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

Antibody-mediated Rejection Clinical Trial

— IMAGINE  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03744910
• Other study ID #: CSL300_3001
• Secondary ID: 2018-003682-34VK
• Status: Terminated
• Phase: Phase 3
• Start date: October 14, 2019
• Est. completion date: April 8, 2024

Study information

• Verified date: April 2024
• Source: CSL Behring
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 194
• Est. completion date: April 8, 2024
• Est. primary completion date: April 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

• 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.

Related Conditions & MeSH terms

• Antibody-mediated Rejection

Intervention

Biological:
• Clazakizumab
Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6

Drug:
• Physiologic saline solution
Normal saline

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Royal Prince Alfred Hospital	Camperdown
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Health Monash Medical Centre	Clayton	Victoria
Australia	Monash Medical Centre	Clayton
Australia	Linear Clinical Research	Nedlands
Australia	Sir Charles Gairdner Hospital (SCGH)	Nedlands	Western Australia
Australia	The Royal Melbourne Hospital	Parkville	Victoria
Australia	Westmead Hospital	Westmead
Australia	WSLHD, Westmead Hospital	Westmead	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Australia	Princess Alexandra Hospital	Woolloongabba
Australia	The University of Queensland - Princess Alexandra Hospital (PAH)	Woolloongabba	Queensland
Austria	LKH-Universität Hospital Graz	Graz
Austria	Universitätsklinik für Innere Medizin III Innsbruck	Innsbruck
Austria	Medizinische Universität Wien, Allgemeines Krankenhaus der S	Vienna
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire Sart Tilman	Liège
Canada	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM)	Montréal
Canada	McGill University Health Center	Montréal	Quebec
Canada	St Paul's Hospital Foundation	Saskatoon	Saskatchewan
Canada	St. Michael's Health Centre	Toronto	Ontario
Canada	University Health Network	Toronto
Canada	St. Paul's Hospital, Providence Health Care, Univ. Of British Columbia	Vancouver	British Columbia
Canada	Vancouver General Hospital - Gordon & Leslie Diamond Centre	Vancouver	British Columbia
Canada	Shared Health Inc. operating as the Health Sciences Centre	Winnipeg	Manitoba
Czechia	Centrum kardiovaskulární a transplantacní chirurgie Brno	Brno Stred
Czechia	Fakultní Nemocnice Olomouc	Olomouc
Czechia	IKEM	Prague
France	Néphrologie - Pavillon Sainte Venise - CHU de Rouen - Hôpital de Bois Guillaume	Bois-Guillaume
France	Centre Hospitalier Universitaire (CHU) de Bordeaux - Groupe Hospitalier Pellegrin	Bordeaux
France	Centre Hospitalier Universitaire (CHU) - Hopital Henri Mondor	Créteil
France	CHU GRENOBLE ALPES - Consultation Néphrologie Bureau des ARC (Côté Chartreuse, Rez-de-Chaussée Haut)	Grenoble	Grenoble Cédex 09
France	Hopital Kremlin Bicetre	Le Kremlin-Bicêtre
France	Centre Hospitalier Universitaire (CHU) De Limoges Hopital Dupuytren	Limoges Cedex
France	Hopital Edouard Herriot	Lyon
France	Hopital de la Conception - APHM	Marseille
France	Centre Hospitalier Regional Universitaire (CHRU) Montpellier Arnaud de Villeneuve	Montpellier
France	CHU de Nantes - Houtel Dieu	Nantes Cedex 1
France	Centre Hospitalier Universitaire de Nice, Hopital Pasteur 2	Nice Cedex 1
France	Hopital Necker Enfants Malades	Paris
France	Hospital Saint-Louis - APHP	Paris
France	Centre Hospitalier Universitaire de Poitiers	Poitiers
France	Hopitaux Universitaire de Strasbourg-Centre de References des Maladies Autoimmunes	Strasbourg
France	CHU Rangueil	Toulouse
France	Centre Hospitalier Regional Universitaire de Tours (CHRU de Tours) - Hopital Bretonneau	Tours Cedex 9
Germany	Charite - Universitaetsmedizin Berlin - Campus Charite Mitte (CCM)	Berlin
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Debreceni Egyetem, Klinikai Központ, Auguszta	Debrecen
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Keimyung Dongsan Medical Center	Daegu
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Kangdong Sacred Heart Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Kosin University Gospel Hospital	Seoul
Korea, Republic of	Kyung Hee University Hospital at Gangdong	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital Yonsei University	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Pusan National University Yangsan Hospital	Yangsan
Netherlands	Amsterdam UMC location AMC	Amsterdam
Netherlands	Amsterdam University Medical Center (Amsterdam UMC), Academic Medical Center (AMC)	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Center (LUMC)	Leiden
Netherlands	Maastricht University Medical Centre	Maastricht
Netherlands	Radboud UMC	Nijmegen
Netherlands	Erasmus University Medical Center	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
New Zealand	Auckland City Hospital	Auckland
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Del Mar	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Universitario 12 de Octubre-Centro de Actividades Ambulatorias	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Marques De Valdecilla	Santander
Spain	Centro Hospital Universitario Dr. Preset	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Sweden	Karolinska University Hospital	Huddinge
Sweden	Karolinska University Hospital	Solna
Sweden	Uppsala Universitet - Akademiska Sjukhuset	Uppsala
Sweden	Uppsala Universitet - Akademiska Sjukhuset	Uppsala
Taiwan	Hualien Tzu Chi Hospital	Hualien City
Taiwan	Far Eastern Memorial Hospital	New Taipei City
Taiwan	Taichung Veterans General Hospital	Taichang
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Linkou Chang Gung Memorial Hospital	Taoyuan
United States	Lehigh Valley Health Network	Allentown	Pennsylvania
United States	University Of Colorado Hospital - Anschutz Medical Campus	Aurora	Colorado
United States	University of Alabama at Birmingham (UAB) - University of Alabama Hospital (UAB Hospital)	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Cancer Center	Boston	Massachusetts
United States	Erie County Medical Center Corp.	Buffalo	New York
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Rush University Medical Center - University Cardiovascular Surgeons	Chicago	Illinois
United States	The Ohio State University, Comprehensive Transplant Center	Columbus	Ohio
United States	Renal Disease Research Institute	Dallas	Texas
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Unity Point Health	Des Moines	Iowa
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke Cancer Institute	Durham	North Carolina
United States	Central Pennsylvania Transplant Foundation	Harrisburg	Pennsylvania
United States	Indiana University (IU) Health Physicians - Kidney Diseases Clinic - Medical Diagnostic Center Location	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Keck Medical Center Of USC	Los Angeles	California
United States	UCLA Kidney Transplant Research Program	Los Angeles	California
United States	University of Louisville Research Foundation	Louisville	Kentucky
United States	University of Wisconsin School of Medicine and Public Health (UWSMPH)	Madison	Wisconsin
United States	Medical College of WI Froedtert Hospital	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	New York Presbyterian Hospital / Weill Cornell Medical Center	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	Integris Baptist Medical Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Rhode Island Hospital	Providence	Rhode Island
United States	VCU Health	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California Davis Medical Center	Sacramento	California
United States	Washington University School of Medicine - Infectious Diseases (WU ID) Clinic	Saint Louis	Missouri
United States	Methodist Healthcare System of San Antonio	San Antonio	Texas
United States	California Institute of Renal Research	San Diego	California
United States	North America Research Institute	San Dimas	California
United States	California Pacific Medical Center	San Francisco	California
United States	Kaiser Permanente	San Francisco	California
United States	University of California, San Francisco Medical Center	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Tampa General Medical Group	Tampa	Florida
United States	University of Cincinnati	Toledo	Ohio
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
CSL Behring	ICON Clinical Research

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Hungary,  Korea, Republic of,  Netherlands,  New Zealand,  Spain,  Sweden,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time to composite all-cause allograft loss		Baseline and up to approximately 8 years
Secondary	Incidence and time to irreversible loss of allograft function		Baseline and up to approximately 8 years
Secondary	Incidence of composite all-cause allograft loss or irreversible loss of allograft function		Up to approximately 8 years
Secondary	Incidence and time to death-censored allograft loss		Up to approximately 8 years
Secondary	Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT)		Baseline and up to approximately 8 years
Secondary	Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT		Baseline and up to approximately 8 years
Secondary	Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT		Baseline and up to approximately 8 years
Secondary	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
Secondary	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
Secondary	Overall patient survival		Up to approximately 8 years
Secondary	Maximum concentration (Cmax, Cmax ss) of CSL300		Up to 21 days
Secondary	Trough concentrations (Ctrough, Ctrough ss) of CSL300		Up to 21 days
Secondary	Area under the concentration-time curve (AUC0-tau) at steady state of CSL300		Up to 21 days
Secondary	Time of maximum concentration (Tmax, Tmax ss) of CSL300		Up to 21 days