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

Phase 3TerminatedNCT03744910

CSL Behring194 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

194

Conditions

Antibody-mediated Rejection

Interventions

ClazakizumabBIOLOGICAL

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

Physiologic saline solutionDRUG

Normal saline

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

* 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.

Locations (142)

Outcomes

Primary Outcomes

Change From Baseline to Week 52 in Estimated Glomerular Filtration Rate (eGFR)

This primary outcome measure was the one from the first interim analysis.

Time frame: From Baseline to Week 52

Number of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function

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 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2)\* * return to dialysis\* * allograft nephrectomy * retransplantation * death from any cause, or * a sustained (greater than or equal to \[\>=\] 60 days) 40% decline in eGFR from Baseline. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 number of participants with composite all-cause allograft loss or irreversible loss of allograft function are reported here. Time-to-event data were not calculated due to the study's termination.

Time frame: From Baseline to 4 years

Percentage of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function

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 m\^2\* * return to dialysis\* * allograft nephrectomy * retransplantation * death from any cause, or * a sustained (greater than or equal to \[\>=\] 60 days) 40% decline in eGFR from Baseline. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 percentage of participants with composite all-cause allograft loss or irreversible loss of allograft function are reported here.

Time frame: From Baseline to 4 years

Data from ClinicalTrials.gov

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University of Alabama at Birmingham (UAB) - University of Alabama Hospital (UAB Hospital)

Birmingham, Alabama, United States

Mayo Clinic Hospital

Phoenix, Arizona, United States

Keck Medical Center Of USC

Los Angeles, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

UCLA Kidney Transplant Research Program

Los Angeles, California, United States

University of California Davis Medical Center

Sacramento, California, 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

...and 132 more locations

Secondary Outcomes

Number of Participants With Composite All-cause Allograft Loss

Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components: * eGFR \< 15 mL/min/1.73 m\^2\* * return to dialysis\* * allograft nephrectomy * retransplantation, or * death from any cause. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 number of participants with composite all-cause allograft loss are reported here.

Time frame: From Baseline to 4 years

Percentage of Participants With Composite All-cause Allograft Loss

Composite all-cause allograft loss, defined as, time to first occurrence of any of the following components: * eGFR \< 15 mL/min/1.73 m\^2\* * return to dialysis\* * allograft nephrectomy * retransplantation, or * death from any cause. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 percentage of participants with composite all-cause allograft loss are reported here.

Time frame: From Baseline to 4 years

Number of Participants With Irreversible Loss of Allograft Function

Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days.

Time frame: From Baseline to 4 years

Percentage of Participants With Irreversible Loss of Allograft Function

Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days.

Time frame: From Baseline to 4 years

Number of Participants With Death-censored Allograft Loss

Time to death-censored allograft loss, was defined as occurrence of any of the following components: * eGFR \< 15 mL/min/1.73 m\^2\* * return to dialysis\* * allograft nephrectomy, or * retransplantation. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 number of participants with death-censored allograft loss are reported here.

Time frame: From Baseline to 4 years

Percentage of Participants With Death-censored Allograft Loss

Death-censored allograft loss was defined as the occurrence of any of the following components: * eGFR \< 15 mL/min/1.73 m\^2\* * return to dialysis\* * allograft nephrectomy, or * retransplantation. (\*Total cumulative duration of sustained eGFR \< 15 mL/min/1.73 m\^2 AND / OR dialysis \>= 60 days.) If the eGFR \< 15 mL/min/1.73 m\^2 was 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 percentage of participants who experienced death-censored allograft loss are reported here.

Time frame: From Baseline to 4 years

Change From Baseline in Urine Albumin Creatinine Ratio (UACR)

Time frame: From Baseline to Week 52

Percent Change From Baseline in Mean Fluorescent Intensity for Donor-Specific Antibodies (DSA)

Time frame: From Baseline to Week 52

Change From Baseline in Banff Lesion Grading Score (2015 Criteria) of Pre-treatment to Post-treatment (Week 52) Kidney Biopsies

Banff lesion grading scores assess the presence and the degree of histopathological changes in the different compartments of kidney biopsies. Here, the improved category is defined as a decline in the Banff lesion grading score. Participants with improved scores, not improved scores, and missing biopsies for C4d staining, interstitial fibrosis, tubular atrophy, glomerular basement membrane double contours, glomerulitis and peritubular capillaritis are reported for this outcome measure.

Time frame: From Baseline to Week 52

Incidence of Acute Rejection Episodes of T Cell-mediated Rejection (TCMR) and Antibody-mediated Rejection (ABMR)

Number of participants who had at least one acute rejection episode (TCMR or ABMR) are reported for this outcome measure.

Time frame: Baseline up to End of treatment (up to approximately 4 years)

Overall Participant Survival

Number of participants who were alive up to Week 52 are reported for this outcome measure.

Time frame: Up to Week 52

Maximum Concentration at Steady State (Cmax ss) of CSL300

A subset of participants (out of the enrolled participants in the main study) had the option to participate in a pharmacokinetic (PK)/ Pharmacodynamic (PD) sub-study.

Time frame: Up to Week 24

Trough Concentrations at Steady State (Ctrough ss) of CSL300

A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study.

Time frame: Up to Week 24

Area Under the Concentration-time Curve (AUC0-tau) at Steady State of CSL300

A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study.

Time frame: Up to Week 24

Time of Maximum Concentration at Steady State (Tmax ss) of CSL300

A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study.

Time frame: Up to Week 24