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

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. For eligibility, kidney
biopsy must not be older than 12 months and DSA analysis must be
performed no longer than 6 months prior to the start of Screening.
NOTE: • Within 3 months prior to the start of Screening, treatments for
ABMR or TCMR, with the exception of steroids*, are not allowed (see
Exclusion Criterion 3).
• If treatment for ABMR (including CABMR) or TCMR (other than
steroids*) was given between 3 to 12 months of Screening, a repeat
kidney biopsy and DSA analysis are required at least 6 weeks after the
end of treatment to confirm continuing CABMR and presence of HLA DSA
and to determine eligibility.
* A maximum dose of 2g of methylprednisolone intravenously (or dose
equivalent of other steroids), followed by a taper to the original
maintenance steroid dose is allowed.
The following histopathologic and serologic diagnostic criteria (based on
Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:
a. Morphologic evidence of chronic tissue injury, as demonstrated by
transplant glomerulopathy (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.
b. Evidence of current/recent antibody interaction with vascular
endothelium, including 1 or more of the following:
i. Linear C4d staining in peritubular capillaries or medullary vasa recta
(Banff scores C4d2 or C4d3 by immunofluorescence on frozen sections,
or C4d > 0 by immunohistochemistry on paraffin sections).
ii. At least moderate microvascular inflammation (glomerulitis score, [g]
+ peritubular capillaritis score [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.
c. Serologic evidence of circulating HLA DSA.
NOTE: The local laboratory DSA results must be reviewed and confirmed
by the central HLA reviewer during the screening period.
4. Written informed consent obtained from subject (or legally acceptable
representative) before any trial-related procedures.

11.A8 Subject is unable or unwilling to comply with study procedures in the
opinion of
the Investigator.
2.A6 Multi-organ transplant recipient (except for simultaneous kidney-pancreas
or
previous multiple kidney transplants) or cell transplant (islet, bone marrow,
stem
cell) recipient.
3. Treatment for ABMR (including CABMR) or TCMR within 3 months prior to
the start of Screening with the exception of steroids.
4. Received T cell depleting agents (eg, alemtuzumab, anti-thymocyte globulin)
within 3 months prior to the start of Screening.
5. Treatment with mTOR inhibitors within 4 weeks prior to the start of Screening
(see Section 7.6.1).
6.A8 Biopsy indicating predominant cause of renal dysfunction caused by
pathology
other than CABMR, within 12 months (± 3 weeks) of Screening.
7.A8 Impaired renal function due to disorders in the transplanted allograft
(eg, renal
artery stenosis, significant vascular disease of the donor, hydronephrosis).
8. eGFR < 25 mL/min/1.73 m2 or > 65 mL/min/1.73 m2 (MDRD4).
9.A8 Nephrotic range proteinuria defined as spot urine albumin-to-creatinine
ratio
(UACR) >= 2200 mg/g (>= 248.4 mg/mmol). If spot UACR is above the defined
limits, a single repeat test can be performed on a separate day to confirm
ineligibility.
10. Pregnant, breastfeeding, or unwillingness to practice adequate
contraception (eg,
a highly effective or acceptable method of contraception) during the study and
for 5 months after the last dose of IP.
11. History of anaphylaxis or known hypersensitivity to clazakizumab or to any
constituent of the drug product.
12.A8 Abnormal liver function tests (LFTs [alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) or bilirubin > 1.5 x upper limit of normal]) or
other significant liver disease. Subjects with an established diagnosis of
Gilbert*s
syndrome are allowed.
13.A8 Active tuberculosis (TB) or history of active TB.
14.A8 History of latent TB (eg, positive QuantiFERON-TB test) without history of
active TB unless the subject has completed a documented 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.A8 Known EBV mismatch (at time of transplant): donor seropositive, recipient
seronegative. Seroconversion to EBV IgG-positive post-transplant is allowed, if
documented.
19.A8 History of gastrointestinal (GI) perforation; diverticular disease
defined as
clinically significant diverticulosis (except if disease has been fully excised
and
the subject has recovered from surgery) or diverticulitis (except if disease has
been fully excised and the subject has recovered from surgery); or inflammatory
bowel disease (except fully excised ulcerative colitis and the subject has
recovered from surgery).
20.A8 Neutropenia (< 1500/mm3) or thrombocytopenia (< 75,000/mm3).
21. Active infections requiring systemic antimicrobial agents and unresolved
prior to
Screening.
22.A8 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, etc.
23.A8 Active viral infections such as BKV, CMV, or EBV based on plasma
polymerase chain reaction (PCR) testing. Active infection is defined as a test
result >= lower limit of quantification (LLOQ) (see definition in Table 6).
24. Current or recent (within 3 months) participation in an interventional
trial.
25. Administration of a live vaccine within 6 weeks prior to the start of
Screening,
including but not limited to the following:
a. Adenovirus.
b. Measles, mumps, and rubella.
c. Oral polio.
d. Oral typhoid.
e. Rotavirus.
f. Varicella zoster.
g. Yellow fever.
26.A8 History of alcohol or illicit substance (including marijuana) abuse < 5
years
before Screening.
27.A8 Present or previous (within 3 years) malignancy except for basal cell
carcinoma,
fully excised squamous cell carcinoma of the skin; other malignancies or those
that required significant therapy may require longer duration documented
cancerfree
(5 years) such as nonrecurrent cervical carcinoma in-situ or malignancy
treated with resection and chemotherapy. These cases should be discussed with
the Medical Monitor and Sponsor on a case-by-case basis.
28. The presence of a condition or abnormality (ie, clinically significant
endocrine,
autoimmune, metabolic, neurological, psychiatric / psychological, renal, GI,
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 subject or the quality of
the data.
29History of intolerance to trimethoprim and / or sulfamethoxazole. This
criterion
does not apply if the subject is already taking another suitable
Investigatorapproved
alternative therapy for PJP prophylaxis, or if the subject is willing to
begin taking a suitable Investigator-approved alternative prophylactic therapy
at
least 1 week prior to the Day 1 Baseline Visit (Visit 2).
30. Prior exposure to clazakizumab, TCZ, 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 prior to the start of Screening) exposure to
proteasome
inhibitors (eg, bortezomib).
34.A8 Active infection with coronavirus disease 2019 (COVID-19):
a. Subject not known to have been previously infected with COVID-19 must
have a negative PCR test result during the Screening Period as near to the
Day 1 Baseline Visit (Visit 2) as possible. If the subject is unwell with
symptoms suggestive of COVID-19 but PCR test result is negative, other
causes for symptoms must be ruled out to determine subject eligibility.
Note: If the subject was not previously known to have been infected with
COVID-19 and has a positive PCR test result at Screening, criterion 34.A8b
must be met.
b. Subject known to have been previously infected with COVID-19 must meet
all the following conditions:
i. Must be without symptoms attributable to COVID-19 for at least
1 month prior tothe start of Screening.
ii. Must be re-established on background immunosuppressants for at least
2 weeks prior to the start of Screening.
35.A8 For subjects receiving anti-hypertensive agents (eg, ACEIs or ARBs), the
dose
of the agent should be stable for at least 2 months prior to the start of
Screening
and not planned to be increased.