Canakinumab for Treatment of Adult Onset Still's Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): A Phase 2, Multi-Centre, Placebo-Controlled Study

Abstract

Background: Inhibition of interleukin-1 (IL-1) represents a promising treatment option in adult-onset Still's disease (AOSD). Canakinumab is approved for treatment of systemic juvenile idiopathic arthritis and has a marked impact on systemic as well as articular activity of the disease. Objective: To investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multi-centre, double-blinded, randomized, placebo controlled trial. Methods: Patients with AOSD and active joint involvement (tender and swollen joint count ≥4 each) were stratified by pre-treatment status with biologic DMARDs to canakinumab (4 mg/kg, maximum 300 mg s.c. q4w) or placebo. After approval of canakinumab for AOSD by the European Medicines Agency, recruitment was stopped prematurely with enrollment of 35 out of 68 planned patients. The primary endpoint was the proportion of patients with a clinically-relevant reduction in disease activity at week 12 as determined by the change in disease activity score (ΔDAS28 >1·2). Results: At enrollment, patients had high active disease with a mean DAS28(ESR) of 5·4 in the canakinumab group (n=18, [CI 43·1 ; 85·2]) and 5·3 in the placebo group (n=17, [CI 20·1 ; 65·0]). In the intention-to-treat analysis, 12 (67%) canakinumab and 7 (41%) placebo patients fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher ACR30 (61% vs. 33% p=0.033), ACR50 (50% vs. 6·7% p= 0.009) and ACR70 (28% vs. 0% p=0·049) response rates were observed in the canakinumab group compared with placebo. Two patients in the canakinumab group experienced an SAE. Conclusion: Although the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD. Trial Registration: EudraCT No. 2011-001027-20. Funding Statement: Novartis Pharma GmbH Deutschland for financial support and study drug provision. Declaration of Interests: CK has received personal advisory board and congress fees from Novartis, Pfizer, Roche, and Sobi. FB has received grants from Abbvie, Pfizer, Roche, Chugai, Janssen and consultant, speaker, or advisory board fees from Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; and Sandoz. NB has received grants from Novartis and Sobi, and personal fees from Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, and Roche. JH has received grants from Novartis, Roche, Celgene, and advisory board and speaker fees from Novartis, Roche, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim, and Celgene. ARR has received speaker fees from UCB, and advisory board and speaker fees from Novartis, Roche, Lilly, Pfizer, Abbvie, BMS, Janssen, Sanofi, and Celgene. CS has received personal fess from Abbvie, BoehringerIngelheim, Chugai, Lilly, Novartis, Sobi, UCB, Celgene, Janssen-Cilag, MSD, Pfizer, Roche, UCB, and Toshiba. EF has received advisory board and speaker fees from Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, and Sanofi. The remaining authors declare no competing interests. Ethics Approval Statement: The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol and all amendments were reviewed by the Independent Ethics Commission of the State of Berlin (Ethik-Kommission des Landes Berlin) and Independent Ethics Committees for each center (EudraCT No. 2011-001027-20, Protocol No.: CACZ885GDE01T, ethic No 11/0561 – ZS EK 11). All patients provided written informed consent before any assessment was performed.