Ensayos clínicos

Unless specified otherwise, all eligibility criteria time-intervals are assessed with respect to the screening visit.

Inclusion Criteria:

• Age 18 to 70 years.
• Living donor / deceased donor kidney transplant recipients ≥ 6 months from time of transplant.
• Diagnosis of CABMR determined by kidney biopsy and the presence of human leukocyte antigen (HLA) donor specific antibodies (DSA) using single-antigen bead-based assays.
  • NOTE: If conducted within 6 months (+ 3 weeks) of the start of the Screening Period, the biopsy and DSA analysis do not need to be repeated at Screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed and should occur 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, treatments for ABMR or TCMR are not allowed within 3 months of 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 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;
    • Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following.
    • Linear complement component 4d (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 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 (e.g., 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.
  • 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.
• Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.

Exclusion Criteria:

• Participant is unable or unwilling to comply with study procedures in the opinion of the investigator.
• Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.
• Treatment for ABMR (including CABMR) or TCMR within 3 months of the start of Screening.
• Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of Screening.
• Treatment with mTOR inhibitors within 4 weeks of the start of Screening.
• Biopsy indicating predominant cause of renal dysfunction caused by pathology other than CABMR.
• Impaired renal function due to disorders in the transplanted allograft (eg, renal artery stenosis, hydronephrosis).
• eGFR < 25 mL/min/1.73 m^2 or > 65 mL/min/1.73 m^2 (MDRD4).
• Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (UACR) ≥ 2200 mg/g (≥ 220 mg/mmol). If spot UACR is above defined limits, a single repeat test can be performed on a separate day to confirm ineligibility.
• 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 last dose of IP.
• History of anaphylaxis or known hypersensitivity to clazakizumab or to any constituent of the drug product.
• Abnormal liver function tests (LFTs [alanine aminotransferase (ALT) / aspartate aminotransferase (AST) / bilirubin > 1.5 x upper limit of normal]) or other significant liver disease.
• History of active tuberculosis (TB).
• History of latent TB (eg, positive QuantiFERON-TB test) without history of active TB unless subject has completed a full course of prophylactic treatment.
• History of human immunodeficiency virus (HIV) infection or positive for HIV.
• Seropositive for hepatitis B surface antigen (HBsAg).
• Hepatitis C virus (HCV) RNA positive.
• Known EBV mismatch (at time of transplant): donor seropositive, recipient seronegative.
• History of gastrointestinal (GI) perforation; diverticular disease defined as clinically significant diverticulosis (except if disease has been fully excised) or diverticulitis (except if disease has been fully excised); or inflammatory bowel disease (except fully excised ulcerative colitis).
• Neutropenia (< 1000/mm^3 ) or thrombocytopenia (< 50,000/mm^3 ).
• Active infections requiring systemic antimicrobial agents and unresolved prior to Screening.
• 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.
• 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 quantification (LLOQ).
• Current or recent (within 3 months) participation in an interventional trial.
• 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.
• History of alcohol or illicit substance (including marijuana) abuse.
• Present or previous (within 3 years) malignancy except for basal cell carcinoma, fully excised squamous cell carcinoma of the skin, or nonrecurrent (within 5 years) cervical carcinoma in-situ.
• Presence of a condition or abnormality (i.e., 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 patient or the quality of the data.
• 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).
• Prior exposure to clazakizumab, TCZ, or other IL-6 / IL-6R blockers.
• ABO-incompatible transplant recipient.
• Severe hypogammaglobulinemia (defined as immunoglobulin G (IgG) < 400 mg/dL).
• Prior (within 2 years of the start of Screening) exposure to proteasome inhibitors (e.g., bortezomib).
• Active infection with coronavirus disease 2019 (COVID-19):
  • Subject not known to have been previously infected with COVID-19 must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible. If subject is unwell with symptoms suggestive of COVID 19 disease but PCR test is negative, other causes for symptoms must be ruled out to determine subject eligibility;
  • Subject known to have been previously infected with COVID-19 must meet all the following conditions:
  • Must be without symptoms attributable to COVID-19 for at least 1 month before the start of screening and have had 2 consecutive negative PCR tests at least 24 hours apart (either prior to or during screening) to confirm recovery. If the subject has tested negative > 3 months before start of screening, the subject must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible;
  • Must be re-established on background immunosuppressants for at least 2 weeks prior to the start of Screening.