Interleukin 6 Blockade Modifying Antibody-Mediated Graft Injury and Estimated Glomerular Filtration Rate (eGFR) Decline
This trial investigates whether clazakizumab (an anti-interleukin (IL)-6 monoclonal antibody (mAb)) may be beneficial for the treatment of CABMR in recipients of a kidney transplant by inhibiting the production of Donor Specific Antibodies (DSA) and re-shaping T cell alloimmune responses.
- Antibody-mediated Rejection
- Eligible Ages
- Between 18 Years and 70 Years
- Eligible Genders
- Accepts Healthy Volunteers
Unless specified otherwise, all eligibility criteria time-intervals are assessed with
respect to the screening visit.
1. Age 18-70 years.
2. Living donor/deceased donor kidney transplant recipients ≥6 months from time of
3. Diagnosis of CABMR (according to Banff 2015 diagnostic criteria) to include all of the
- 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 must be performed after halting/completing treatment (to show continuing
4. Written informed consent obtained from subject (or legally acceptable representative)
before any trial-related procedures.
1. Participant is unable or unwilling to comply with study procedures in the opinion of
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
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., polyoma BK virus (BKV) nephropathy, glomerulonephritis).
7. Impaired renal function due to disorders in the transplanted allograft (e.g., renal
artery stenosis, hydronephrosis).
8. eGFR <25 mL/min/1.73 m2 or >65 mL/min/1.73 m2 (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 birth controlor 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
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,
19. History of gastrointestinal perforation, diverticular disease or diverticulitis
(except if disease has been fully excised); or inflammatory bowel disease.
20. Neutropenia (<1,000/mm3) or thrombocytopenia (<50,000/mm3).
21. Active infections requiring systemic antimicrobial agents and unresolved prior to
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
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:
- Measles, mumps, and rubella
- Oral polio
- Oral typhoid
- Varicella zoster
- Yellow fever
26. History of alcohol or illicit substance (including marijuana) abuse.
27. Present or previous (within 3 years) malignancy except for basal cell carcinoma, fully
excised squamous cell carcinoma of the skin, or non-recurrent (within 5 years)
cervical carcinoma in-situ.
28. Presence of a condition or abnormality (i.e., clinically significant endocrine,
autoimmune, metabolic, neurological, psychiatric/psychological, renal,
gastrointestinal, hepatic, and hematological or any other system abnormalities that
are uncontrolled with standard treatment) that in the opinion of the Investigator
would compromise the safety or life expectancy of the patient or the quality of the
29. History of intolerance to trimethoprim and/or sulfamethoxazole. This criterion does
not apply if subject is already taking another suitable Investigator-approved
alternative for PJP prophylaxis, or if subject is willing to begin taking an
Investigator-approved alternative prophylactic therapy at least 1 week prior to the
Day 1 Baseline visit (Visit 2).
30. Prior exposure to clazakizumab, tocilizumab, or other IL-6/IL-6R blockers.
31. ABO-incompatible transplant recipient.
32. Severe hypogammaglobulinemia (defined as immunoglobulin G (IgG) <400 mg/dL).
33. Prior (within 2 years of the start of screening) exposure to proteasome inhibitors
- Phase 3
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
|350 subjects will have a 50/50 chance of being randomly assigned to receive a 12.5 mg subcutaneous (SC) injection once every 4 weeks (Q4W). 175 subjects will be treated with clazakizumab for up to 260 weeks.||
|350 subjects will have a 50/50 chance of being randomly assigned to receive a SC injection of normal saline once every 4 weeks (Q4W). 175 subjects will be treated with normal saline for up to 260 weeks.||
- Vitaeris INC
Study ContactHead Project Management and Clinical Operations
This multi-center, randomized, double-blind, parallel-group, placebo-controlled, Phase 3 trial investigates whether clazakizumab may be beneficial for the treatment of CABMR in kidney transplant recipients by inhibiting the production of DSA and re-shaping T cell alloimmune responses. Subjects will be administered clazakizumab at a target dose of 12.5 mg (or placebo) by SC injection, Q4W for up to 260 weeks (or until graft loss or death). This "event driven" trial has been designed to evaluate the benefits of clazakizumab in prolonging the time to an all-cause composite allograft loss endpoint (primary endpoint) in patients with CABMR.