Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis

Abstract

Objective: To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).

Methods: Patients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.

Results: Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).

Conclusion: Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.

Trial registration: ClinicalTrials.gov NCT02384538.

Keywords: DMOADs (biologic); hand osteoarthritis; inflammation; interleukin-1.

Figure 1

LS mean change from baseline in AUSCAN pain over time (A) and LS mean change from baseline in AUSCAN function over time (B). Last observation carried forward imputation was used for analysis when values were missing. All comparisons of lutikizumab versus placebo were not significant using an analysis of covariance adjusted for treatment group and country as factors, and including baseline value as a covariate. AUSCAN, Australian/Canadian Osteoarthritis Hand Index; LS, least squares.

Figure 2

Assessment of radiographic endpoints (A) and MRI endpoints using the Outcome Measures in Rheumatology Clinical Trials/Hand Osteoarthritis MRI Scoring system (HOAMRIS) (B). *Defined by Verbruggen et al as joints that entered the erosive, erosive with remodelling or remodelling phase but were normal, stationary or only starting to lose joint space at baseline. P values for lutikizumab versus placebo are from an analysis of covariance model adjusted for age group and Kellgren-Lawrence score as factors, and including baseline value as a covariate. BML, bone marrow lesions; JSN, joint space narrowing; LS, least squares; OARSI, Osteoarthritis Research Society International.

Figure 3

Mean hsCRP levels (A), neutrophil counts (B) and C1M levels (C) over time. *P<0.05, †P<0.01, ‡P<0.001, for lutikizumab versus placebo, one-way analysis of variance. C1M, metalloproteinase-degraded type I collagen; hsCRP, high-sensitivity C reactive protein.