| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Immunosuppression after kidney transplantion in elderly patients ≥65 years of age |
| In dieser Studie wird die Immunsuppression bei älteren Nierentransplantierten ≥ 65 Jahre untersucht. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Immunosuppression after kidney transplantion in elderly patients ≥65 years of age |
| In dieser Studie wird die Immunsuppression bei älteren Nierentransplantierten ≥ 65 Jahre untersucht. |
|
| E.1.1.2 | Therapeutic area | Not possible to specify |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062016 |
| E.1.2 | Term | Immunosuppression |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054990 |
| E.1.2 | Term | Immunodeficiency secondary to organ transplantation |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10074474 |
| E.1.2 | Term | Transplantation complications |
| E.1.2 | System Organ Class | 100000004863 |
|
| 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 establish efficacy and safety of a reduced immunosuppressive therapy with tacrolimus once daily for senior (>65 years of age) renal transplant recipients.
Main objective:
Non-inferiority of a reduced immunosuppressive therapy compared to standard therapy regarding a combined efficacy endpoint (BPAR, graft loss and death) between randomization (at month 3 post-transplant) and month 12 post-transplant |
Die Studie dient zur Untersuchung der Effektivität und Sicherheit einer reduzierten Immunsuppression bei älteren Nierentransplantierten ≥65 Jahre.
Hauptziel der Studie:
Nicht-Unterlegenheit eines reduzierten immunsuppressiven Therapieschemas im Vergleich zur Standardtherapie bezogen auf einen kombinierten Effektivitätsendpunkt (BPAR, Transplantatversagen, Tod) von Randomisierung (Monat 3 nach Transplantation) bis Monat 12 nach Transplantation.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
- Incidence and time of graft loss
- Incidence and time of death
- Incidence and time of biopsy proven rejection
- Evaluation infections: opportunistic (CMV, BKV), severe infections between study groups
- Evaluation of kidney function by estimation of eGFR (CKD-EPI) between study Groups
- Evaluation of hospitalisations
- Evaluation of HLA antibody development and donor specific antibody (DSA) development
- Evaluation of adverse and severe adverse events
- Evaluation of post transplant Diabetes mellitus
- Evaluation of laboratory result bundles (blood counts, etc.)
- Evaluation of concomittant medication
- Evaluation of quality of life measures
- Assessment of Frailty |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Protocol chapter 4.1.1.
Inclusion criteria
1. Males or females, aged ≥65 years and participating in the European SENIOR transplant registry
2. Patients who received a renal allograft 3 – 3.5 months prior to randomization.
3. Patient must have received primary or secondary renal allograft from a blood group compatible donor
4. Standard criteria donors (SCD), expanded criteria donors (ECD), donors after cardiac death (DCD) and living donors (LD) are eligible
5. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained
6. Patients on continuous standard triple therapy with tacrolimus once daily (Advagraf®, trough level ≥5ng/ml) in combination with mycophenolate (either ≥1.0g/day MMF or ≥720mg/d EC-MPS) and steroids (≥5mg prednisolone or equivalent) since transplantation
7. Stable graft function with serum creatinine ≤2.5 mg/dl.
8. Patients with low to standard immunological risk, who had a PRA below 20% or 20% and no known donor specific antibodies (DSA) at transplantation
|
|
| E.4 | Principal exclusion criteria |
Protocol chapter 4.1.2. Exclusion criteria
1. Patient with mental dysfunction or inability to comply with the study protocol
2. Patients, who - according to the investigator - require for medical reasons (e.g. previous rejections) continuous triple therapy or a different tacrolimus exposure
3. Multi-organ recipients (other solid organ (e.g. pancreas) or bone marrow)
4. Blood group ABO-incompatible allografts
5. Patients who suffered from severe T-cell mediated rejection (at least Banff II acute rejection), recurrent acute rejection (>1 episode), or steroid resistant rejection post-transplant
6. History of antibody-mediated rejection (acute or chronic)
7. History of rejection 2 months prior to inclusion
8. Documented presence of donor specific antibodies (DSA) according to local lab results at baseline
9. Panel reactive antibody (PRA) >20% prior to transplantation, measured according to local standard
10. Patients receiving or having received Sirolimus, Everolimus, Azathioprine, Belatacept or Cyclophosphamide within 3 months prior to enrolment
11. Patients having received any other induction therapy than Basiliximab (e.g. depleting polyclonal antithymocyte antibodies (ATG), OKT3, Alemtuzumab)
12. Patients with proteinuria >1.0 g/day (or >1.0 g/g creatinine) at screening or having experienced nephrotic syndrome due to recurrence of focal segmental glomerulosclerosis (FSGS)
13. History of alcohol or drug abuse with less than 6 months of sobriety
14. Patient with a known hereditary immunodeficiency
15. Patient with active malignancy posttransplant with the exception of local, non-invasive, fully excised, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma in situ
16. Patients with clinically symptomatic congestive heart failure or symptomatic coronary artery disease
17. Patients with documented (either by serology and/or nuclear acid testing (NAT) clinically active infections (e.g. with a known Hepatitis B, Hepatitis C, HIV, CMV or BK virus infection). Patients who do not have been screened in the previous 6 months, should be screened to confirm seronegativity before enrolment.
18. Participation in any other investigational clinical trial 3 months before participation in this study, except the SENIOR transplant registry
19. Patients with leukopenia (<2500 cells/mcl) or neutropenia (<1500 cells/mcl)
20. Patients with thrombocytopenia (<100 cells/nl)
21. Patients with liver transaminases or bilirubin values > 3x normal values
22. Any significant diseases or clinically significant findings, including psychiatric and behavioural problems, medical history and/or physical examination findings that would in the opinion of the investigator preclude the patient from participating in the study.
23. Patients who have been institutionalized by official or court order
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Combined efficacy endpoint (BPAR, graft loss and death) between randomization (month 3 post-transpant) and month 12 posttransplant |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Month 12 after transplantation. |
|
| E.5.2 | Secondary end point(s) |
- Severe after randomization
- Opportunistic infections after randomization, in particular
- CMV Infection and CMV Viremia
- BK Nephropathy and BK Viremia
- Combined endpoint CMV and BK Viremia
- Difference in renal function as estimated by the CKD-EPI [34], determined between treatment groups at month 6, 9 and 12 posttransplant.
- Hospitalisations, hospitalisations for infections and hospitalisations for opportunistic infections (as confirmed by the investigator) after randomization
- Time to efficacy failure (defined as any patient experiencing death, graft failure, BPAR) after randomization
- Incidence and time of BPAR and/or graft loss, of graft loss and/or death, graft loss alone, death alone
- Incidence and time to BPAR (Banff grade of at least IA) and Borderline rejection(s) after randomization according to BANFF classes 2013
- Incidence and time to clinically suspected and treated rejection episodes (treated acute rejection despite the absence of confirmatory evidence on a biopsy) and to steroid-resistant rejections, recurrent rejections, antibody-treated rejections and antibody-mediated acute rejection after randomization
- Proportion of severity grades of the first episode of BPAR (Banff grade) occurring after randomization
- Development of circulating anti-HLA-antibodies, non HLA-antibodies and/or de novo donor specific antibodies (DSA)
- Change of renal function (according to CKD-EPI formula) from randomization to month 12 after transplantation.
- Comparison of the GFR-slope between randomization and month 12 (according to CKD-EPI-formula) between groups
- Incidence of patients with different stages of chronic kidney disease (CKD) according to CKD-EPI formula and with suboptimal GFR (<60ml/min, <45ml/min and <30 ml/min according to CKD-EPI formula)
- Comparison of the incidence of patients with improved renal function compared to baseline at randomization
- Differences between treatment groups after randomization with respect to the incidence of adverse events (AEs), serious Adverse events (SAEs), predefined AEs, vital signs and potentially clinically significant laboratory measures
- Incidence of any malignancy and infection after randomization
- Differences of hospitalisation days between treatment groups after randomization and in hospitalisation days due to infections and opportunistic infections (as confirmed by the investigator) between treatment groups after randomization
- Incidence and time to premature discontinuation of randomly assigned treatment (as confirmed by the investigator) for any reason
- Comparison of reasons for treatment discontinuation or treatment changes (as confirmed by the investigator)
- Incidence of posttransplant diabetes (PTDM) at month 12 as defined by need for any antidiabetic agent (oral or insulin) and/or HbA1c >48 mmol/mol (>6,5%) in a patient with no prior medical history of diabetes before transplantation and of posttransplant hyperglycemia within 9 months after randomization as defined by a fasting plasma glucose ≥126 mg/dL, and/or afternoon capillary glucose ≥200mg/dl with or without insulin requirement or need for an oral antidiabetic agent in a patient with no prior medical history of diabetes
- Incidences of Hb1Ac elevation a) >42 mmol/mol (>6.0%), b) >48 mmol/mol (>6,5%) and c) >53 mmol/mol (>7.0% ) at month 12 post transplantation
- Differences in the parameters of glucose control including HbA1c and blood lipids (total Cholesterol, LDL, HDL, Trigylcrides)
- Difference in blood pressure and blood pressure medication
- Difference in cardiovascular events defined as any cardiac event, stroke or peripheral vascular disease including invasive therapeutic cardiovascular interventions after randomization
- Difference in cardiovascular risk as estimated by the cardiovascular risk calculator for renal transplant recipients[35]
- Difference in the incidence of anemia as reported as adverse events, or the use of erythropoietin stimulating agents, or haemoglobin value <10g/dl after randomization and at month 12 posttransplant
- Difference in the use of erythropoietin stimulating agents after randomization and at month 12 posttransplant
- Incidence of patients with a low haemoglobin <10.0g/dl, or <11g/dl at month 12 after transplantation
- Difference in leucocyte and neutrophil counts at 12 months after transplantation
- Difference in the incidence of leucopenia (<3,5/nl) and neutropenia (<1,5/nl) and the use of colony stimulating factors after randomization and of patients with a leucopenia <4,0/nl, <3,0/nl or <2,5/nl after randomization
- IgG levels
- Incidence of Bone disease and/ fractures as confirmed by the investigator, differences in height between groups
- Assessment of frailty
- Evaluation and comparison of quality of life (as assessed by PROMIS Profile 29 questionnaire) and medical symptom burden (as assessed by MTSODS questionnaire) between groups at month 3 and 12 posttransplant
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Month 12 after transplantation |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Combination of tacrolimus (Advagraf), mycophenolate, steroids |
|
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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
|
| LVLS - The study ends when the last data element is available from the last subject to complete the month 12 visit. |
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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 | 4 |
| 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 | 4 |
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