Clinical trial NCT03797196: RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Renal Transplant Recipients
Elderly Patients
Immunosuppression
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Radboud University Medical Center
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Amsterdam UMC, location VUmc
name: UMC Utrecht
name: Leiden University Medical Center
name: Erasmus Medical Center
name: Universitaire Ziekenhuizen KU Leuven
First posted: 2019-01-09
Enrollment: 374
Sex: ALL
Minimum age (years): 65
Maximum age (years): 99
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: successful transplantation
timeFrame: 24 months
Secondary outcomes:
measure: death
timeFrame: 24 months
measure: graft loss
timeFrame: 24 months
measure: acute rejection
timeFrame: 24 months
measure: eGFR
timeFrame: 12 and 24 months
measure: type of rejection treatment
timeFrame: 24 months
measure: The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis
timeFrame: 24 months
measure: The incidence of adverse events, serious adverse events and adverse reactions
timeFrame: 24 months
measure: The incidence of clinically relevant infections, post transplantation diabetes mellitus, malignancies and cardiovascular events
timeFrame: 24 months
measure: Presence of frailty after transplantation and change in frailty from baseline frailty from baseline
timeFrame: 12 and 24 months
measure: Physical functioning and changes over time
timeFrame: 24 months
measure: Cognitive functioning and changes over time
timeFrame: 24 months
measure: Presence of T-cell immunosenescence at 12 and 24 months and changes from baseline
timeFrame: 24 months
measure: HRQoL at 0, 12 and 24 months and changes from baseline
timeFrame: 24 months
measure: Development of donor-specific anti-HLA antibodies (DSA)
timeFrame: 24 months
measure: Difference in illness perception at 0, 12 and 24 months and changes from baseline
timeFrame: 24 months
measure: Difference in adherence of immunosuppressive medication at 12 and 24 months
timeFrame: 24 months
measure: Difference in symptoms at 0, 12 and 24 months and changes from baseline
timeFrame: 24 months
measure: Difference in iBOX predicted outcome at 3, 5 and 7 years
timeFrame: 24 months
measure: Development of a pharmacokinetic model for tacrolimus once-daily (Envarsus®), using data on AUC's
timeFrame: 24 months
measure: o evaluate the response to the COIVD-19 vaccine and identify possible differences between both treatment groups at the University Medical Center Groningen.
timeFrame: 24 months
Other outcomes:
measure: Evaluation of Cost-effectiveness of the new immunosuppressive regimen, and comparison to the current standard of care
timeFrame: 24 months
Locations:
city: Leuven
country: Belgium
facility: Leuven University Hospital
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Groningen
country: Netherlands
facility: UMCG
city: Leiden
country: Netherlands
facility: LUMC
city: Nijmegen
country: Netherlands
facility: Radboud University Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC
city: Utrecht
country: Netherlands
facility: UMCU
Study officials:
affiliation: EMC
name: Dennis Hesselink, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: AIDS Malignancy Consortium
name: Frederike Bemelman, Md, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMCG
name: Stefan Berger, Md, PhD
role: STUDY_CHAIR
affiliation: UMCG
name: Jan-Stephan Sanders, MD, PhD
role: STUDY_DIRECTOR
affiliation: VUMC
name: Azam Nurmohamed, Md, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: LUMC
name: Aiko De Vries, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud MC
name: Luuk Hilbrands, Md, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UMCU
name: Arjan Van Zuilen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leuven MC
name: Dirk Kuypers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Boer SE, Sanders JSF, Bemelman FJ, Betjes MGH, Burgerhof JGM, Hilbrands L, Kuypers D, van Munster BC, Nurmohamed SA, de Vries APJ, van Zuilen AD, Hesselink DA, Berger SP. Rationale and design of the OPTIMIZE trial: 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 patients. BMC Nephrol. 2021 Jun 2;22(1):208. doi: 10.1186/s12882-021-02409-8.