Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

Ian N Bruce; Richard A Furie; Eric F Morand; Susan Manzi; Yoshiya Tanaka; Kenneth C Kalunian; Joan T Merrill; Patricia Puzio; Emmanuelle Maho; Christi Kleoudis; Marius Albulescu; Micki Hultquist; Raj Tummala

doi:10.1136/annrheumdis-2021-221847

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

Ann Rheum Dis. 2022 Jul;81(7):962-969. doi: 10.1136/annrheumdis-2021-221847. Epub 2022 May 17.

Authors

Ian N Bruce^{1

2}, Richard A Furie³, Eric F Morand⁴, Susan Manzi⁵, Yoshiya Tanaka⁶, Kenneth C Kalunian⁷, Joan T Merrill⁸, Patricia Puzio⁹, Emmanuelle Maho¹⁰, Christi Kleoudis¹¹, Marius Albulescu¹⁰, Micki Hultquist⁹, Raj Tummala¹²

Affiliations

¹ Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal & Dermatological Sciences, The University of Manchester, Manchester, UK.
² NIHR Manchester Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
³ Division of Rheumatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York, USA.
⁴ Center for Inflammatory Disease, Monash University, Melbourne, Victoria, Australia.
⁵ Department of Medicine, Lupus Center of Excellence, Autoimmunity Institute, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
⁶ First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
⁷ Division of Rheumatology, Allergy, and Immunology, University of California San Diego, La Jolla, California, USA.
⁸ Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
⁹ BioPharmaceuticals R&D, AstraZeneca US, Gaithersburg, Maryland, USA.
¹⁰ BioPharmaceuticals R&D, AstraZeneca R&D, Cambridge, UK.
¹¹ BioPharmaceuticals R&D, AstraZeneca US, Durham, North Carolina, USA.
¹² BioPharmaceuticals R&D, AstraZeneca US, Gaithersburg, Maryland, USA Raj.Tummala@astrazeneca.com.

Abstract

Objectives: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.

Methods: TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.

Results: Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.

Conclusions: Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.

Trial registration numbers: NCT02446912 and NCT02446899.

Keywords: Autoimmune Diseases; Biological Therapy; Lupus Erythematosus, Systemic.

Publication types

Clinical Trial, Phase II
Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Alprostadil / therapeutic use
Antibodies, Monoclonal, Humanized
Glucocorticoids* / therapeutic use
Humans
Lupus Erythematosus, Systemic* / drug therapy
Severity of Illness Index
Treatment Outcome

Substances

Antibodies, Monoclonal, Humanized
Glucocorticoids
anifrolumab
Alprostadil

Associated data

ClinicalTrials.gov/NCT02446912
ClinicalTrials.gov/NCT02446899