Clinical trial NCT03744910: Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Antibody-mediated Rejection
Keywords: Chronic Active
Antibody-mediated Rejection (AMR)
Lead sponsor: CSL Behring
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
First posted: 2018-11-19
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: * 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.

Primary outcomes:
measure: Time to composite all-cause allograft loss or irreversible loss of allograft function
timeFrame: Up to approximately 8 years
Secondary outcomes:
measure: Time to composite all-cause allograft loss
timeFrame: Baseline and up to approximately 8 years
measure: Incidence and time to irreversible loss of allograft function
timeFrame: Baseline and up to approximately 8 years
measure: Incidence of composite all-cause allograft loss or irreversible loss of allograft function
timeFrame: Up to approximately 8 years
measure: Incidence and time to death-censored allograft loss
timeFrame: Up to approximately 8 years
measure: Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT)
timeFrame: Baseline and up to approximately 8 years
measure: Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT
timeFrame: Baseline and up to approximately 8 years
measure: Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT
timeFrame: Baseline and up to approximately 8 years
measure: Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post-treatment (Week 52) kidney biopsies
timeFrame: Up to 52 weeks
measure: Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT
timeFrame: Baseline and up to 8 years
measure: Overall patient survival
timeFrame: Up to approximately 8 years
measure: Maximum concentration (Cmax, Cmax ss) of CSL300
timeFrame: Up to 21 days
measure: Trough concentrations (Ctrough, Ctrough ss) of CSL300
timeFrame: Up to 21 days
measure: Area under the concentration-time curve (AUC0-tau) at steady state of CSL300
timeFrame: Up to 21 days
measure: Time of maximum concentration (Tmax, Tmax ss) of CSL300
timeFrame: Up to 21 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (UAB) - University of Alabama Hospital (UAB Hospital)
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Keck Medical Center Of USC
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: UCLA Kidney Transplant Research Program
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Diego
country: United States
facility: California Institute of Renal Research
state: California
city: San Dimas
country: United States
facility: North America Research Institute
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: Aurora
country: United States
facility: University Of Colorado Hospital - Anschutz Medical Campus
state: Colorado
city: Tampa
country: United States
facility: Tampa General Medical Group
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center - University Cardiovascular Surgeons
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University (IU) Health Physicians - Kidney Diseases Clinic - Medical Diagnostic Center Location
state: Indiana
city: Des Moines
country: United States
facility: Unity Point Health
state: Iowa
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: University of Louisville Research Foundation
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Infectious Diseases (WU ID) Clinic
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Erie County Medical Center Corp.
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital / Weill Cornell Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University, Comprehensive Transplant Center
state: Ohio
city: Toledo
country: United States
facility: University of Cincinnati
state: Ohio
city: Oklahoma City
country: United States
facility: Integris Baptist Medical Center
state: Oklahoma
city: Allentown
country: United States
facility: Lehigh Valley Health Network
state: Pennsylvania
city: Harrisburg
country: United States
facility: Central Pennsylvania Transplant Foundation
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Dallas
country: United States
facility: Renal Disease Research Institute
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Healthcare System of San Antonio
state: Texas
city: Richmond
country: United States
facility: VCU Health
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health (UWSMPH)
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of WI Froedtert Hospital
state: Wisconsin
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Westmead
country: Australia
facility: WSLHD, Westmead Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: The University of Queensland - Princess Alexandra Hospital (PAH)
state: Queensland
city: Clayton
country: Australia
facility: Monash Health Monash Medical Centre
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital (SCGH)
state: Western Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Clayton
country: Australia
facility: Monash Medical Centre
city: Nedlands
country: Australia
facility: Linear Clinical Research
city: Westmead
country: Australia
facility: Westmead Hospital
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
city: Graz
country: Austria
facility: LKH-Universität Hospital Graz
city: Innsbruck
country: Austria
facility: Universitätsklinik für Innere Medizin III Innsbruck
city: Vienna
country: Austria
facility: Medizinische Universität Wien, Allgemeines Krankenhaus der S
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire Sart Tilman
city: Vancouver
country: Canada
facility: Vancouver General Hospital - Gordon & Leslie Diamond Centre
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital, Providence Health Care, Univ. Of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: Shared Health Inc. operating as the Health Sciences Centre
state: Manitoba
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Health Centre
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Saskatoon
country: Canada
facility: St Paul's Hospital Foundation
state: Saskatchewan
city: Montréal
country: Canada
facility: Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM)
city: Toronto
country: Canada
facility: University Health Network
city: Brno Střed
country: Czechia
facility: Centrum kardiovaskulární a transplantacní chirurgie Brno
city: Olomouc
country: Czechia
facility: Fakultní Nemocnice Olomouc
city: Prague
country: Czechia
facility: IKEM
city: Grenoble
country: France
facility: CHU GRENOBLE ALPES - Consultation Néphrologie Bureau des ARC (Côté Chartreuse, Rez-de-Chaussée Haut)
state: Grenoble Cédex 09
city: Bois-Guillaume
country: France
facility: Néphrologie - Pavillon Sainte Venise - CHU de Rouen - Hôpital de Bois Guillaume
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire (CHU) de Bordeaux - Groupe Hospitalier Pellegrin
city: Créteil
country: France
facility: Centre Hospitalier Universitaire (CHU) - Hopital Henri Mondor
city: Le Kremlin-Bicêtre
country: France
facility: Hopital Kremlin Bicetre
city: Limoges Cedex
country: France
facility: Centre Hospitalier Universitaire (CHU) De Limoges Hopital Dupuytren
city: Lyon
country: France
facility: Hopital Edouard Herriot
city: Marseille
country: France
facility: Hopital de la Conception - APHM
city: Montpellier
country: France
facility: Centre Hospitalier Regional Universitaire (CHRU) Montpellier Arnaud de Villeneuve
city: Nantes Cedex 1
country: France
facility: CHU de Nantes - Houtel Dieu
city: Nice Cedex 1
country: France
facility: Centre Hospitalier Universitaire de Nice, Hopital Pasteur 2
city: Paris
country: France
facility: Hospital Saint-Louis - APHP
city: Paris
country: France
facility: Hopital Necker Enfants Malades
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Strasbourg
country: France
facility: Hopitaux Universitaire de Strasbourg-Centre de References des Maladies Autoimmunes
city: Toulouse
country: France
facility: CHU Rangueil
city: Tours Cedex 9
country: France
facility: Centre Hospitalier Regional Universitaire de Tours (CHRU de Tours) - Hopital Bretonneau
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Charite Mitte (CCM)
city: Debrecen
country: Hungary
facility: Debreceni Egyetem, Klinikai Központ, Auguszta
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung Dongsan Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Kangdong Sacred Heart Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Kosin University Gospel Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital at Gangdong
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center (Amsterdam UMC), Academic Medical Center (AMC)
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC location AMC
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Center (LUMC)
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre-Centro de Actividades Ambulatorias
city: Santander
country: Spain
facility: Hospital Universitario Marques De Valdecilla
city: Valencia
country: Spain
facility: Centro Hospital Universitario Dr. Preset
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Huddinge
country: Sweden
facility: Karolinska University Hospital
city: Solna
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Uppsala Universitet - Akademiska Sjukhuset
city: Uppsala
country: Sweden
facility: Uppsala Universitet - Akademiska Sjukhuset
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Hospital
city: New Taipei City
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taichang
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan
country: Taiwan
facility: Linkou Chang Gung Memorial Hospital
Study officials:
affiliation: CSL Behring
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.