Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients (IMAGINE)

A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the Treatment of Chronic Active Antibody-mediated Rejection in Kidney Transplant Recipients

This trial investigates the efficacy and safety of clazakizumab [an anti-interleukin (IL)-6 monoclonal antibody (mAb)] for the treatment of CABMR in recipients of a kidney transplant.

Study Overview

• Status: Active, not recruiting
• Conditions: Antibody-mediated Rejection
• Intervention / Treatment: Biological: Clazakizumab; Drug: Physiologic saline solution

• Study Type: Interventional
• Enrollment (Estimated): 350
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Trial Registration Coordinator; Phone Number: 610-878-4000; Email: clinicaltrials@cslbehring.com

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Camperdown, Australia
    • Royal Prince Alfred Hospital
  • Clayton, Australia
    • Monash Medical Centre
  • Nedlands, Australia
    • Linear Clinical Research
  • Westmead, Australia
    • Westmead Hospital
  • Woolloongabba, Australia
    • Princess Alexandra Hospital
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Westmead, New South Wales, Australia, 2145
      • WSLHD, Westmead Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • The University of Queensland - Princess Alexandra Hospital (PAH)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health Monash Medical Centre
    • Parkville, Victoria, Australia, 3064
      • The Royal Melbourne Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital (SCGH)
• Austria
  • Graz, Austria
    • LKH-Universität Hospital Graz
  • Innsbruck, Austria
    • Universitätsklinik für Innere Medizin III Innsbruck
  • Vienna, Austria
    • Medizinische Universität Wien, Allgemeines Krankenhaus der S
• Belgium
  • Edegem, Belgium
    • UZ Antwerpen
  • Leuven, Belgium
    • UZ Leuven
  • Liège, Belgium
    • Centre Hospitalier Universitaire Sart Tilman
• Canada
  • Montréal, Canada
    • Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)
  • Toronto, Canada
    • University Health Network
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital - Gordon & Leslie Diamond Centre
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital, Providence Health Care, Univ. Of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Shared Health Inc. operating as the Health Sciences Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Queen Elizabeth II Health Sciences Centre
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M5C 2T2
      • St. Michael's Health Centre
  • Quebec
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Center
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7M 0Z9
      • St Paul's Hospital Foundation
• Czechia
  • Brno Střed, Czechia
    • Centrum kardiovaskulární a transplantacní chirurgie Brno
  • Olomouc, Czechia
    • Fakultní nemocnice Olomouc
  • Prague, Czechia, 14000
    • IKEM
• France
  • Bois-Guillaume, France, 76230
    • Néphrologie - Pavillon Sainte Venise - CHU de Rouen - Hôpital de Bois Guillaume
  • Bordeaux, France, 33076
    • Centre Hospitalier Universitaire (CHU) de Bordeaux - Groupe Hospitalier Pellegrin
  • Créteil, France, 94010
    • Centre Hospitalier Universitaire (Chu) - Hopital Henri Mondor
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Kremlin Bicetre
  • Limoges Cedex, France, 87042
    • Centre Hospitalier Universitaire (CHU) De Limoges Hopital Dupuytren
  • Lyon, France, 69003
    • Hôpital Edouard Herriot
  • Marseille, France, 13005
    • Hopital de la Conception - APHM
  • Montpellier, France, 34295
    • Centre Hospitalier Regional Universitaire (CHRU) Montpellier Arnaud de Villeneuve
  • Nantes Cedex 1, France, 44093
    • CHU de Nantes - Houtel Dieu
  • Nice Cedex 1, France, 06001
    • Centre Hospitalier Universitaire de Nice, Hopital Pasteur 2
  • Paris, France, 75015
    • Hopital Necker Enfants Malades
  • Paris, France, 75010
    • Hospital Saint-Louis - APHP
  • Poitiers, France, 86021
    • Centre Hospitalier Universitaire de Poitiers
  • Strasbourg, France, 67098
    • Hopitaux Universitaire de Strasbourg-Centre de References des Maladies Autoimmunes
  • Toulouse, France, 31059
    • CHU Rangueil
  • Tours Cedex 9, France, 37044
    • Centre Hospitalier Regional Universitaire de Tours (CHRU de Tours) - Hopital Bretonneau
  • Grenoble Cédex 09
    • Grenoble, Grenoble Cédex 09, France, 38043
      • CHU GRENOBLE ALPES - Consultation Néphrologie Bureau des ARC (Côté Chartreuse, Rez-de-Chaussée Haut)
• Germany
  • Berlin, Germany, 10117
    • Charite - Universitaetsmedizin Berlin - Campus Charite Mitte (CCM)
• Hungary
  • Debrecen, Hungary
    • Debreceni Egyetem Klinikai Központ
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem, Klinikai Központ, Auguszta
• Korea, Republic of
  • Busan, Korea, Republic of
    • Pusan National University Hospital
  • Daegu, Korea, Republic of
    • Keimyung Dongsan Medical Center
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Kyung Hee University Hospital at Gangdong
  • Seoul, Korea, Republic of
    • Kangdong Sacred Heart Hospital
  • Seoul, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • Severance Hospital Yonsei University
  • Seoul, Korea, Republic of
    • Kosin University Gospel Hospital
  • Yangsan, Korea, Republic of
    • Pusan National University Yangsan Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Amsterdam UMC location AMC
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam University Medical Center (Amsterdam UMC), Academic Medical Center (AMC)
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center (LUMC)
  • Maastricht, Netherlands, 6248 HX
    • Maastricht University Medical Centre
  • Nijmegen, Netherlands
    • Radboud UMC
  • Rotterdam, Netherlands
    • Erasmus University Medical Center
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
• New Zealand
  • Auckland, New Zealand
    • Auckland City Hospital
• Spain
  • Barcelona, Spain, 8003
    • Hospital del Mar
  • Barcelona, Spain, 8035
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 8036
    • Hospital Clinic Barcelona
  • Barcelona, Spain, 8907
    • Hospital Universitari de Bellvitge
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre-Centro de Actividades Ambulatorias
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Valencia, Spain, 46017
    • Centro Hospital Universitario Dr. Preset
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• Sweden
  • Huddinge, Sweden, SE-141 86
    • Karolinska University Hospital
  • Solna, Sweden
    • Karolinska University Hospital
  • Uppsala, Sweden, 75185
    • Uppsala Universitet - Akademiska Sjukhuset
  • Uppsala, Sweden
    • Uppsala Universitet - Akademiska Sjukhuset
• Taiwan
  • Hualien City, Taiwan
    • Hualien Tzu Chi Hospital
  • New Taipei City, Taiwan
    • Far Eastern Memorial Hospital
  • Taichang, Taiwan
    • Taichung Veterans General Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taoyuan, Taiwan
    • Linkou Chang Gung Memorial Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham (UAB) - University of Alabama Hospital (UAB Hospital)
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90033
      • Keck Medical Center of USC
    • Los Angeles, California, United States, 90095
      • UCLA Kidney Transplant Research Program
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92123
      • California Institute of Renal Research
    • San Dimas, California, United States, 91773
      • North America Research Institute
    • San Francisco, California, United States, 94143
      • University of California, San Francisco Medical Center
    • San Francisco, California, United States, 94118
      • Kaiser Permanente
    • San Francisco, California, United States, 94109
      • California Pacific Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Medical Campus
  • Florida
    • Tampa, Florida, United States, 33606
      • Tampa General Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center - University Cardiovascular Surgeons
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University (IU) Health Physicians - Kidney Diseases Clinic - Medical Diagnostic Center Location
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Unity Point Health
    • Iowa City, Iowa, United States, 52242
      • Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University Of Louisville Research Foundation
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Cancer Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55095
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine - Infectious Diseases (WU ID) Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University of Nebraska Medical Center
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • New York
    • Buffalo, New York, United States, 14215
      • Erie County Medical Center Corp.
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital / Weill Cornell Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University, Comprehensive Transplant Center
    • Toledo, Ohio, United States, 43614
      • University of Cincinnati
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
    • Harrisburg, Pennsylvania, United States, 17104
      • Central Pennsylvania Transplant Foundation
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson University Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Rhode Island Hospital
  • Texas
    • Dallas, Texas, United States, 75235
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75204
      • Renal Disease Research Institute
    • San Antonio, Texas, United States, 78229
      • Methodist Healthcare System of San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Health
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin School of Medicine and Public Health (UWSMPH)
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of WI Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• Inclusion criteria:

  1. Age 18-75 years.
  2. Living donor/deceased donor kidney transplant recipients ≥6 months from time of transplant.

  3. Diagnosis of CABMR determined by kidney biopsy and the presence of HLA DSA using single-antigen bead-based assays. For eligibility, kidney biopsy must not be older than 12 months and DSA analysis must be performed no longer than 6 months prior to the start of Screening.

     NOTE: • Within 3 months prior to the start of Screening, treatments for ABMR or TCMR, with the exception of steroids*, are not allowed (see Exclusion Criterion 3).

     • If treatment for ABMR (including CABMR) or TCMR (other than steroids*) was given between 3 to 12 months of Screening, a repeat kidney biopsy and DSA analysis are required at least 6 weeks after the end of treatment to confirm continuing CABMR and presence of HLA DSA and to determine eligibility.

     * A maximum dose of 2g of methylprednisolone intravenously (or dose equivalent of other steroids), followed by a taper to the original maintenance steroid dose is allowed.

     The following histopathologic and serologic diagnostic criteria (based on Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:

     1. Morphologic evidence of chronic tissue injury, as demonstrated by transplant glomerulopathy (TG) (cg) > 0). Biopsies without evidence of chronic tissue injury on light microscopy, but with glomerular basement membrane double contours on electron microscopy (cg1a) are eligible.
     2. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:

     i. Linear C4d staining in peritubular capillaries or medullary vasa recta (Banff scores C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections).

     ii. At least moderate microvascular inflammation ([glomerulitis score, g + peritubular capillaritis score, ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥ 1.

     NOTE: The local pathologist's diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. Biopsies with other histopathologic changes (eg, BKV nephropathy or recurrent glomerulonephritis) may be eligible if concurrent CABMR changes (as detailed above) are present and determined to be the predominant cause of renal dysfunction.

     c. Serologic evidence of circulating HLA DSA. NOTE: The local laboratory DSA results must be reviewed and confirmed by the central HLA reviewer during the screening period.

  4. Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.

• Exclusion criteria:

  1. Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.
  2. Treatment for ABMR (including CABMR) or TCMR within 3 months prior to the start of screening with the exception of steroids.
  3. Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months prior to the start of screening.
  4. Pregnant, breastfeeding, or unwillingness to practice adequate contraception.
  5. Active tuberculosis (TB) or history of active TB.
  6. History of human immunodeficiency virus (HIV) infection or positive for HIV.
  7. Seropositive for hepatitis B surface antigen (HBsAg)
  8. Hepatitis C virus (HCV) RNA positive.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Clazakizumab; Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6 that is administered subcutaneously.	Biological: Clazakizumab; Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6
Placebo Comparator: Placebo; Physiologic saline solution that is administered subcutaneously.	Drug: Physiologic saline solution; Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to composite all-cause allograft loss or irreversible loss of allograft function	Defined as time to first occurrence of any of the following components: eGFR < 15 mL/min/1.73 m2*,; return to dialysis*,; allograft nephrectomy,; retransplantation,; death from any cause, or; a sustained (≥ 60 days) 40% decline in eGFR from Baseline. *total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after ≥ 60 days from the first measurement. The primary efficacy endpoint will be analyzed as part of the final analysis when at least 221 composite all-cause allograft loss or irreversible loss of allograft function events have occurred.	Up to approximately 8 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum concentration (Cmax, Cmax ss) of CSL300	Up to 21 days
Trough concentrations (Ctrough, Ctrough ss) of CSL300	Up to 21 days
Area under the concentration-time curve (AUC0-tau) at steady state of CSL300	Up to 21 days
Time of maximum concentration (Tmax, Tmax ss) of CSL300	Up to 21 days
Time to composite all-cause allograft loss	Baseline and up to approximately 8 years
Incidence and time to irreversible loss of allograft function	Baseline and up to approximately 8 years
Incidence of composite all-cause allograft loss or irreversible loss of allograft function	Up to approximately 8 years
Incidence and time to death-censored allograft loss	Up to approximately 8 years
Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT)	Baseline and up to approximately 8 years
Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT	Baseline and up to approximately 8 years
Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT	Baseline and up to approximately 8 years
Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post-treatment (Week 52) kidney biopsies	Up to 52 weeks
Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT	Baseline and up to 8 years
Overall patient survival	Up to approximately 8 years

Collaborators and Investigators

• Sponsor: CSL Behring
• Collaborators: ICON Clinical Research
• Investigators: Study Director: Study Director, CSL Behring

Publications and helpful links

General Publications

• Jordan SC, Ammerman N, Choi J, Huang E, Najjar R, Peng A, Sethi S, Sandhu R, Atienza J, Toyoda M, Ge S, Lim K, Gillespie M, Zhang X, Haas M, Vo A. Evaluation of Clazakizumab (Anti-Interleukin-6) in Patients With Treatment-Resistant Chronic Active Antibody-Mediated Rejection of Kidney Allografts. Kidney Int Rep. 2022 Feb 9;7(4):720-731. doi: 10.1016/j.ekir.2022.01.1074. eCollection 2022 Apr.

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2019
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 13, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Chronic Active; Antibody-mediated Rejection (AMR)
• Other Study ID Numbers: CSL300_3001; 2018-003682-34 (EudraCT Number); VKTX01 (Other Identifier: Vitaeris)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No