Purpose

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.

Condition

Eligibility

Eligible Ages
Between 18 Years and 70 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


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
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
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. A single
antigen bead MFI >1,000 will be considered positive. If presence of HLA DSA is
confirmed within 6 months 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
CABMR).

4. Written informed consent obtained from subject (or legally acceptable representative)
before any trial-related procedures.

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.

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., 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 highly effective birth control
during the study and for 5 months after last dose of investigational drug.

11. History of anaphylaxis.

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: donor seropositive, recipient seronegative.

19. History of gastrointestinal perforation, diverticular disease or diverticulitis, 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
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.

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. 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
data.

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 exposure to proteasome inhibitors (e.g., bortezomib).

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Active Comparator
Clazakizumab
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.
  • Biological: Clazakizumab
    Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6
Placebo Comparator
Placebo
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.
  • Drug: Normal saline
    Normal saline

Recruiting Locations

Montefiore Medical Center
Bronx, New York 10467
Contact:
Study Coordinator
347-671-8217

More Details

NCT ID
NCT03744910
Status
Recruiting
Sponsor
Vitaeris INC

Study Contact

Head Project Management and Clinical Operations
844-448-2580
chemise.overton@vitaerisbio.com

Detailed Description

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.