Study to Evaluate the Efficacy and Safety of Treatment with the Investigational Drug Clazakizumab Compared to a Placebo (Inactive Substance) in Recipients of Kidney Transplants with Chronic Active Antibody-Mediated Rejection (CABMR)
Summary description of the study
The aim of this study is to investigate the efficacy and safety of treatment with Clazakizumab compared to a placebo (inactive substance) in recipients of kidney transplants with CABMR. The study investigates whether Clazakizumab can slow or prevent the loss of function of the transplanted kidney and prolong the time before patients need to return to dialysis or receive a new kidney. Clazakizumab or the placebo will be administered subcutaneously (injections under the skin) every 4 weeks. The study will consist of the following treatment periods: - The screening procedure lasts up to 6 weeks. The screening visit consists of an assessment to determine if patients meet all eligibility criteria for participation in the study. - The treatment duration is up to 260 weeks, with patients receiving a subcutaneous injection (either Clazakizumab 12.5 mg / ml or placebo 1 ml) every 4 weeks. - The follow-up period is up to 5 months after the last dose of the investigational product. The maximum study duration for an individual patient is approximately 5.5 years.
(BASEC)
Intervention under investigation
Patients will be randomly assigned to receive either:
Clazakizumab 12.5 mg / ml SC injection once every 4 weeks for up to 260 weeks or until loss of the allograft or death
or
- Placebo-1-ml SC injection every 4 weeks up to 260 weeks or until loss of the allograft or death
- Patients must also receive prophylactic treatment (oral Trimethoprim / Sulfamethoxazole 80 mg as Trimethoprim daily or 160 mg as Trimethoprim x 3 per week) for PJP (Pneumocystis jiroveci pneumonia) from the screening date until week 52 inclusive. Alternative prophylactic PJP therapy at screening may remain at the discretion of the investigator or if the current therapy is not appropriate, Trimethoprim / Sulfamethoxazole should be started at least 1 week prior to V2. For the remainder of the study (> week 52), PJP prophylaxis should be continued at the discretion of the investigator.
(BASEC)
Disease under investigation
Treatment of chronic active antibody-mediated rejection in kidney transplant patients
(BASEC)
1. Age 18-70 years 2. Recipients of living donor / deceased donor kidney transplants ≥ 6 months from the date of transplantation 3. Diagnosis of CABMR (according to the diagnostic criteria of Banff 2015) (BASEC)
Exclusion criteria
1. eGFR <25 mL/min/1.73 m2 or >65 mL/min/1.73 m2 (MDRD4) 2. History of gastrointestinal perforations, diverticular disease or diverticulitis or inflammatory bowel disease 3. Active infections requiring systemic antimicrobial agents and unresolved before screening (BASEC)
Trial sites
Bern, Zurich
(BASEC)
Sponsor
CSL Behring LLC (CSLB) 1020 First Avenue, King of Prussia PA 19406 USA CSL Behring AG, Wankdorfstrasse 10, 3014 Bern, Switzerland
(BASEC)
Contact
Contact Person Switzerland
Prof. Dr. Thomas Müller
+41 44 255 27 75
Thomas.Mueller@clutterusz.chUniversitätsSpital Zürich
(BASEC)
Name of the authorising ethics committee (for multicentre studies, only the lead committee)
Ethics Committee Zurich
(BASEC)
Date of authorisation
03.12.2019
(BASEC)
ICTRP Trial ID
NCT03744910 (ICTRP)
Official title (approved by ethics committee)
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 (BASEC)
Academic 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 (ICTRP)
Public title
Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients (ICTRP)
Disease under investigation
Antibody-mediated Rejection (ICTRP)
Intervention under investigation
Biological: Clazakizumab;Drug: Physiologic saline solution (ICTRP)
Type of trial
Interventional (ICTRP)
Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor). (ICTRP)
Inclusion/Exclusion 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.
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.
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.
- Linear C4d staining in peritubular capillaries or medullary vasa recta (C4d2
or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by
immunohistochemistry on paraffin sections).
- At least moderate microvascular inflammation ([g + 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.
4. 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.
- 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.
(ICTRP)
not available
Primary and secondary end points
Time to all-cause composite allograft loss (ICTRP)
Incidence and time to loss of allograft function as defined by a 40% decline in eGFR from Baseline;Incidence and time to all-cause composite allograft loss;Incidence and time to death-censored allograft loss;Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT);Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT;Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT;Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT;Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pretreatment to posttreatment (Week 52) kidney biopsies;Overall patient survival;Maximum concentration (Cmax, Cmax ss) of CSL300;Trough concentrations (Ctrough, Ctrough ss) of CSL300;Area under the concentration-time curve (AUC0-tau) at steady state of CSL300;Time of maximum concentration (Tmax, Tmax ss) of CSL300 (ICTRP)
Registration date
06.11.2018 (ICTRP)
Incorporation of the first participant
14.10.2019 (ICTRP)
Secondary sponsors
ICON Clinical Research (ICTRP)
Additional contacts
Study Director;Trial Registration Coordinator, clinicaltrials@cslbehring.com, 610-878-4000, CSL Behring, (ICTRP)
Secondary trial IDs
2018-003682-34, VKTX01, CSL300_3001 (ICTRP)
Results-Individual Participant Data (IPD)
not available
Further information on the trial
https://clinicaltrials.gov/show/NCT03744910 (ICTRP)
Results of the trial
Results summary
not available
Link to the results in the primary register
not available