E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Antibody-mediated rejection of a kidney transplant |
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E.1.1.1 | Medical condition in easily understood language |
Patients who received a kidney transplantation and the transplant is now rejected. The rejection is mediated by specific antibodies. This needs to be established in blood and biopsy investigations. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate safety and tolerability of Interleukin-6 blockade by clazakizumab in kidney transplant recipients on baseline immunosuppresion. |
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E.2.2 | Secondary objectives of the trial |
- To investigate the pharmacokinetics and pharmacodynamics of clazakizumab
- To investigate the effects of IL-6 blockade on Antibody-mediated rejection (ABMR) biomarkers: Donor specific antigen mean fluorescence intensity, serum markers of inflammation and endothelial injury
- To investigate the effects of IL-6 blockade on biopsy results, microcirculation, inflammation, chronic injury and gene expression
- To investigate the effects of IL-6 blockade on kidney function parameters (eGFR, urinary protein, cytokine measurements)
- To investigate the effects of IL-6 blockade on cytochrome dependent drug metabolism
- To investigate the effects of IL-6 blockade on leukocyte subpopulations
- To investigate the effects of IL-6 blockade on Torque Teno Viremia |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Voluntary written informed consent
- Age >18 years
- functioning living or deceased donor allograft >365 days post-transplantation
- eGFR>30ml/min/1.73m2
- 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 |
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E.4 | Principal exclusion criteria |
- active participation in another clinical trial
- age <18 years
- female subject is pregnant or lactating
- index biopsy results:
*T-cell medated rejection classified BANFF grade ≥ I
*de novo or recurrent severe thrombotic microangiopathy
*Polyoma virus nephropathy
* de novo or recurrrent glomerulonephritis
- acute rejection treatment <3 months before screening
- acute deterioration of graft function (eGFR decline within 1-3 months >25%)
- nephrotic range proteinuria >3500mg/g protein/creatinine ratio
- Active vrial, bacterial or fungal infection precluding intensified immunosuppression
- Active malignant disease precluding intensified immunosuppression
- Abnormal liver function tests (ALT, AST, bilirubin >1.5x upper limit of normal)
- Other significant liver disease
- latent or active tuberculosis (positive QuantiFERON- TB GOD 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
- history of alcohol or illicit substance abuse
- serious medical or psychiatric illness likely to interfere with participation in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Safety and Tolerability of Clazakizumab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Weeks 12
Part B: Week 52 |
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E.5.2 | Secondary end point(s) |
- PK of clazakizumab (every visit; measurement of anti-Claza antibodies included) and of pantoprazole (0, 12, 52 weeks)
- PD of clazakizumab (CRP suppression) (every visit)
- Cytokines patterns and endothelial activation/injury markers in serum (0, 12, 52 weeks)
- Effect on leukocyte subsets in peripheral blood
- Effect on IL-6 and IL-6R gene expression in peripheral blood cells
- HLA antibody levels (0, 12, 52 weeks)
Maximum and sum of mean fluorescence intensity (MFI) of DSA
Number of DSA
Broadness of sensitization (virtual PRA)
- Total Ig classes (IgG, IgA, IgM) and IgG subclasses (IgG1, 2, 3, 4)
- Protocol biopsy results at 11 and 51 weeks
ABMR category
Microcirculation inflammation (g+ptc score)
Transplant glomerulopathy (cg) and interstitial fibrosis/tubular atrophy (IFTA) scores
Molecular ABMR score (molecular microscope, MMDx)
Archetype analysis of gene expression profiles (molecular microscope, MMDx)
- eGFR (every visit)
- Protein excretion (protein/creatinine ratio) (every visit)
- 1-year graft and patient survival
- Occurrence of biopsy-proven acute rejection necessitating rejection treatment (52 weeks)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 0, 12 and 52 (as applicable for each study part) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of Study Visit of Last Patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |