Elderly Patients, Immunosuppression, Renal Transplant Recipients
Conditions
Brief summary
Open label, randomized, multicenter, intervention trial comparing standard immunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen in combination with everolimus. The primary objective is to test the hypothesis that an age-adapted immunosuppressive regimen targeted at reduced immunosuppression with low calcineurin inhibitor (tacrolimus) exposure in combination with everolimus will result in improved outcome in elderly recipients of A: Kidneys from older deceased donors (\>64 years) and B: Kidneys from living donors (all ages) and younger deceased donors (\<65 years).
Detailed description
In this study two immunosuppressive regimes will be tested; In both groups basiliximab induction will be applied. Additionally, the standard therapy consisting of prednisolone, mycophenolic acid and tacrolimus once-daily (Envarsus®), or the comparator in which mycophenolic acid will be replaced by everolimus combined with strongly reduced levels of tacrolimus once-daily (Envarsus®). When not tolerated,tacrolimus may be replaced by ciclosporin. The hypothesis is that reduced calcineurin inhibitor (CNI) exposure in combination with everolimus will lead to improved allograft function, a reduced incidence of complications and improved quality of life. This study will consist of two strata: Stratum A: Elderly recipients (≥65 years) of kidneys from elderly deceased donors (≥65 years) within the Eurotransplant Senior Program. Stratum B: Elderly recipients (≥65 years) of kidneys from living donors (all ages) or deceased donors (\<65 years). The primary endpoint will be successful transplantation which is defined as survival with a functioning allograft with a minimum estimated GFR of 30 ml/min per 1.73 m2 in stratum A and 45 ml/min per 1.73 m2 in stratum B, after 2 years. The study will be performed by the Dutch transplant centers and the Dutch Kidney Patient Organization (NVN) will participate.
Interventions
DRUGlow dose tacrolimus in combination with everolimus
a low exposure Tacrolimus once-daily (Envarsus®) regimen in combination with Everolimus will be evaluated in elderly transplant recipients
DRUGstandard dose tacrolimus with mycophenolate mofetil
A standard Tacrolimus once-daily (Envarsus) regimen in combination with Everolimus will be evaluated in elderly transplant recipients
Sponsors
Radboud University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Amsterdam UMC, location VUmc
UMC Utrecht
Leiden University Medical Center
Erasmus Medical Center
Universitaire Ziekenhuizen KU Leuven
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed 2. Male or female subject ≥65 years old 3. Subject randomized within 24 hours of completion of transplant surgery 4. Stratum A: Recipient of a primary (or secondary, if first graft is not lost due to immunological reasons) renal transplant from a deceased donor aged 65 years or older 5. Stratum B: Recipient of a primary (or secondary, if first graft is not lost due to immunological reasons) renal transplant from a deceased donor aged below 65 years or a living donor of any age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| successful transplantation | 24 months | The overall primary study endpoint successful transplantation as defined for the individual strata and analyzed for the whole study population. Stratum A: Primary endpoint: successful transplantation at two years after transplantation defined as: absence of graft or patient loss in the presence of an eGFR above 30 ml/min/1.73m2. Stratum B: Primary endpoint: successful transplantation at two years after transplantation defined as absence of graft or patient loss in the presence of an eGFR above 45 ml/min/1.73m2 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| death | 24 months | patient survival |
| graft loss | 24 months | graft survival |
| acute rejection | 24 months | treated biopsy-proven rejection (tBPAR) |
| eGFR | 12 and 24 months | estimated Glomerular Filtration Rate below 30 and 45 ml/min/1.73m2 |
| type of rejection treatment | 24 months | type of rejection treatment will be scored by questionnaire to the treating nephrologist |
| The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis | 24 months | The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis |
| The incidence of adverse events, serious adverse events and adverse reactions | 24 months | The incidence of adverse events, serious adverse events and adverse reactions |
| The incidence of clinically relevant infections, post transplantation diabetes mellitus, malignancies and cardiovascular events | 24 months | The incidence of clinically relevant infections, post transplantation diabetes, malignancies and cardiovascular events |
| Presence of frailty after transplantation and change in frailty from baseline frailty from baseline | 12 and 24 months | frailty is measured by clinical frailty score, hand grip strength and fried frailty index |
| Physical functioning and changes over time | 24 months | Short Physical Performance Battery |
| Presence of T-cell immunosenescence at 12 and 24 months and changes from baseline | 24 months | T cell differentiation, exhaustion and telomere length will be assessed by flowcytometry |
| HRQoL at 0, 12 and 24 months and changes from baseline | 24 months | Questionnaire: EQ-5D and SF-12 |
| Development of donor-specific anti-HLA antibodies (DSA) | 24 months | DSA as measured by Luminex |
| Difference in illness perception at 0, 12 and 24 months and changes from baseline | 24 months | Questionnaire: Brief Illness Perception Questionnaire |
| Difference in adherence of immunosuppressive medication at 12 and 24 months | 24 months | Questionnaire: Basel Assessment of Adherence to Immunosuppressive Medication Scale |
| Difference in symptoms at 0, 12 and 24 months and changes from baseline | 24 months | Questionnaire: Dialysis Symptom Index with additional items from the Modified Transplant Symptom Occurrence and Symptom Distress Scale-59 |
| Difference in iBOX predicted outcome at 3, 5 and 7 years | 24 months | Based on the available data |
| Development of a pharmacokinetic model for tacrolimus once-daily (Envarsus®), using data on AUC's | 24 months | In addition to trough levels, additional AUC's will be withdrawn at the Leiden University Medical Center as routine patient care on week 2 and 6. |
| o evaluate the response to the COIVD-19 vaccine and identify possible differences between both treatment groups at the University Medical Center Groningen. | 24 months | Humoral and T-cell response |
| Cognitive functioning and changes over time | 24 months | Montreal Cognitive Assessment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Cost-effectiveness of the new immunosuppressive regimen, and comparison to the current standard of care | 24 months | Cost-effectiveness of the immunosuppressive regimen will be evaluated using state-of-the-art health-economic techniques; costs and effectiveness of immunosuppressive therapy will be derived from the study |
Countries
Belgium, Netherlands
Outcome results
None listed