A Phase 2 interventional study of Clazakizumab / Clazakizumab and Placebo / Clazakizumab in Antibody-mediated Rejection, sponsored by Medical University of Vienna. Completed at 2 sites in 2 countries. Open to participants aged 18 Years to 100 Years. Per ClinicalTrials.gov, last updated 2020-09-09.
Sponsored by Medical University of Vienna · Phase 2, Interventional, and Treatment
This bi-center study (Medical University of Vienna \& Charité Berlin) is an investigator-driven pilot trial designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy (preliminary assessment) of humanized anti-IL-6 monoclonal antibody clazakizumab in kidney transplant recipients with late antibody-mediated rejection (ABMR). The study is designed as a phase 2 trial and has two subsequent sub-parts, a randomized placebo-controlled trial (part A) of 12 weeks, where recipients are allocated to receive either anti-IL-6 antibody clazakizumab (n=10) or placebo (n=10), followed by an open-label prospective study, where all 20 study patients will receive clazakizumab for a period of 40 weeks. Study protocol biopsies will be performed at the end of part A and part B.
Part A:
Patients positive for anti-HLA donor-specific antibodies (DSA) and with biopsy-proven late ABMR (Acute/active or chronic/active phenotype according to the Banff 2015 classification) will be identified and recruited at the kidney transplantation outpatient services of the two center sites. Participants will be randomized to receive either clazakizumab or placebo subcutaneously (1:1 randomization stratified for ABMR type) for a period of 12 weeks (administration of clazakizumab/placebo at day 0, and after 4 and 8 weeks). After 12 weeks, patients will be subjected to a first follow-up biopsy. Primary goals of this part of the trial are to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a short course of treatment. Moreover, part A will allow for a first preliminary assessment of the impact of clazakizumab on ABMR-associated inflammation detected in peripheral blood and in the rejecting organ allograft, on the pharmacokinetics of pantoprazole as a probe drug to investigate influence of IL-6 blockade on cytochrome P450 (CYP) dependent drug metabolism (potential effects on the half-life of CYP-metabolized drugs such as pantoprazole, and on the short-term course of DSA mean fluorescence intensity (MFI) and kidney allograft function (eGFR, urinary protein excretion). The randomization sequence will be unblinded for a first data analysis after the last patient has completed the 12-week follow-up period.
Part B:
After completion of part A after 12 weeks, all study patients will enter part B, an open-label part of the study. All 20 subjects will receive subcutaneous clazakizumab in 4-weekly intervals until the end-of-study (EOS) visit after 52 weeks and will then be subjected to a second protocol biopsy. Major goals of part B are to evaluate the safety and tolerability of a prolonged period of treatment with clazakizumab and the long-term impact of this antibody on the evolution of ABMR, rejection-associated biomarkers and kidney allograft function and survival over a period of 12 months.
Exclusion Criteria:
Monthly subcutaneous injections of 25mg clazakizumab for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Drug: Clazakizumab / Clazakizumab
Monthly subcutaneous injections of placebo (saline) for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Drug: Placebo / Clazakizumab
Humanized monoclonal anti-IL-6 antibody
Also known as: Anti-IL-6 antibody
0.9% Saline
Also known as: Saline
Number of adverse events and severe adverse events (AE's, SAE's)
Serious and Non-Serious adverse events probably or possibly attributable to clazakizumab
Time frame: 12 months
Anti-clazakizumab antibodies in serum
- Concentration of anti-clazakizumab antibodies in serum (ng/mL)
Time frame: At 0, 12 and 52 weeks
Clazakizumab serum concentration
- Total clazakizumab serum concentration (ng/mL)
Time frame: At 0, 12 and 52 weeks
Pantoprazole serum concentration
- Effect of clazakizumab on pantoprazole serum concentration (nanogram per mL)
Time frame: At 0, 12 and 52 weeks
Protocol biopsy results - microcirculation inflammation
- Microcirculation inflammation (g+ptc score), scale 0-3, higher = worse prognosis
Time frame: At week 11 and at week 52
Protocol biopsy results - chronic damage
- Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores, scale 0-3, higher = worse prognosis
Time frame: At week 11 and at week 52
Protocol biopsy results - molecular signs of ABMR
- Molecular ABMR score (molecular microscope, MMDx), scale 0-1 in 0.1 steps, higher = worse prognosis
Time frame: At week 11 and at week 52
Protocol biopsy results - ABMR phenotype
- Archetype analysis of gene expression profiles (molecular microscope, MMDx), ABMR archetype score, scale 0-1 in 0.1 steps, higher = worse prognosis
Time frame: At week 11 and at week 52
Anti-HLA antibody levels - antibody strength
- Maximum and sum of mean fluorescence intensity (MFI) of DSA (Luminex) - higher is worse
Time frame: At 0, 12 and 52 weeks
Anti-HLA antibody levels - number of DSA
- Number of DSA (Luminex) - more is worse
Time frame: At 0, 12 and 52 weeks
Anti-HLA antibody levels - broadness of antibody reactivity
- Broadness of sensitization (virtual PRA, Luminex), scale: %, higher = worse
Time frame: At 0, 12 and 52 weeks
Allograft function - eGFR
- Estimated GFR (CKD-EPI, mL/min/1.73m2)
Time frame: At day 0, week 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 51 and 52
Allograft function - protein excretion in spot urine
- Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g)
Time frame: At day 0, week 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 51 and 52
Total IgG concentration
- Nephelometry, mg/dL
Time frame: At 0, 12 and 52 weeks
Total IgM concentration
- Nephelometry, mg/dL
Time frame: At 0, 12 and 52 weeks
Total IgA concentration
- Nephelometry, mg/dL
Time frame: At 0, 12 and 52 weeks
IgG subclass 1 (IgG1)
- ELISA, mg/dL
Time frame: At 0, 12 and 52 weeks
IgG subclass 2 (IgG2)
- ELISA, mg/dL
Time frame: At 0, 12 and 52 weeks
IgG subclass 3 (IgG3)
- ELISA, mg/dL
Time frame: At 0, 12 and 52 weeks
IgG subclass 4 (IgG4)
- ELISA, mg/dL
Time frame: At 0, 12 and 52 weeks
Effect on leukocyte subsets in peripheral blood
- Fluorescence intensity (0 to no upper limit)
Time frame: At 0, 12 and 52 weeks
Cytokine patterns and endothelial activation/injury markers in serum
- Luminex bead panels, mean fluorescence intensities (MFI)
Time frame: At 0, 12 and 52 weeks
Effect on IL-6 gene expression in peripheral blood cells
rtPCR
Time frame: At 0, 12 and 52 weeks
Effect on IL-6R gene expression in peripheral blood cells
rtPCR
Time frame: At 0, 12 and 52 weeks
Patient survival
Death: number of events, time to event
Time frame: 12 months
Graft survival
Graft loss: number of events, time to event
Time frame: 12 months
Occurrence of biopsy-proven acute rejection necessitating rejection treatment
Number of anti-rejection treatments with a substance other than the study drug
Time frame: At week 52
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Medical University of Vienna