A Pilot Trial of Clazakizumab in Late ABMR
Condition: Antibody-mediated Rejection
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Clazakizumab / Clazakizumab; Placebo / Clazakizumab
Intervention type(s): Drug; Drug
Intervention description(s): Humanized monoclonal anti-IL-6 antibody; 0.9% Saline
Other intervention name(s): Anti-IL-6 antibody; Saline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: IL-6 blockade