Study Results
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Basic Information
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COMPLETED
PHASE2
20 participants
INTERVENTIONAL
2018-01-16
2020-06-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Clazakizumab / Clazakizumab
Monthly subcutaneous injections of 25mg clazakizumab for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Clazakizumab / Clazakizumab
Humanized monoclonal anti-IL-6 antibody
Placebo / Clazakizumab
Monthly subcutaneous injections of placebo (saline) for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Placebo / Clazakizumab
0.9% Saline
Interventions
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Clazakizumab / Clazakizumab
Humanized monoclonal anti-IL-6 antibody
Placebo / Clazakizumab
0.9% Saline
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
100 Years
ALL
No
Sponsors
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CSL Behring
INDUSTRY
University of Alberta
OTHER
Charite University, Berlin, Germany
OTHER
Medical University of Vienna
OTHER
Responsible Party
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Farsad Eskandary
Principal Investigator
Principal Investigators
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Bernd Jilma, MD
Role: PRINCIPAL_INVESTIGATOR
Department of Clinical Pharmacology, Medical University Vienna
Locations
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Medical University of Vienna
Vienna, , Austria
Charité University
Berlin, , Germany
Countries
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References
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Mease PJ, Gottlieb AB, Berman A, Drescher E, Xing J, Wong R, Banerjee S. The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6 Monoclonal Antibody, in a Phase IIb Study of Adults With Active Psoriatic Arthritis. Arthritis Rheumatol. 2016 Sep;68(9):2163-73. doi: 10.1002/art.39700.
Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, Kim I, Louie S, Kang A, Peng A, Kahwaji J, Reinsmoen N, Toyoda M, Jordan SC. Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients. Am J Transplant. 2017 Sep;17(9):2381-2389. doi: 10.1111/ajt.14228. Epub 2017 Mar 10.
Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, Hidalgo LG, Haslacher H, Kaltenecker CC, Aretin MB, Oberbauer R, Posch M, Staudenherz A, Handisurya A, Reeve J, Halloran PF, Bohmig GA. A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection. J Am Soc Nephrol. 2018 Feb;29(2):591-605. doi: 10.1681/ASN.2017070818. Epub 2017 Dec 14.
Mayer KA, Doberer K, Halloran PF, Budde K, Haindl S, Muhlbacher J, Eskandary F, Viard T, Casas S, Jilma B, Bohmig GA. Anti-interleukin-6 Antibody Clazakizumab in Antibody-mediated Kidney Transplant Rejection: Effect on Donor-derived Cell-free DNA and C-X-C Motif Chemokine Ligand 10. Transplant Direct. 2022 Nov 10;8(12):e1406. doi: 10.1097/TXD.0000000000001406. eCollection 2022 Dec.
Muhlbacher J, Schorgenhofer C, Doberer K, Durr M, Budde K, Eskandary F, Mayer KA, Schranz S, Ely S, Reiter B, Chong E, Adler SH, Jilma B, Bohmig GA. Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism. Transpl Int. 2021 Aug;34(8):1542-1552. doi: 10.1111/tri.13954. Epub 2021 Jul 8.
Eskandary F, Durr M, Budde K, Doberer K, Reindl-Schwaighofer R, Waiser J, Wahrmann M, Regele H, Spittler A, Lachmann N, Firbas C, Muhlbacher J, Bond G, Halloran PF, Chong E, Jilma B, Bohmig GA. Clazakizumab in late antibody-mediated rejection: study protocol of a randomized controlled pilot trial. Trials. 2019 Jan 11;20(1):37. doi: 10.1186/s13063-018-3158-6.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Related Links
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Vienna Transplant and Complement Laboratory (VIETAC) website
Vitaeris website
Other Identifiers
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2017-001604-30
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
EK1428/2017
Identifier Type: -
Identifier Source: org_study_id
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