, patients with active PsA who had concomitant moderate-to-severe plaque psoriasis defined as involvement of body surface area (BSA) > 10% or PASI ≥ 10 at baseline (henceforth, referred to as the psoriasis subset) were analysed.

The prespecified endpoints at week 52 evaluated in the psoriasis subset included ACR 20 response, PASI 90 response, ACR 50 response, mean change from baseline in HAQ-DI, resolution of enthesitis, the proportion of patients achieving PASI 75 and PASI 100 responses, and combined ACR 50 and PASI 100 response (defined as the proportion of patients who simultaneously achieved an ACR 50 and PASI 100 response).

In addition, composite indices outcomes often used in the management of PsA, such as the proportion of patients achieving low disease activity (LDA) and/or remission (REM) based on the Disease Activity index for PsA (DAPSA) and PsA Disease Activity Score (PASDAS) were also assessed. Quality of life was assessed using HAQ-DI response (≥ 0·35), Dermatology Life Quality Index (DLQI) 0/1 response, and mean change from baseline in DLQI. Mean change from baseline in the short form-36 survey – physical/mental component summary (SF-36 PCS/MCS) and Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) score were also evaluated.

In order to better understand the selection of certain outcome measures for clinical assessment of disease activity in patients with PsA adopted in the primary analysis, we have briefly summarized outcome measures in Appendix S1 (see Supporting Information).

Statistical Analysis

The full analysis set (FAS) used for the primary efficacy analysis included all patients who were randomized and to whom study treatment was assigned.

The psoriasis subset considered in the present analysis included all patients with active PsA (FAS) with concomitant moderate-to-severe plaque psoriasis with BSA > 10% or PASI ≥ 10 at baseline.

It is important to note that the primary efficacy endpoint was defined as meeting all of the three following conditions: achieving an ACR 20 response, with no permanent termination of study treatment (secukinumab or adalimumab) before or at week 50 (the last dosing visit), and no concomitant use of csDMARDs (including but not limited to MTX) after week 36 (irrespective of the time initiation of csDMARDs).[17] There were only three patients who were taking csDMARDs while on study treatment (protocol deviators) but none of these patients were on csDMARDs after week 36. In the overall study and for the current prespecified analyses, all the secondary and binary (exploratory) endpoints were defined in a similar fashion to that of the primary endpoint.

For binary endpoint analyses, odds ratios (ORs), 95% CIs and P-values were computed for comparative assessments of secukinumab vs. adalimumab from a logistic regression model with treatment as a factor and baseline weight as a covariate. Between-group differences in continuous endpoints were evaluated using a mixed-effect model with repeated measures approach, with treatment and assessment visit as factors, weight and baseline values of the endpoints as continuous covariates, and treatment by analysis visit and baseline score by analysis visit as interaction terms. For analyses of continuous efficacy endpoints, data for patients who discontinued study treatment before week 50 or who took csDMARDs after week 36 were considered as 'missing' for the visits after discontinuation of treatment or use of csDMARDs.

Although the analyses for the psoriasis subset were prespecified, the study was not prospectively powered for testing treatment difference. Thus, unadjusted nominal P-values (without adjusting for multiplicity) are presented.

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