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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Antibody-mediated Rejection

Intervention / Treatment
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* Biological: Clazakizumab
* Drug: Physiologic saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18-75 years. Living donor/deceased donor kidney transplant recipients ≥6 months from time of transplant. 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: 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. 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. Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures. Exclusion criteria: Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient. Treatment for ABMR (including CABMR) or TCMR within 3 months prior to the start of screening with the exception of steroids. Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months prior to the start of screening. Pregnant, breastfeeding, or unwillingness to practice adequate contraception. Active tuberculosis (TB) or history of active TB. History of human immunodeficiency virus (HIV) infection or positive for HIV. Seropositive for hepatitis B surface antigen (HBsAg) Hepatitis C virus (HCV) RNA positive.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Active, Antibody-mediated Rejection (AMR)