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Interleukin 6 Blockade Modifying Antibody-Mediated Graft Injury and Estimated Glomerular Filtration Rate (eGFR) Decline (IMAGINE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03744910
Recruitment Status : Not yet recruiting
First Posted : November 19, 2018
Last Update Posted : April 3, 2019
ICON Clinical Research
Information provided by (Responsible Party):
Vitaeris INC

Brief Summary:
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 or disease Intervention/treatment Phase
Antibody-mediated Rejection Biological: Clazakizumab Drug: Normal saline Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : January 2028
Estimated Study Completion Date : April 2028

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Incidence of all cause composite allograft loss [ Time Frame: Five years ]
    The aim of this study is to follow enrolled participants until 221 occurrences of all-cause allograft loss, defined as return to dialysis, allograft nephrectomy, re-transplantation, eGFR <15 mL/min/1.73 m2 or death from any cause have been observed. The analysis will be a stratified log rank test of the effect of treatment on all-cause composite allograft loss, with stratification factors of dichotomized baseline eGFR (25-45 mL/min/1.73 m2 versus >45-65 mL/min/1.73 m2), baseline proteinuria, treatment for early (within 6 months of transplant) ABMR rejection episodes (yes/no), and treatment for late (greater than 6 months post transplant) ABMR rejection episodes (yes/no). Surviving subjects without allograft loss will be censored at the time of their last assessment.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03744910

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Contact: Head Project Management and Clinical Operations 844-448-2580
Contact: Head Regulatory Affairs 844-448-2580

Sponsors and Collaborators
Vitaeris INC
ICON Clinical Research
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Study Chair: Edward Chong, MBChB, MRCP Vitaeris INC

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Responsible Party: Vitaeris INC Identifier: NCT03744910     History of Changes
Other Study ID Numbers: VKTX01
First Posted: November 19, 2018    Key Record Dates
Last Update Posted: April 3, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Vitaeris INC:
Chronic Active
Antibody-mediated Rejection (AMR)

Additional relevant MeSH terms:
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Immunologic Factors
Physiological Effects of Drugs