RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients (OPTIMIZE)

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Elderly Patients; Immunosuppression; Renal Transplant Recipients
• Intervention / Treatment: Drug: standard dose tacrolimus with mycophenolate mofetil; Drug: low dose tacrolimus in combination with everolimus

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.

• Study Type: Interventional
• Enrollment (Anticipated): 374
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Leuven University Hospital
• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam UMC
  • Groningen, Netherlands
    • UMCG
  • Leiden, Netherlands
    • LUMC
  • Nijmegen, Netherlands
    • Radboud University Hospital
  • Rotterdam, Netherlands
    • Erasmus MC
  • Utrecht, Netherlands
    • UMCU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years to 99 years (Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Cost-effectiveness of the new immunosuppressive regimen, and comparison to the current standard of care	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	24 months

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Radboud University Medical Center; Universitaire Ziekenhuizen KU Leuven; UMC Utrecht; Erasmus Medical Center; Amsterdam UMC, location VUmc; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Leiden University Medical Center
• Investigators: Principal Investigator: Dennis Hesselink, MD, PhD, EMC; Principal Investigator: Frederike Bemelman, Md, PhD, AIDS Malignancy Consortium; Study Chair: Stefan Berger, Md, PhD, UMCG; Study Director: Jan-Stephan Sanders, MD, PhD, UMCG; Principal Investigator: Azam Nurmohamed, Md, PhD, VUmc; Principal Investigator: Aiko De Vries, MD, PhD, LUMC; Principal Investigator: Luuk Hilbrands, Md, PhD, Radboud MC; Principal Investigator: Arjan Van Zuilen, MD, PhD, UMCU; Principal Investigator: Dirk Kuypers, MD, PhD, Leuven MC

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2019
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: January 4, 2019
• First Posted (Actual): January 9, 2019

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: OPTIMIZE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No