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Antibody-mediated RejectionPhase 2NCT03444103

A Pilot Trial of Clazakizumab in Late ABMR

A Phase 2 study testing Clazakizumab / Clazakizumab in people with Antibody-mediated Rejection, run by Medical University of Vienna at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 100 years
Conditions the study is for
Antibody-mediated Rejection
What is being tested?
Clazakizumab / Clazakizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
20 participants
Where
2 sitesin 2 countries
Study dates
16 Jan 2018to 30 Jun 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 22Show fewer
  • 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

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

Austria1 site
  • Medical University of Vienna

    Vienna, 1090

Other trials in Austria

Germany1 site
  • Charité University

    Berlin, 10117

Other trials in Germany

About this study

Official title: 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.

Read the 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.

Being tested
Clazakizumab / Clazakizumab, Placebo / Clazakizumab
Keywords
IL-6 blockade

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Clazakizumab / ClazakizumabDrug

    Also called Anti-IL-6 antibody

    Humanized monoclonal anti-IL-6 antibody

  • Placebo / ClazakizumabDrug

    Also called Saline

    0.9% Saline

Study groups in NCT03444103
Study groupRoleWhat they receive
Clazakizumab / ClazakizumabActive comparatorMonthly subcutaneous injections of 25mg clazakizumab for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Receives: Drug: Clazakizumab / Clazakizumab
Placebo / ClazakizumabPlacebo comparatorMonthly subcutaneous injections of placebo (saline) for three months (after completion of part A, monthly injection of 25mg clazakizumab for nine months).
Receives: Drug: Placebo / Clazakizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of adverse events and severe adverse events (AE's, SAE's)

    Serious and Non-Serious adverse events probably or possibly attributable to clazakizumab

    Measured: 12 months

Secondary outcomes (26)
  1. Anti-clazakizumab antibodies in serum

    • Concentration of anti-clazakizumab antibodies in serum (ng/mL)

    Measured: At 0, 12 and 52 weeks

  2. Clazakizumab serum concentration

    • Total clazakizumab serum concentration (ng/mL)

    Measured: At 0, 12 and 52 weeks

  3. Pantoprazole serum concentration

    • Effect of clazakizumab on pantoprazole serum concentration (nanogram per mL)

    Measured: At 0, 12 and 52 weeks

  4. Protocol biopsy results - microcirculation inflammation

    • Microcirculation inflammation (g+ptc score), scale 0-3, higher = worse prognosis

    Measured: At week 11 and at week 52

  5. Protocol biopsy results - chronic damage

    • Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores, scale 0-3, higher = worse prognosis

    Measured: At week 11 and at week 52

  6. Protocol biopsy results - molecular signs of ABMR

    • Molecular ABMR score (molecular microscope, MMDx), scale 0-1 in 0.1 steps, higher = worse prognosis

    Measured: At week 11 and at week 52

  7. 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

    Measured: At week 11 and at week 52

  8. Anti-HLA antibody levels - antibody strength

    • Maximum and sum of mean fluorescence intensity (MFI) of DSA (Luminex) - higher is worse

    Measured: At 0, 12 and 52 weeks

  9. Anti-HLA antibody levels - number of DSA

    • Number of DSA (Luminex) - more is worse

    Measured: At 0, 12 and 52 weeks

  10. Anti-HLA antibody levels - broadness of antibody reactivity

    • Broadness of sensitization (virtual PRA, Luminex), scale: %, higher = worse

    Measured: At 0, 12 and 52 weeks

  11. Allograft function - eGFR

    • Estimated GFR (CKD-EPI, mL/min/1.73m2)

    Measured: 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

  12. Allograft function - protein excretion in spot urine

    • Urinary protein excretion in spot urine (protein/creatinine ratio in mg/g)

    Measured: 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

  13. Total IgG concentration

    • Nephelometry, mg/dL

    Measured: At 0, 12 and 52 weeks

  14. Total IgM concentration

    • Nephelometry, mg/dL

    Measured: At 0, 12 and 52 weeks

  15. Total IgA concentration

    • Nephelometry, mg/dL

    Measured: At 0, 12 and 52 weeks

  16. IgG subclass 1 (IgG1)

    • ELISA, mg/dL

    Measured: At 0, 12 and 52 weeks

  17. IgG subclass 2 (IgG2)

    • ELISA, mg/dL

    Measured: At 0, 12 and 52 weeks

  18. IgG subclass 3 (IgG3)

    • ELISA, mg/dL

    Measured: At 0, 12 and 52 weeks

  19. IgG subclass 4 (IgG4)

    • ELISA, mg/dL

    Measured: At 0, 12 and 52 weeks

  20. Effect on leukocyte subsets in peripheral blood

    • Fluorescence intensity (0 to no upper limit)

    Measured: At 0, 12 and 52 weeks

  21. Cytokine patterns and endothelial activation/injury markers in serum

    • Luminex bead panels, mean fluorescence intensities (MFI)

    Measured: At 0, 12 and 52 weeks

  22. Effect on IL-6 gene expression in peripheral blood cells

    rtPCR

    Measured: At 0, 12 and 52 weeks

  23. Effect on IL-6R gene expression in peripheral blood cells

    rtPCR

    Measured: At 0, 12 and 52 weeks

  24. Patient survival

    Death: number of events, time to event

    Measured: 12 months

  25. Graft survival

    Graft loss: number of events, time to event

    Measured: 12 months

  26. Occurrence of biopsy-proven acute rejection necessitating rejection treatment

    Number of anti-rejection treatments with a substance other than the study drug

    Measured: At week 52

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Feb 2018
  2. Study start16 Jan 2018
  3. Primary completion30 Jun 2020
  4. Study completion30 Jun 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03444103
Sponsor's protocol ID
EK1428/2017
Other IDs
2017-001604-30, 2017
Status last verified
Sep 2020
First submitted
16 Jan 2018
Last updated
9 Sep 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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.

    PubMed 27059799
  • 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.

    PubMed 28199785
  • 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.

    PubMed 29242250
  • 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.

    PubMed 36382130
  • 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.

    PubMed 34153143
  • 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.

    PubMed 30635033

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Clazakizumab / Clazakizumab in people with Antibody-mediated Rejection, run by Medical University of Vienna at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Austria, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of adverse events and severe adverse events (AE's, SAE's) (time frame: 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03444103, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2020.

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