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

Phase 3

Terminated

Conditions: Antibody-mediated Rejection

Interventions: Biological: Clazakizumab
Drug: Physiologic saline solution

Registration Number: NCT03744910

Lead Sponsor: CSL Behring

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 194

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Clazakizumab	Clazakizumab	Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6 that is administered subcutaneously.
Placebo	Physiologic saline solution	Physiologic saline solution that is administered subcutaneously.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Week 52 in Estimated Glomerular Filtration Rate (eGFR)	From Baseline to Week 52	This primary outcome measure was the one from the first interim analysis.
Number of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function	From Baseline to 4 years	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.
Percentage of Participants With Composite All-cause Allograft Loss or Irreversible Loss of Allograft Function	From Baseline to 4 years	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.
Number of Participants With Positive Anti-drug Antibodies	Baseline, Weeks 12, 24, and 48
Percentage of Participants With Positive Anti-drug Antibodies	Baseline, Weeks 12, 24, and 48
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and Adverse Events of Special Interest (AESIs)	Up to 4 years
Percentage of Participants With TEAEs, Serious TEAEs, and AESIs	Up to 4 years
Number of Participants Who Tested Positive for Polyoma BK Virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV)	From baseline up to 4 years	Number of participants who tested positive for BKV, CMV or EBV according to the maximum measured viral amount (International Units/mL \[IU/mL\]) after baseline are reported here.
Number of Participants With Abnormal Laboratory Test Results	Up to 4 years	Laboratory tests included liver function test (LFTs), complete blood count (CBC), plasma lipids, high-sensitivity C-reactive protein (hsCRP). Only participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase.
Percentage of Participants With Abnormal Laboratory Test Results	Up to 4 years	Laboratory tests included LFTs, CBC, plasma lipids, hsCRP. Only percentage of participants with abnormal laboratory test results are reported here. Here, ULN = upper limit of normal, LLN = lower limit of normal, ALT = Alanine aminotransferase and AST = Aspartate aminotransferase.
Number of Participants With Clinically Significant Change in Vital Signs, Electrocardiograms (ECGs), and Physical Examination	Up to 4 years

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Irreversible Loss of Allograft Function	From Baseline to 4 years	Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days.
Number of Participants With Composite All-cause Allograft Loss	From Baseline to 4 years	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.
Percentage of Participants With Composite All-cause Allograft Loss	From Baseline to 4 years	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.
Percentage of Participants With Irreversible Loss of Allograft Function	From Baseline to 4 years	Irreversible loss of allograft function as defined by a 40% decline in eGFR from Baseline sustained for at least 60 days.
Number of Participants With Death-censored Allograft Loss	From Baseline to 4 years	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.
Percentage of Participants With Death-censored Allograft Loss	From Baseline to 4 years	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.
Change From Baseline in Urine Albumin Creatinine Ratio (UACR)	From Baseline to Week 52
Percent Change From Baseline in Mean Fluorescent Intensity for Donor-Specific Antibodies (DSA)	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	From Baseline to Week 52	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.
Incidence of Acute Rejection Episodes of T Cell-mediated Rejection (TCMR) and Antibody-mediated Rejection (ABMR)	Baseline up to End of treatment (up to approximately 4 years)	Number of participants who had at least one acute rejection episode (TCMR or ABMR) are reported for this outcome measure.
Overall Participant Survival	Up to Week 52	Number of participants who were alive up to Week 52 are reported for this outcome measure.
Maximum Concentration at Steady State (Cmax ss) of CSL300	Up to Week 24	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.
Trough Concentrations at Steady State (Ctrough ss) of CSL300	Up to Week 24	A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study.
Area Under the Concentration-time Curve (AUC0-tau) at Steady State of CSL300	Up to Week 24	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 of Maximum Concentration at Steady State (Tmax ss) of CSL300	Up to Week 24	A subset of participants (out of the enrolled participants in the main study) had the option to participate in a PK/PD sub-study.

Trial Locations

Locations (138): 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
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University of Alabama at Birmingham (UAB) - University of Alabama Hospital (UAB Hospital)
🇺🇸Birmingham, Alabama, United States