Chronic Active Antibody-Mediated Rejection (CABMR) in Kidney Transplant Recipients
Conditions
Interventions
Product Name: Clazakizumab 12.5 mg/mL
Pharmaceutical Form: Solution for injection
INN or Proposed INN: CLAZAKIZUMAB
CAS Number: 1236278-28-6
Other descriptive name: CLAZAKIZUMAB
Concentration unit: mg
Sponsors
Vitaeris Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age 18-70 years. 2. Living donor/deceased donor kidney transplant recipients =6 months from time of transplant. 3. Diagnosis of CABMR (according to Banff 2015 diagnostic criteria) to include all of the following: • Biopsy-proven CABMR (i.e., chronic glomerulopathy (cg) >0) with/without C4d staining. Repeat biopsy to be performed if previous biopsy is not within 6 months (+3 weeks) of the start of the screening period. The local pathologist’s diagnosis will be reviewed by a central pathologist to confirm eligibility for entry into the study. Subjects without evidence of chronic tissue injury on light microscopy but who have glomerular basement membrane double contours on electron microscopy (cg1a) are eligible. • Positive for human leukocyte antigen (HLA) DSA (using single-antigen bead-based assays) post-transplant. Local laboratory DSA results will be reviewed by the central HLA reviewer to confirm eligibility for entry into the study. If presence of HLA DSA is confirmed within 6 months (+3 weeks) of the start of the screening period, the test does not need to be repeated for eligibility. • Note: Treatments for ABMR (including CABMR) or TCMR are not allowed within 3 months of the start of screening (see Exclusion Criterion 3). If a subject has received one of these treatments at any time prior, a repeat biopsy and repeat DSA test must be performed after halting / completing treatment (to show continuing CABMR). At least 2 months ± 2 weeks should elapse from the end of treatment before the repeat biopsy and DSA test can be performed. 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. Participant is unable or unwilling to comply with study procedures in the opinion of the Investigator. 2. Multi-organ transplant recipient or cell transplant (islet, bone marrow, stem cell) recipient. Note: recipients of multiple previous kidney transplants are allowed. 3. Treatment for ABMR (including CABMR) or TCMR within 3 months of the start of screening. 4. Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of screening. 5. Treatment with mTOR inhibitors within 4 weeks of the start of screening. 6. Biopsy showing pure TCMR or advanced interstitial fibrosis (ci3), advanced tubular atrophy (ct3), vascular fibrous intimal thickening (cv3) or other significant causes of renal dysfunction (e.g., BK virus (BKV) nephropathy, glomerulonephritis). 7. Impaired renal function due to disorders in the transplanted allograft (e.g., renal artery stenosis, hydronephrosis). 8. eGFR 65 mL/min/1.73 m^2 (MDRD4). 9. Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (UACR) =2,200 mg/g (=220 mg/mmol). If spot UACR is above defined limits, repeat test on separate day to confirm ineligibility (or collect 24-hour urine to confirm nephrotic range proteinuria (=3.0 g/day)). 10. Pregnant, breastfeeding, or unwillingness to practice adequate contraception (i.e., a highly effective or acceptable method of contraception) during the study and for 5 months after last dose of investigational drug. 11. History of anaphylaxis or known hypersensitivity to clazakizumab or to any constituent of the drug product. 12. Abnormal liver function tests (LFTs) (alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/bilirubin >1.5 x upper limit of normal) or other significant liver disease. 13. History of active tuberculosis (TB). 14. History of latent TB (e.g., positive QuantiFERON-TB test) without history of active TB unless subject has completed a full course of prophylactic treatment. 15. History of human immunodeficiency virus (HIV) infection or positive for HIV. 16. Seropositive for hepatitis B surface antigen (HBsAg). 17. Hepatitis C virus (HCV) RNA positive. 18. Known Epstein-Barr virus (EBV) mismatch (at time of transplant): donor seropositive, recipient seronegative. 19. History of gastrointestinal perforation; diverticular disease or divertikulitis (except if disease has been fully excised); or inflammatory bowel disease (except fully excised ulcerative colitis). 20. Neutropenia (<1,000/mm^3) or thrombocytopenia (<50,000/mm^3). 21. Active infections requiring systemic antimicrobial agents and unresolved prior to screening. 22. History of or current invasive fungal infection or other opportunistic infection, including (but not limited to) the following: a nontuberculous mycobacterial infection, aspergillosis, pneumocystosis, and toxoplasmosis. 23. Active viral infections such as BKV, CMV, or EBV based on polymerase chain reaction (PCR) testing. Active infection is defined as a test result = lower limit of quantification (LLOQ). 24. Current or recent (within 3 months) participation in an interventional trial. 25. Administration of a live vaccine within 6 weeks of the start of screening, including but not limited to the following: • Adenovirus • Measles, mumps, and rubella • Oral polio • Oral typhoid • Rotavirus • Varicella zoster • Yellow fever 26. History of alcohol or illicit substance (including marijuana) abuse. 27.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To evaluate the efficacy of clazakizumab in preventing all-cause composite allograft loss due to CABMR (defined as return to dialysis, allograft nephrectomy, re-transplantation, estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m^2 or death from any cause) (Final Analysis). 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) (Interim Analysis #2 (IA #2)). 3. To evaluate the safety of clazakizumab. ;Secondary Objective: 1. To evaluate the effects of clazakizumab on death-censored allograft loss (defined as return to dialysis, allograft nephrectomy, re-transplantation or eGFR <15 mL/min/1.73 m^2 but excluding death from any cause). 2. To evaluate the effects of clazakizumab on albuminuria. 3. To evaluate the effects of clazakizumab on DSA titers and mean fluorescence intensity (MFI) scores. 4. To evaluate the effects of clazakizumab on incidence of acute rejection episodes (TCMR and ABMR). 5. To evaluate the effects of clazakizumab on the histology of kidney biopsies according to the Banff 2015 lesion grading scores. 6. To evaluate the effects of clazakizumab on overall patient survival. 7. To evaluate the effects of clazakizumab on healthcare utilization due to ABMR and patient reported outcomes including health-related quality of life (HRQoL). ;Primary end point(s): Final Analysis Primary Endpoint: • Time to all-cause composite allograft loss (defined as return to dialysis, allograft nephrectomy, re-transplantation, eGFR <15 mL/min/1.73 m^2 or death from any cause (including death with functioning allograft)). An eGFR <15 mL/min/1.73 m^2 must be confirmed by a repeat measurement taken between 14 to 30 days later. Temporary return to dialysis due to acute kidney injury (AKI) and temporary eGFR decline to <15 mL/min/1.73 m^2 due to AKI are both excluded. ;Timepoint(s) of evaluation of this end poin | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Incidence and time to death-censored allograft loss. • Change in mean eGFR from Baseline to End of Study (EOS). • Change in spot UACR from Baseline to EOS. • Change in DSA titers and MFI scores from Baseline to EOS. • Incidence of acute rejection episodes (TCMR and ABMR) from Baseline to EOS. • Change in Banff lesion grading score (2015 criteria) of pre-treatment to post treatment (Week 52) kidney biopsies. • Overall patient survival. • Healthcare utilization associated with the treatment of ABMR to Week 52 as well as to EOS. • Change in patient reported outcomes (including HRQoL) from Baseline to Week 52 as well as to EOS, using multiple tools. ;Timepoint(s) of evaluation of this end point: From Baseline to Week 52 and / or End of Study (EOS) as detailed above | — |
Countries
Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Hungary, Netherlands, Spain, Switzerland, United States
Contacts
Public ContactRegulatory Affairs
Vitaeris Inc.
Outcome results
None listed