Chronic Active Antibody-Mediated Rejection (CABMR) in Kidney Transplant Recipients
Conditions
Interventions
Product Name: CSL300
Product Code: Clazakizumab
Pharmaceutical Form: Solution for injection
INN or Proposed INN: CLAZAKIZUMAB
CAS Number: 1236278-28-6
Other descriptive name: CLAZAKIZUMAB
Concentratio
Sponsors
CSL Behring LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age 18 to 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. NOTE: If conducted within 12 months (+ 3 weeks) prior to the start of the Screening Period and no intervening treatments have been administered, the biopsy does not need to be repeated at Screening. If conducted within 6 months (+ 3 weeks) prior to the start of Screening, the DSA analysis does not need to be repeated at Screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed at least 2 months ± 2 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR and presence of HLA DSA. In addition, with the exception of steroids, treatments for ABMR or TCMR are not allowed within 3 months prior to the start of Screening (see Exclusion Criterion 3). 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 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 ([g + 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. . Serologic evidence of circulating DSA to HLA. 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 310 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
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-thymocite globulin) within 3 months of the start of screening. 4. Pregnant, breastfeeding, or unwillingness to practice adequate contraception. 5. Active tuberculosis (TB) or history of active tuberculosis (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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To evaluate the efficacy of clazakizumab in preventing all-cause composite allograft loss (including death) due to CABMR. 2. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 (MDRD4) equation). 3. To evaluate the safety of clazakizumab. ;Secondary Objective: 1. To evaluate the effects of clazakizumab on loss of allograft function (defined as a 40% decline in eGFR from Baseline that is sustained for at least 60 days). 2. To evaluate the effects of clazakizumab on death-censored allograft loss. 3. To evaluate the effects of clazakizumab on albuminuria. 4. To evaluate the effects of clazakizumab on DSA titers and mean fluorescence intensity (MFI) scores. 5. To evaluate the effects of clazakizumab on incidence of acute rejection episodes (TCMR and ABMR). 6. To evaluate the effects of clazakizumab on the histology of kidney biopsies according to the Banff 2015 lesion grading scores. 7. To evaluate the effects of clazakizumab on overall patient survival. 8. To evaluate the PK of clazakizumab following subcutaneous injection in kidney transplant recipients with CABMR (for those in the PK/PD substudy only). 9. To evaluate the immunogenicity of clazakizumab in kidney transplant recipients with CABMR ;Primary end point(s): Time to all-cause composite allograft loss defined as oeGFR < 15 mL/min/1.73 m2*, oreturn to dialysis*, oallograft nephrectomy, oretransplantation, or odeath from any cause (Final Analysis), *total cumulative duration of eGFR < 15 mL/min/1.73 m2 AND / OR dialysis = 60 days. An eGFR <15 mL/min/1.73 m2 must be confirmed by a repeat measurement The time window for confirmation of an eGFR < 15 mL/min/1.73 m2 is = 60 days from when initially noted. The date of the initial eGFR < 15 mL/min/1.73 m2 is the date when first determined from local or central laboratories. The primary efficacy endpoint will be analyzed as part of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Incidence and time to loss of allograft function as defined by a 40% decline in eGFR from Baseline. 2) Incidence of time to all-cause composite allograft loss 3) Incidence and time to death-censored allograft loss. 4) Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT). 5) Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT. 6) Change in (Donor-specific antibodies) DSA titers and Mean fluorescence Intensity (MFI) scores from Baseline to EOT. 7) Incidence of acute rejection episodes of T cell-mediated rejection (TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT. 8) Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post treatment (Week 52) kidney biopsies. 9) Overall patient survival. 10) Maximum concentration (Cmax, Cmax ss) of CSL300) 11) Trough concentrations (Ctrough, Ctrough ss) of CSL300 12) Area under the concentration-time curve (AUCO-tau ss) at steady state of CSL300 13) Time of maximum concentration (Tmax, Tmax ss) of CSl300 ;Timepoint(s) of evaluation of this end point: 1) Baseline and up to approximately 7 years 2-7) Up to approximately 7 years 8) Up to 52 weeks 9) Up to approximately 7 years 10-13) Up to 21 days | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Czechia, Czech Republic, France, Germany, Hungary, Korea, Republic of, Mexico, Netherlands, New Zealand, Spain, Sweden, Switzerland, Taiwan, United States
Contacts
Public ContactTrial Registration Coordinator
CSL Behring LLC
Outcome results
None listed