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. 2023 Dec;10(6):1795-1808.
doi: 10.1007/s40744-023-00593-7. Epub 2023 Oct 4.

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial

Cory Perugino  1 , Emma L Culver  2 , Arezou Khosroshahi  3 , Wen Zhang  4 , Emanuel Della-Torre  5 , Kazuichi Okazaki  6 , Yoshiya Tanaka  7 , Matthias Löhr  8 , Nicolas Schleinitz  9 , Judith Falloon  10 , Dewei She  10 , Daniel Cimbora  10 , John H Stone  11   12
Affiliations

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial

Cory Perugino et al. Rheumatol Ther. 2023 Dec.

Abstract

Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE).

Methods: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries.

Planned outcomes: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue.

Trial registration: NCT04540497.

Keywords: Anti-CD19 monoclonal antibody; B-cell depletion; Clinical trial; IgG4-RD; IgG4-related disease; Inebilizumab; Trial design.

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Conflict of interest statement

Cory Perugino receives consulting fees from Horizon Therapeutics and funding from the National Institutes of Health (NIH/NIAMS K08AR079615). Emma L. Culver receives funding from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) Oxford and receives consulting fees from Horizon Therapeutics. Arezou Khosroshahi has participated in advisory boards and served in a consulting role for Viela Bio, Horizon Therapeutics, and Sanofi, and has received grants from Pfizer unrelated to this manuscript. Wen Zhang received consulting fees from Horizon Therapeutics. Emanuel Della-Torre received consulting fees from Horizon Therapeutics. Kazuichi Okazaki has nothing to disclose. Yoshiya Tanaka has received speaking fees and/or honoraria from Behringer-Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, received research grants from Asahi-Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim. Matthias Löhr has nothing to disclose. Nicolas Schleinitz has participated in advisory boards and received consulting fees from Viela Bio and Horizon Therapeutics. Judith Falloon is a former employee of Horizon Therapeutics and owns stock. Dewei She and Daniel Cimbora are employees of Horizon Therapeutics and own stock. John H. Stone has received consulting fees from Horizon Therapeutics, is the global Principal Investigator of the MITIGATE trial, and receives funding from the National Institutes of Health (NIH/NIAID UM1AI144295).

Figures

Fig. 1
Fig. 1
MITIGATE study schema. OLP open-label period, IP investigational product
Fig. 2
Fig. 2
Data collection and diagnostic criteria for immunoglobulin G4-related disease (IgG4-RD) flare in the pancreas and common bile duct. GGT gamma-glutamyl transferase, HbA1C hemoglobin A1c, PE physical examination
Fig. 3
Fig. 3
Process for the identification, assessment, and adjudication of disease flares
See this image and copyright information in PMC

References

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