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Trials
Published in: Trials 1/2022

Open Access 01-12-2022 | Kidney Transplantation | Study protocol

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design

Authors: Peter W. Nickerson, Georg A. Böhmig, Steve Chadban, Deepali Kumar, Roslyn B. Mannon, Teun van Gelder, James C. Lee, Scott Adler, Edward Chong, Arjang Djamali

Published in: Trials | Issue 1/2022

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Abstract

Background

Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR.

Methods

IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia.

Discussion

IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR.

Trial registration

ClinicalTrials.​govNCT03744910. Registered on November 19, 2018.
Appendix
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Metadata
Title
Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design
Authors
Peter W. Nickerson
Georg A. Böhmig
Steve Chadban
Deepali Kumar
Roslyn B. Mannon
Teun van Gelder
James C. Lee
Scott Adler
Edward Chong
Arjang Djamali
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-022-06897-3

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