Elsevier

The Lancet

Volume 382, Issue 9894, 31 August–6 September 2013, Pages 780-789
The Lancet

Articles
Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial

https://doi.org/10.1016/S0140-6736(13)60594-2Get rights and content

Summary

Background

Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis.

Methods

In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3·0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice–web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. This trial is registered with ClinicalTrials.gov (NCT01009086) and EudraCT (2009-012264-14).

Findings

Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned—206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42·4%] in the 45 mg group and 101 of 204 [49·5%] in the 90 mg group) than placebo-treated (47 of 206 [22·8%]) patients achieved ACR20 at week 24 (p<0·0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41·8%] vs 86 of 205 [42·0%]).

Interpretation

Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments.

Funding

Janssen Research & Development.

Introduction

Psoriatic arthritis is a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures and is associated with skin psoriasis and nail involvement.1 Substantial proportions of patients with psoriasis develop psoriatic arthritis,2, 3 which is associated with reduced quality of life, several comorbidities, and increased mortality.4, 5, 6, 7, 8, 9

Conventional treatment for psoriatic arthritis usually begins with disease-modifying antirheumatic drugs and non-steroidal anti-inflammatory drugs, followed by tumour necrosis factor α (TNFα) inhibitors when necessary. T-helper-17 (Th17) cells are postulated to have a major role in psoriatic inflammation, and thus various biological drugs directed against interleukins 17 and 23 are being investigated.10, 11, 12, 13, 14, 15

Ustekinumab is a fully human IgG 1κ monoclonal antibody that binds to the common p40 subunit shared by interleukins 12 and 23. Efficacy against plaque psoriasis and an acceptable safety profile have been shown in large phase 3 trials,12, 13, 14 and the drug is approved for use in the treatment of moderate-to-severe psoriasis. In a phase 2 trial15 of patients with active psoriatic arthritis, ustekinumab significantly improved signs and symptoms of psoriatic arthritis and improved quality of life compared with placebo. Thus, we did the phase 3, placebo-controlled PSUMMIT 1 trial to further assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis.

Section snippets

Study design and participants

PSUMMIT 1 was a phase 3, randomised, placebo-controlled trial at 104 sites in 14 countries—specifically, Australia, Austria, Canada, Finland, Germany, Hungary, Latvia, Lithuania, New Zealand, Poland, Russia, Spain, the UK, and the USA. Patients were recruited by individual study sites via clinics, outside referrals, and advertisements. Patients were screened and randomly assigned between Nov 30, 2009, and March 30, 2011. The week 52 database was locked on July 12, 2012. The trial continues, and

Results

1174 patients were screened, 615 of whom were randomly assigned (figure 1). Most of the patients who were not randomly assigned did not meet the inclusion criteria of five or more swollen and tender joints at screening and baseline and CRP concentrations of 3·0 mg/L or more at screening. 397 patients were randomly assigned at European sites, 175 at North American sites, and 43 at Asia-Pacific sites. 78 (12·7%) patients discontinued study agent by week 52 (figure 1).

The study population

Discussion

In this multicentre, phase 3, double-blind, placebo-controlled trial, subcutaneous ustekinumab was effective and well tolerated in patients with active psoriatic arthritis at week 52 (panel). ACR20 responses were significantly higher in ustekinumab-treated than in placebo-treated patients at week 24, and thus we met our primary study endpoint. We noted differences in efficacy by weeks 4–8. Data about the effects of ustekinumab on radiographic progression are forthcoming.

The highest ACR20

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