A Pilot Trial of Clazakizumab in Late ABMR

Safety, Tolerability and Efficacy of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Rejection After Kidney Transplantation - a Pilot Trial

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.

Study Overview

• Status: Completed
• Conditions: Antibody-mediated Rejection
• Intervention / Treatment: Drug: Clazakizumab / Clazakizumab; Drug: Placebo / Clazakizumab

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
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
• Germany
  • Berlin, Germany, 10117
    • Charité University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of adverse events and severe adverse events (AE's, SAE's)	Serious and Non-Serious adverse events probably or possibly attributable to clazakizumab	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-clazakizumab antibodies in serum	- Concentration of anti-clazakizumab antibodies in serum (ng/mL)	At 0, 12 and 52 weeks
Clazakizumab serum concentration	- Total clazakizumab serum concentration (ng/mL)	At 0, 12 and 52 weeks
Pantoprazole serum concentration	- Effect of clazakizumab on pantoprazole serum concentration (nanogram per mL)	At 0, 12 and 52 weeks
Protocol biopsy results - microcirculation inflammation	- Microcirculation inflammation (g+ptc score), scale 0-3, higher = worse prognosis	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	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	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	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	At 0, 12 and 52 weeks
Anti-HLA antibody levels - number of DSA	- Number of DSA (Luminex) - more is worse	At 0, 12 and 52 weeks
Anti-HLA antibody levels - broadness of antibody reactivity	- Broadness of sensitization (virtual PRA, Luminex), scale: %, higher = worse	At 0, 12 and 52 weeks
Allograft function - eGFR	- Estimated GFR (CKD-EPI, mL/min/1.73m2)	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)	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	At 0, 12 and 52 weeks
Total IgM concentration	- Nephelometry, mg/dL	At 0, 12 and 52 weeks
Total IgA concentration	- Nephelometry, mg/dL	At 0, 12 and 52 weeks
IgG subclass 1 (IgG1)	- ELISA, mg/dL	At 0, 12 and 52 weeks
IgG subclass 2 (IgG2)	- ELISA, mg/dL	At 0, 12 and 52 weeks
IgG subclass 3 (IgG3)	- ELISA, mg/dL	At 0, 12 and 52 weeks
IgG subclass 4 (IgG4)	- ELISA, mg/dL	At 0, 12 and 52 weeks
Effect on leukocyte subsets in peripheral blood	- Fluorescence intensity (0 to no upper limit)	At 0, 12 and 52 weeks
Cytokine patterns and endothelial activation/injury markers in serum	- Luminex bead panels, mean fluorescence intensities (MFI)	At 0, 12 and 52 weeks
Effect on IL-6 gene expression in peripheral blood cells	rtPCR	At 0, 12 and 52 weeks
Effect on IL-6R gene expression in peripheral blood cells	rtPCR	At 0, 12 and 52 weeks
Patient survival	Death: number of events, time to event	12 months
Graft survival	Graft loss: number of events, time to event	12 months
Occurrence of biopsy-proven acute rejection necessitating rejection treatment	Number of anti-rejection treatments with a substance other than the study drug	At week 52

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Charite University, Berlin, Germany; University of Alberta; CSL Behring
• Investigators: Principal Investigator: Bernd Jilma, MD, Department of Clinical Pharmacology, Medical University Vienna

Publications and helpful links

General Publications

• 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.

Helpful Links

• Vienna Transplant and Complement Laboratory (VIETAC) website

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 16, 2018
• Primary Completion (ACTUAL): June 30, 2020
• Study Completion (ACTUAL): June 30, 2020

Study Registration Dates

• First Submitted: January 16, 2018
• First Submitted That Met QC Criteria: February 18, 2018
• First Posted (ACTUAL): February 23, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 9, 2020
• Last Update Submitted That Met QC Criteria: September 6, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: IL-6 blockade
• Other Study ID Numbers: EK1428/2017; 2017-001604-30 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No