E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute cellular rejection after kidney transplantation |
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E.1.1.1 | Medical condition in easily understood language |
Canakinumab in acute allograft rejection for the regression of the infiltrate |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023439 |
E.1.2 | Term | Kidney transplant rejection |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 |
We want to demonstrate that treatment with canakinumab in patients with histological evidence of acute T-cell-mediated rejection after kidney transplantation leads to a regression of the infiltrates in the graft biopsy. |
Es soll nachgewiesen werden, dass eine Behandlung mit Canakinumab bei Patienten mit histologischem Nachweis einer akuten T-Zell-vermittelten Rejektion nach Nierentransplantation zu einer Rückbildung der Infiltrate in der Transplantatbiopsie führt. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1 Male or female patients aged at least 18 years at the time of study inclusion
2 Kidney transplant within the last 14 months
3 Evidence of acute cellular tubulointerstitial rejection in kidney transplant according to Banff criteria (grade IA or IB ), which has been detected in a protocol or indication biopsy, without evidence of more than 20 CD20-positive B cells per high power field in the infiltrate and without evidence glomerulitis or capillaritis
4 C4d and SV40 negativity in the biopsy
5 eGFR ≥ 30 ml/min/1,73 m2 calculated by MDRD formula before diagnosis of rejection
6 In female patients of childbearing potential existence of a negative pregnancy test and consent to a highly effective method of contraception (Pearl Index < 1, i.e., hormonal implants, injectables, oral combination contraceptives, hormonal intrauterine devices, history of two-sided sterilization or oophorectomy, vasectomy of the partner, sexual abstinence, exclusively female sexual partners)
7 In male patients consent to a highly effective method of contraception (Pearl Index < 1, i.e., history of vasectomy, sexual abstinence, only male sexual partners; hormonal implants, injectables, oral combination contraceptives, hormonal intrauterine devices, history of sterilization or bilateral oophorectomy of the female partner with childbearing potential)
8 Written consent |
1. männliche oder weibliche Patienten im Alter von mindestens 18 Jahren zum Zeitpunkt des Studieneinschlusses
2. Nierentransplantation innerhalb der letzten 14 Monate
3. Nachweis einer akuten zellulären tubulointerstitiellen Rejektion im Nierentransplantat nach Banff-Kriterien (Grad IA oder IB), die im Rahmen einer Protokoll- oder Indikationsbiopsie entdeckt wird, ohne Nachweis von mehr als 20 CD20-positiven B-Zellen pro Gesichtsfeld im Infiltrat und ohne Nachweis einer Glomerulitis oder Kapillaritis
4. C4d- und SV40-Negativität in der Biopsie
5. eGFR nach der MDRD-Formel ≥ 30 ml/min/1,73 m2 vor Diagnose der Rejektion
6. Bei Patientinnen im gebärfähigen Alter Vorliegen eines negativen Schwangerschaftstests und Einverständnis zu einer hoch effektiven Methode der Kontrazeption (Pearl-Index < 1, d.h. Implantate, Injektionspräparate, kombinierte orale Kontrazeptiva, hormonelle Intrauterinpessare, Z.n. beidseitiger Sterilisation oder Ovarektomie, Vasektomie des Partners, sexuelle Abstinenz, ausschließlich weibliche Sexualpartnerinnen)
7. Bei männlichen Patienten Einverständnis zu einer hoch effektiven Methode der Kontrazeption (Pearl-Index < 1, d.h. Z.n. Vasektomie, sexuelle Abstinenz, ausschließlich männliche Sexualpartner; Implantate, Injektionspräparate, kombinierte orale Kontrazeptiva, hormonelle Intrauterinpessare, Z.n. beidseitiger Sterilisation oder Ovarektomie der Partnerin)
8. Schriftliche Einverständniserklärung.
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E.4 | Principal exclusion criteria |
1 Known contraindications or intolerance of canakinumab or concomitant medication
2 Administration of canakinumab within 14 months of study entry
3 Administration of another biologicals (eg, rituximab or basiliximab) or of a TNF-alpha blocker within the last 4 weeks prior to study entry
4 Simultaneous participation in another clinical trial
5 Body weight < 40 kg
6 Pregnant or lactating women
7 People who are not in a position to understand nature, significance and implications of the clinical study and to identify and align their will hereafter (pursuant to § 40 para 4 and § 41 para 2 and para 3 AMG)
8 Presence of CMV infection, HIV infection, replicative hepatitis B or hepatitis C, other serious infections, or a high risk for TB
9 Patients with previously known neutropenia (< 1.5/nl)
10 Heart failure NYHA stage III-IV
11 High-grade arrhythmias (eg ventricular tachycardia, symptomatic bradycardia , other hemodynamically significant arrhythmias )
12 Unstable coronary artery disease
13 History of splenectomy
14 Contraindication regarding a re-biopsy of the allograft (eg, coagulopathy, anticoagulation)
15 Presence of malignoma
16 Seronegativity (IgG) for EBV and VZV
17 Other exclusion criteria after assessment of the treating physician (eg, deterioration of general condition, derailed metabolic situation, high risk, such as AB0-incompatible kidney transplantation) |
1. Bekannte Gegenanzeigen bzw. Unverträglichkeit für Canakinumab bzw. für die Begleitmedikation
2. Gabe von Canakinumab innerhalb von 14 Monaten vor Studieneinschluss
3. Gabe eines anderen Biologicals (z.B. Rituximab oder Basiliximab) oder eines TNF-alpha-Blockers innerhalb der letzten 4 Wochen vor Studieneinschluss
4. Gleichzeitige Teilnahme an einer anderen klinischen Prüfung.
5. Körpergewicht < 40 kg
6. Stillende Frauen oder Schwangere
7. Personen, die nicht in der Lage sind, Wesen, Bedeutung und Tragweite der klinischen Prüfung zu erkennen und ihren Willen hiernach auszurichten (gemäß § 40 Abs. 4 und § 41 Abs. 2 und Abs. 3 AMG)
8. Vorliegen eines CMV-Infekts, Vorliegen einer HIV-Infektion, Vorliegen einer replikativen Hepatitis B oder Hepatitis C, Vorliegen sonstiger schwerer Infektionen, Vorliegen eines hohen Risikos für eine TBC
9. Patienten mit vorbekannter Neutropenie (< 1,5/nl)
10. Herzinsuffizienz im Stadium NYHA III-IV
11. Höhergradige Herzrhythmusstörungen (z.B. ventrikuläre Tachykardien, symptomatische Bradykardien, andere hämodynamisch relevante Arrhythmien)
12. Instabile koronare Herzkrankheit
13. Z.n. Splenektomie
14. Kontraindikation bzgl. einer erneuten Transplantatbiopsie (z.B. Gerinnungsstörung, Antikoagulation)
15. Vorliegen einer malignen Erkrankung
16. Sero-Negativität (IgG) für EBV und für VZV
17. Andere Ausschlusskriterien nach Einschätzung des behandelnden Arztes (z.B. Verschlechterung des Allgemeinzustands, entgleiste Stoffwechselsituation, hohes Risiko wie AB0-inkompatible Nierentransplantation)
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E.5 End points |
E.5.1 | Primary end point(s) |
Regression of the infiltrate in the graft biopsy 14 days after treatment with canakinumab, i.e., rejection according to Banff criteria is no longer detectable. |
Rückbildung des Infiltrats in der Transplantatbiopsie 14 Tage nach Behandlung mit Canakinumab, so dass keine Rejektion nach Banff-Kriterien mehr nachweisbar ist. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
14 days after treatment with study drug. |
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E.5.2 | Secondary end point(s) |
1 Delta eGFR using the change in serum creatinine between the time of diagnosis of rejection and 14 and 28 days after treatment with canakinumab, as well as in relation to the baseline eGFR, which was present before the rejection .
2 Proportion of patients with stable graft function based on serum creatinine (stage I) and with improvement of graft function after 14-28 days based on serum creatinine (stage II) .
3 Proportion of patients with persistent rejection, graft loss, severe infection or death within the follow-up period of 1 year after administration of study drug
4 Differentially expressed genes in the first biopsy with rejection diagnosis versus the second biopsy after 14 days (intraindividual comparison) as well as comparison of patients with regression of the infiltrates in the second biopsy after 14 days versus lack of regression using microarray RNA analysis
5 Serum and urine biomarkers (eg proteomics), that are associated with acute rejection, at the time of diagnosis of rejection compared to 14 days after treatment (intra-individual comparison) as well as comparison of patients with regression of the infiltrates in the second biopsy after 14 days versus lack of regression. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
14 and 28 days and within the 1 year follow-up period after treatment with study drug. |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
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 | No |
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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The trial is monitored by a committee independent by the investigators |
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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 | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |