RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients

Phase 4

Active, not recruiting

• Conditions: Renal Transplant Recipients; Elderly Patients; Immunosuppression
• Interventions: Drug: standard dose tacrolimus with mycophenolate mofetil; Drug: low dose tacrolimus in combination with everolimus

• Registration Number: NCT03797196
• Lead Sponsor: University Medical Center Groningen

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2018-12-11
• Study First Submitted QC: 2019-01-04
• Study First Posted: 2019-01-09
• Study Start: 2019-07-29
• Status Verified: 2023-05
• Last Update Submitted: 2023-05-09
• Last Update Posted: 2023-05-10
• Primary Completion: 2025-06
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 374

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
group 1	standard dose tacrolimus with mycophenolate mofetil	standard tacrolimus with mycophenolate mofetil
group 2	low dose tacrolimus in combination with everolimus	low dose tacrolimus with everolimus

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
death	24 months	patient survival
graft loss	24 months	graft survival
eGFR	12 and 24 months	estimated Glomerular Filtration Rate below 30 and 45 ml/min/1.73m2
acute rejection	24 months	treated biopsy-proven rejection (tBPAR)
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
Cognitive functioning and changes over time	24 months	Montreal Cognitive Assessment
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

Trial Locations

Locations (7)

LUMC; 🇳🇱 Leiden, Netherlands

UMCU; 🇳🇱 Utrecht, Netherlands

Leuven University Hospital; 🇧🇪 Leuven, Belgium

UMCG; 🇳🇱 Groningen, Netherlands

Amsterdam UMC; 🇳🇱 Amsterdam, Netherlands

Radboud University Hospital; 🇳🇱 Nijmegen, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Netherlands