RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Open Label Multicenter Randomized Trial Comparing Standard Immunosuppression With Tacrolimus and Mycophenolate Mofetil With a Low Exposure Tacrolimus Regimen in Combination With Everolimus in de Novo Renal Transplantation in Elderly Patient

Conditions
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Renal Transplant Recipients, Elderly Patients, Immunosuppression

Intervention / Treatment
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* Drug: low dose tacrolimus in combination with everolimus
* Drug: standard dose tacrolimus with mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained before any assessment is performed Male or female subject ≥65 years old Subject randomized within 24 hours of completion of transplant surgery 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 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 Exclusion Criteria: Exclusion criteria for both stratum A and B Subject is a multi-organ transplant recipient Recipient of bloodgroup ABO incompatible allograft or CDC cross-match positive transplant Subject at high immunological risk for rejection as determined by local practice for assessment of anti-donor reactivity Recipient of a kidney with a cold ischaemia time (CIT) >24 hr Recipients of a kidney from an HLA-identical related living donor Known intolerability for one or more of the study drugs Subject who is HIV positive HBsAg and/or a HCV positive subject with evidence of elevated liver function tests (ALT/AST levels ≥2.5 times ULN). Viral serology results obtained within 6 months prior to randomization are acceptable Recipient of a kidney from a donor who tests positive for human immunodeficiency virus, (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) Subject with severe systemic infections, current or within the two weeks prior to randomization Subject with severe restrictive or obstructive pulmonary disorders Subject with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled Subject with white blood cell (WBC) count ≤ 2,000/mm3 or with platelet count ≤ 50,000/mm3

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group 1<br>standard tacrolimus with mycophenolate mofetil | Drug: standard dose tacrolimus with mycophenolate mofetil<br>* A standard Tacrolimus once-daily (Envarsus) regimen in combination with Everolimus will be evaluated in elderly transplant recipients<br>|
| Experimental: group 2<br>low dose tacrolimus with everolimus | Drug: low dose tacrolimus in combination with everolimus<br>* a low exposure Tacrolimus once-daily (Envarsus®) regimen in combination with Everolimus will be evaluated in elderly transplant recipients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| successful transplantation | 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 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| death | patient survival | 24 months | 
| graft loss | graft survival | 24 months | 
| acute rejection | treated biopsy-proven rejection (tBPAR) | 24 months | 
| eGFR | estimated Glomerular Filtration Rate below 30 and 45 ml/min/1.73m2 | 12 and 24 months | 
| type of rejection treatment | type of rejection treatment will be scored by questionnaire to the treating nephrologist | 24 months | 
| The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis | The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis | 24 months | 
| The incidence of adverse events, serious adverse events and adverse reactions | The incidence of adverse events, serious adverse events and adverse reactions | 24 months | 
| The incidence of clinically relevant infections, post transplantation diabetes mellitus, malignancies and cardiovascular events | The incidence of clinically relevant infections, post transplantation diabetes, malignancies and cardiovascular events | 24 months | 
| Presence of frailty after transplantation and change in frailty from baseline frailty from baseline | frailty is measured by clinical frailty score, hand grip strength and fried frailty index | 12 and 24 months | 
| Physical functioning and changes over time | Short Physical Performance Battery | 24 months | 
| Cognitive functioning and changes over time | Montreal Cognitive Assessment | 24 months | 
| Presence of T-cell immunosenescence at 12 and 24 months and changes from baseline | T cell differentiation, exhaustion and telomere length will be assessed by flowcytometry | 24 months | 
| HRQoL at 0, 12 and 24 months and changes from baseline | Questionnaire: EQ-5D and SF-12 | 24 months | 
| Development of donor-specific anti-HLA antibodies (DSA) | DSA as measured by Luminex | 24 months | 
| Difference in illness perception at 0, 12 and 24 months and changes from baseline | Questionnaire: Brief Illness Perception Questionnaire | 24 months | 
| Difference in adherence of immunosuppressive medication at 12 and 24 months | Questionnaire: Basel Assessment of Adherence to Immunosuppressive Medication Scale | 24 months | 
| Difference in symptoms at 0, 12 and 24 months and changes from baseline | Questionnaire: Dialysis Symptom Index with additional items from the Modified Transplant Symptom Occurrence and Symptom Distress Scale-59 | 24 months | 
| Difference in iBOX predicted outcome at 3, 5 and 7 years | Based on the available data | 24 months | 
| Development of a pharmacokinetic model for tacrolimus once-daily (Envarsus®), using data on AUC's | 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. | 24 months | 
| o evaluate the response to the COIVD-19 vaccine and identify possible differences between both treatment groups at the University Medical Center Groningen. | Humoral and T-cell response | 24 months |