E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Late antibody-mediated kidney allograft rejection |
Späte Antikörper-mediierte Nierentransplantat-Abstoßung |
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E.1.1.1 | Medical condition in easily understood language |
Kidney transplant rejection |
Nierentransplantat-Abstoßung |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
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 |
The primary objective of the planned non-commercial investigator-initiated and -driven study is to assess the efficiency of the innovative concept of proteasome inhibition in the treatment of late AMR. Our primary hypothesis is that, by inhibiting alloantibody production bortezomib halts the progression of ongoing graft injury and dysfunction. |
Im Rahmen dieser prospektiven randomisierten kontrollierten (akademischen; nicht kommerziellen) Studie soll erstmals untersucht werden, ob durch eine Therapie mit dem Proteasom-Inhibitor Bortezomib die Progression einer AMR-getriggerten Nierentransplantat-Funktionsstörung aufgehalten werden kann (Teil B; klinische Prüfung). Die Rekrutierung eines Kollektivs von Patienten/Patientinnen mit später AMR soll dabei in einem ersten Teil der Studie (Teil A) im Rahmen eines Vor-Screenings (Antikörper-Screening; bioptisches Screening nach Identifikation zirkulierender DSA) erfolgen. Alternativhypothese: Bortezomib hemmt die Progression einer Nierentransplantat-Dysfunktion im Rahmen einer späten AMR. Nullhypothese: Bortezomib beeinflusst die Progression einer Nierentransplantat-Progression bei später AMR nicht. |
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E.2.2 | Secondary objectives of the trial |
not applicable |
nicht zutreffend |
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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 allograft after ≥180 days eGFR >20 ml/min/1.73 m2 Serological results HLA class I and/or II DSA-positive Index BX results At least one of the following features (with or without C4d in PTC): Glomerulitis – PTCitis - transplant glomerulopathy - PTC BM lamellation
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Freiwillige Einverständnis, Informed Consent Alter >18 Jahre Funktionierendes Transplantat nach ≥180 Tagen eGFR >20 ml/min/1.73 m2 Serologische Resultate HLA Klasse I und/oder II DSA-positiv Index BX Resultate: Zumindest eines der folgenden Features (mit oder ohne C4d in den PTC): Glomerulitis – PTCitis - Transplant Glomerulopathie - PTC BM Lamellierung
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E.4 | Principal exclusion criteria |
Laboratory tests Thrombocytopenia <30 G/l within 2 weeks before enrolment Neutrophil count <1 G/l within 2 weeks before enrolment Clinical evaluation Peripheral neuropathy ≥grade 2 Index BX results Patients actively participating in another clinical trial Female subject is pregnant or lactating* Acute rejection treatment <1 month before screening Acute deterioration of graft function due to suspected acute rejection Active viral, bacterial or fungal infection precluding bortezomib treatment Active malignant disease precluding intensified immunosuppressive therapy Serious medical or psychiatric illness likely to interfere with participation in the study* Documented intolerance of Bortezomib, boron or mannitol T-cell-mediated rejection classified Banff grade >I De novo or recurrent severe thrombotic microangiopathy Polyoma virus nephropathy De novo or recurrent glomerulonephritis in the allograft
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E.5 End points |
E.5.1 | Primary end point(s) |
Course of calculated GFR over 2 years (0, 6, 12, 18, 24 months) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
0, 6, 12, 18, 24 months after randomization |
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E.5.2 | Secondary end point(s) |
HLA antibody levels (0, 6, 12, 18, 24 months) Maximum and sum of MFI of DSA Number of DSA Broadness of sensitization (virtual PRA) Measured GFR (Cr-EDTA method) at 0 and 24 months Protein excretion (protein/creatinine ratio) at 0, 6, 12, 18, and 24 months Graft and patient survival (12 and 24 months after randomization) Occurrence of biopsy-proven acute rejection necessitating rejection treatment Acute AMR score in a protocol BX performed 24 months after randomization Chronic AMR score in a protocol BX performed 24 months after randomization Peripheral blood leukocyte typing (immune cell subpopulations) at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months TTV virus (Anellovirus) load in plasma at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months Markers of complement activation and strength in plasma and urine at 0, 4, 8, 20 weeks, and 6, 12, 18, and 24 months, in relation to a genetic analysis of the C4 gene and genes of other essential complement proteins |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
0-24 months after randomization |
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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 | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
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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This study will be monitored by an independent data and safety monitoring board (DSMB) of the Medical University of Vienna (MUW). An interim analysis will be performed by the DSMB after 10 and 20 cases in the treatment group are completed. The Lan & DeMets extension of the O’Brian-Fleming stopping rules will be applied. The trial will be stopped if the observed p-value are <0.00001 and <0.00305, respectively. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |