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A Pilot Trial of Clazakizumab in Late ABMR

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ClinicalTrials.gov Identifier: NCT03444103
Recruitment Status : Recruiting
First Posted : February 23, 2018
Last Update Posted : February 23, 2018
Sponsor:
Collaborators:
Vitaeris INC
University of Alberta
Charite University, Berlin, Germany
Information provided by (Responsible Party):
Farsad Eskandary, Medical University of Vienna

Brief 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.

Condition or disease Intervention/treatment Phase
Antibody-mediated Rejection Drug: Clazakizumab / Clazakizumab Drug: Placebo / Clazakizumab Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Safety, Tolerability and Efficacy of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection After Kidney Transplantation - a Pilot Trial
Actual Study Start Date : January 16, 2018
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Clazakizumab / Clazakizumab
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
Humanized monoclonal anti-IL-6 antibody
Other Name: Anti-IL-6 antibody

Placebo Comparator: Placebo / 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
0.9% Saline
Other Name: Saline




Primary Outcome Measures :
  1. Number of adverse events and severe adverse events (AE's, SAE's) [ Time Frame: 12 months ]
    Serious and Non-Serious adverse events probably or possibly attributable to clazakizumab


Secondary Outcome Measures :
  1. Anti-clazakizumab antibodies in serum [ Time Frame: At 0, 12 and 52 weeks ]
    - Concentration of anti-clazakizumab antibodies in serum (ng/mL)

  2. Clazakizumab serum concentration [ Time Frame: At 0, 12 and 52 weeks ]
    - Total clazakizumab serum concentration (ng/mL)

  3. Pantoprazole serum concentration [ Time Frame: At 0, 12 and 52 weeks ]
    - Effect of clazakizumab on pantoprazole serum concentration (nanogram per mL)

  4. Protocol biopsy results - microcirculation inflammation [ Time Frame: At week 11 and at week 52 ]
    - Microcirculation inflammation (g+ptc score), scale 0-3, higher = worse prognosis

  5. Protocol biopsy results - chronic damage [ Time Frame: At week 11 and at week 52 ]
    - Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores, scale 0-3, higher = worse prognosis

  6. Protocol biopsy results - molecular signs of ABMR [ Time Frame: At week 11 and at week 52 ]
    - Molecular ABMR score (molecular microscope, MMDx), scale 0-1 in 0.1 steps, higher = worse prognosis

  7. Protocol biopsy results - ABMR phenotype [ Time Frame: At week 11 and at week 52 ]
    - Archetype analysis of gene expression profiles (molecular microscope, MMDx), ABMR archetype score, scale 0-1 in 0.1 steps, higher = worse prognosis

  8. Anti-HLA antibody levels - antibody strength [ Time Frame: At 0, 12 and 52 weeks ]
    - Maximum and sum of mean fluorescence intensity (MFI) of DSA (Luminex) - higher is worse

  9. Anti-HLA antibody levels - number of DSA [ Time Frame: At 0, 12 and 52 weeks ]
    - Number of DSA (Luminex) - more is worse

  10. Anti-HLA antibody levels - broadness of antibody reactivity [ Time Frame: At 0, 12 and 52 weeks ]
    - Broadness of sensitization (virtual PRA, Luminex), scale: %, higher = worse

  11. Allograft function - eGFR [ 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 ]
    - Estimated GFR (CKD-EPI, mL/min/1.73m2)

  12. Allograft function - protein excretion in spot urine [ 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 ]
    - Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g)

  13. Total IgG concentration [ Time Frame: At 0, 12 and 52 weeks ]
    - Nephelometry, mg/dL

  14. Total IgM concentration [ Time Frame: At 0, 12 and 52 weeks ]
    - Nephelometry, mg/dL

  15. Total IgA concentration [ Time Frame: At 0, 12 and 52 weeks ]
    - Nephelometry, mg/dL

  16. IgG subclass 1 (IgG1) [ Time Frame: At 0, 12 and 52 weeks ]
    - ELISA, mg/dL

  17. IgG subclass 2 (IgG2) [ Time Frame: At 0, 12 and 52 weeks ]
    - ELISA, mg/dL

  18. IgG subclass 3 (IgG3) [ Time Frame: At 0, 12 and 52 weeks ]
    - ELISA, mg/dL

  19. IgG subclass 4 (IgG4) [ Time Frame: At 0, 12 and 52 weeks ]
    - ELISA, mg/dL

  20. Effect on leukocyte subsets in peripheral blood [ Time Frame: At 0, 12 and 52 weeks ]
    - Fluorescence intensity (0 to no upper limit)

  21. Cytokine patterns and endothelial activation/injury markers in serum [ Time Frame: At 0, 12 and 52 weeks ]
    - Luminex bead panels, mean fluorescence intensities (MFI)

  22. Effect on IL-6 gene expression in peripheral blood cells [ Time Frame: At 0, 12 and 52 weeks ]
    rtPCR

  23. Effect on IL-6R gene expression in peripheral blood cells [ Time Frame: At 0, 12 and 52 weeks ]
    rtPCR

  24. Patient survival [ Time Frame: 12 months ]
    Death: number of events, time to event

  25. Graft survival [ Time Frame: 12 months ]
    Graft loss: number of events, time to event

  26. Occurrence of biopsy-proven acute rejection necessitating rejection treatment [ Time Frame: At week 52 ]
    Number of anti-rejection treatments with a substance other than the study drug



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Voluntary written informed consent
  • Age >18 years
  • Functioning living or deceased donor allograft after ≥365 days post-transplantation
  • eGFR >30 ml/min/1.73 m2
  • Detection of HLA class I and/or II antigen-specific antibodies (preformed and/or de novo DSA).
  • Acute/active or chronic/active ABMR (±C4d in PTC) according to Banff 2013/2015
  • Molecular ABMR score (ABMRpm) ≥0.2

Exclusion Criteria:

  • Patients actively participating in another clinical trial
  • Age ≤18 years
  • Female subject is pregnant or lactating
  • Index biopsy results:
  • T-cell-mediated rejection classified Banff grade ≥I
  • De novo or recurrent severe thrombotic microangiopathy
  • Polyoma virus nephropathy
  • De novo or recurrent glomerulonephritis
  • Acute rejection treatment <3 month before screening
  • Acute deterioration of graft function (eGFR decline within 1-3 months >25%)
  • Nephrotic range proteinuria >3500 mg/g protein/creatinine ratio
  • Active viral, bacterial or fungal infection precluding intensified immunosuppression
  • Active malignant disease precluding intensified immunosuppressive therapy
  • Abnormal liver function tests (ALT, AST, bilirubin > 1.5 x upper limit of normal)
  • Other significant liver disease
  • Latent or active tuberculosis (positive QuantiFERON-TB-Gold test, Chest X-ray)
  • Administration of a live vaccine within 6 weeks of screening
  • Neutropenia (<1 G/L) or thrombocytopenia (<100 G/L)
  • History of gastrointestinal perforation, diverticulitis, or inflammatory bowel disease
  • Allergy against proton pump inhibitors
  • History of alcohol or illicit substance abuse
  • Serious medical or psychiatric illness likely to interfere with participation in the study

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 ClinicalTrials.gov identifier (NCT number): NCT03444103


Contacts
Contact: Farsad A Eskandary, MD +43140400 ext 43630 farsad.eskandary@meduniwien.ac.at
Contact: Georg A Böhmig, MD +43140400 ext 43630 georg.boehmig@meduniwien.ac.at

Locations
Austria
Medical University of Vienna Recruiting
Vienna, Austria, 1090
Contact: Farsad A Eskandary, MD    +43140400 ext 43630    farsad.eskandary@meduniwien.ac.at   
Contact: Georg A Böhmig, MD    +43140400 ext 43630    georg.boehmig@meduniwien.ac.at   
Sub-Investigator: Markus Wahrmann, PhD         
Principal Investigator: Georg Böhmig, MD         
Principal Investigator: Farsad Eskandary, MD         
Principal Investigator: Bernd Jilma, MD         
Sub-Investigator: Gregor Bond, MDPhD         
Sub-Investigator: Jakob Mühlbacher, MD         
Sub-Investigator: Heinz Regele, MD         
Germany
Charité University Not yet recruiting
Berlin, Germany, 10117
Contact: Klemens Budde, MD    +4930450514 ext 002    klemens.budde@charite.de   
Contact: Michael Dürr, MD    +4930450614 ext 244    michael.duerr@charite.de   
Sub-Investigator: Johannes Waiser, MD         
Sub-Investigator: Nils Lachmann, MD         
Sponsors and Collaborators
Medical University of Vienna
Vitaeris INC
University of Alberta
Charite University, Berlin, Germany
Investigators
Principal Investigator: Bernd Jilma, MD Department of Clinical Pharmacology, Medical University Vienna
  Study Documents (Full-Text)

Documents provided by Farsad Eskandary, Medical University of Vienna:

Additional Information:
Publications:
Responsible Party: Farsad Eskandary, Principal Investigator, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT03444103     History of Changes
Other Study ID Numbers: EK1428/2017
2017-001604-30 ( EudraCT Number )
First Posted: February 23, 2018    Key Record Dates
Last Update Posted: February 23, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Farsad Eskandary, Medical University of Vienna:
IL-6 blockade

Additional relevant MeSH terms:
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs