A Pilot Trial of Clazakizumab in Late ABMR

Study Overview
=================
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.

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.

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

Conditions
-----------------
Antibody-mediated Rejection

Intervention / Treatment
-----------------
* Drug: Clazakizumab / Clazakizumab
* Drug: Placebo / Clazakizumab


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clazakizumab / Clazakizumab<br>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<br>* Humanized monoclonal anti-IL-6 antibody<br>* Other names: Anti-IL-6 antibody;|
| Placebo Comparator: Placebo / Clazakizumab<br>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<br>* 0.9% Saline<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
IL-6 blockade