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.
Brief Title
Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients
Completion Date
Completion Date Type
Actual
Conditions
Antibody-mediated Rejection
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.
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.
Inclusion 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.
*
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.
*
Gender
All
Gender Based
false
Keywords
Chronic Active
Antibody-mediated Rejection (AMR)
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
75 Years
Minimum Age
18 Years
NCT Id
NCT03744910
Org Class
Industry
Org Full Name
CSL Behring
Org Study Id
CSL300_3001
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
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.
* 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.
Outcome Measure
Time to composite all-cause allograft loss or irreversible loss of allograft function
Outcome Time Frame
Up to approximately 8 years
Secondary Ids
Secondary Id
2018-003682-34
Secondary Id
VKTX01
Secondary Outcomes
Outcome Time Frame
Baseline and up to approximately 8 years
Outcome Measure
Time to composite all-cause allograft loss
Outcome Time Frame
Baseline and up to approximately 8 years
Outcome Measure
Incidence and time to irreversible loss of allograft function
Outcome Time Frame
Up to approximately 8 years
Outcome Measure
Incidence of composite all-cause allograft loss or irreversible loss of allograft function
Outcome Time Frame
Up to approximately 8 years
Outcome Measure
Incidence and time to death-censored allograft loss
Outcome Time Frame
Baseline and up to approximately 8 years
Outcome Measure
Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT)
Outcome Time Frame
Baseline and up to approximately 8 years
Outcome Measure
Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT
Outcome Time Frame
Baseline and up to approximately 8 years
Outcome Measure
Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT
Outcome Time Frame
Up to 52 weeks
Outcome Measure
Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post-treatment (Week 52) kidney biopsies
Outcome Time Frame
Baseline and up to 8 years
Outcome Measure
Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT
Outcome Time Frame
Up to approximately 8 years
Outcome Measure
Overall patient survival
Outcome Time Frame
Up to 21 days
Outcome Measure
Maximum concentration (Cmax, Cmax ss) of CSL300
Outcome Time Frame
Up to 21 days
Outcome Measure
Trough concentrations (Ctrough, Ctrough ss) of CSL300
Outcome Time Frame
Up to 21 days
Outcome Measure
Area under the concentration-time curve (AUC0-tau) at steady state of CSL300
Outcome Time Frame
Up to 21 days
Outcome Measure
Time of maximum concentration (Tmax, Tmax ss) of CSL300
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
75
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Enver Akalin
Investigator Email
eakalin@montefiore.org
Investigator Phone
718-920-4815