RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients

Phase 4Active Not RecruitingNCT03797196

University Medical Center Groningen374 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 65 YearsMax age: 99 Years

Medical Language ↔ Plain English

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 Exclusion Criteria: Exclusion criteria for both stratum A and B 1. Subject is a multi-organ transplant recipient 2. Recipient of bloodgroup ABO incompatible allograft or CDC cross-match positive transplant 3. Subject at high immunological risk for rejection as determined by local practice for assessment of anti-donor reactivity 4. Recipient of a kidney with a cold ischaemia time (CIT) \>24 hr 5. Recipients of a kidney from an HLA-identical related living donor 6. Known intolerability for one or more of the study drugs 7. Subject who is HIV positive 8. 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 9. 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) 10. Subject with severe systemic infections, current or within the two weeks prior to randomization 11. Subject with severe restrictive or obstructive pulmonary disorders 12. Subject with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled 13. Subject with white blood cell (WBC) count ≤ 2,000/mm3 or with platelet count ≤ 50,000/mm3

Locations (7)

Leuven University Hospital

Leuven, Belgium

Amsterdam UMC

Amsterdam, Netherlands

UMCG

Groningen, Netherlands

LUMC

Leiden, Netherlands

Radboud University Hospital

Nijmegen, Netherlands

Erasmus MC

Rotterdam, Netherlands

UMCU

Utrecht, Netherlands

Outcomes

Primary Outcomes

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

Time frame: 24 months

Secondary Outcomes

death

patient survival

Time frame: 24 months

graft loss

graft survival

Time frame: 24 months

acute rejection

treated biopsy-proven rejection (tBPAR)

Time frame: 24 months

eGFR

estimated Glomerular Filtration Rate below 30 and 45 ml/min/1.73m2

Time frame: 12 and 24 months

type of rejection treatment

type of rejection treatment will be scored by questionnaire to the treating nephrologist

Time frame: 24 months

The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis

Time frame: 24 months

The incidence of adverse events, serious adverse events and adverse reactions

Time frame: 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

Time frame: 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

Time frame: 12 and 24 months

Physical functioning and changes over time

Short Physical Performance Battery

Time frame: 24 months

Cognitive functioning and changes over time

Montreal Cognitive Assessment

Time frame: 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

Time frame: 24 months

HRQoL at 0, 12 and 24 months and changes from baseline

Questionnaire: EQ-5D and SF-12

Time frame: 24 months

Development of donor-specific anti-HLA antibodies (DSA)

DSA as measured by Luminex

Time frame: 24 months

Difference in illness perception at 0, 12 and 24 months and changes from baseline

Questionnaire: Brief Illness Perception Questionnaire

Time frame: 24 months

Difference in adherence of immunosuppressive medication at 12 and 24 months

Questionnaire: Basel Assessment of Adherence to Immunosuppressive Medication Scale

Time frame: 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

Time frame: 24 months

Difference in iBOX predicted outcome at 3, 5 and 7 years

Based on the available data

Time frame: 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.

Time frame: 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

Time frame: 24 months

RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients

Overview

Conditions

Interventions

Eligibility

Locations (7)

Outcomes

Primary Outcomes

Secondary Outcomes