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Trial record 1 of 1 for:    NCT03797196
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RCT Comparing Immunosuppressive Regimens in Elderly Renal Transplant Recipients (OPTIMIZE)

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ClinicalTrials.gov Identifier: NCT03797196
Recruitment Status : Recruiting
First Posted : January 9, 2019
Last Update Posted : April 27, 2022
Sponsor:
Collaborators:
Radboud University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Amsterdam UMC, location VUmc
UMC Utrecht
Leiden University Medical Center
Erasmus Medical Center
Universitaire Ziekenhuizen Leuven
Information provided by (Responsible Party):
J.S.F. Sanders, 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).


Condition or disease Intervention/treatment Phase
Renal Transplant Recipients Elderly Patients Immunosuppression Drug: low dose tacrolimus in combination with everolimus Drug: standard dose tacrolimus with mycophenolate mofetil Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 374 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 29, 2019
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : December 2026


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




Primary Outcome Measures :
  1. successful transplantation [ Time Frame: 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 :
  1. death [ Time Frame: 24 months ]
    patient survival

  2. graft loss [ Time Frame: 24 months ]
    graft survival

  3. acute rejection [ Time Frame: 24 months ]
    treated biopsy-proven rejection (tBPAR)

  4. eGFR [ Time Frame: 12 and 24 months ]
    estimated Glomerular Filtration Rate below 30 and 45 ml/min/1.73m2

  5. type of rejection treatment [ Time Frame: 24 months ]
    type of rejection treatment will be scored by questionnaire to the treating nephrologist

  6. The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis [ Time Frame: 24 months ]
    The evolution of renal function (eGFR) and creatinine clearance over time by slope analysis

  7. The incidence of adverse events, serious adverse events and adverse reactions [ Time Frame: 24 months ]
    The incidence of adverse events, serious adverse events and adverse reactions

  8. The incidence of clinically relevant infections, post transplantation diabetes mellitus, malignancies and cardiovascular events [ Time Frame: 24 months ]
    The incidence of clinically relevant infections, post transplantation diabetes, malignancies and cardiovascular events

  9. Presence of frailty after transplantation and change in frailty from baseline frailty from baseline [ Time Frame: 12 and 24 months ]
    frailty is measured by clinical frailty score, hand grip strength and fried frailty index

  10. Physical functioning and changes over time [ Time Frame: 24 months ]
    Short Physical Performance Battery

  11. Cognitive functioning and changes over time [ Time Frame: 24 months ]
    Montreal Cognitive Assessment

  12. Presence of T-cell immunosenescence at 12 and 24 months and changes from baseline [ Time Frame: 24 months ]
    T cell differentiation, exhaustion and telomere length will be assessed by flowcytometry

  13. HRQoL at 0, 12 and 24 months and changes from baseline [ Time Frame: 24 months ]
    Questionnaire: EQ-5D and SF-12

  14. Development of donor-specific anti-HLA antibodies (DSA) [ Time Frame: 24 months ]
    DSA as measured by Luminex

  15. Difference in illness perception at 0, 12 and 24 months and changes from baseline [ Time Frame: 24 months ]
    Questionnaire: Brief Illness Perception Questionnaire

  16. Difference in adherence of immunosuppressive medication at 12 and 24 months [ Time Frame: 24 months ]
    Questionnaire: Basel Assessment of Adherence to Immunosuppressive Medication Scale

  17. Difference in symptoms at 0, 12 and 24 months and changes from baseline [ Time Frame: 24 months ]
    Questionnaire: Dialysis Symptom Index with additional items from the Modified Transplant Symptom Occurrence and Symptom Distress Scale-59

  18. Difference in iBOX predicted outcome at 3, 5 and 7 years [ Time Frame: 24 months ]
    Based on the available data

  19. Development of a pharmacokinetic model for tacrolimus once-daily (Envarsus®), using data on AUC's [ Time Frame: 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.

  20. o evaluate the response to the COIVD-19 vaccine and identify possible differences between both treatment groups at the University Medical Center Groningen. [ Time Frame: 24 months ]
    Humoral and T-cell response


Other Outcome Measures:
  1. Evaluation of Cost-effectiveness of the new immunosuppressive regimen, and comparison to the current standard of care [ Time Frame: 24 months ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   65 Years to 99 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03797196


Contacts
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Contact: Stefan Berger, MD, PhD +31-50-3616161 s.p.berger@umcg.nl
Contact: Jan-Stephan Sanders, MD, PhD +31-50-3616161 j.sanders@umcg.nl

Locations
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Belgium
Leuven University Hospital Recruiting
Leuven, Belgium
Contact: Dirk Kuypers, MD, PhD         
Netherlands
Amsterdam UMC Recruiting
Amsterdam, Netherlands
Contact: Frederike Bemelman, MD, PhD         
Sub-Investigator: Azam Nurmohamed         
UMCG Recruiting
Groningen, Netherlands
Contact: Stefan Berger, MD, PhD         
Principal Investigator: Jan-Stephan Sanders, MD, PhD         
LUMC Recruiting
Leiden, Netherlands
Contact: Aiko De Vries, MD, PhD         
Radboud University Hospital Recruiting
Nijmegen, Netherlands
Contact: Luuk Hilbrands, MD, PhD         
Erasmus MC Recruiting
Rotterdam, Netherlands
Contact: Dennis Hesselink, MD, PhD         
UMCU Recruiting
Utrecht, Netherlands
Contact: Arjan Van Zuilen, MD, PhD         
Sponsors and Collaborators
University Medical Center Groningen
Radboud University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Amsterdam UMC, location VUmc
UMC Utrecht
Leiden University Medical Center
Erasmus Medical Center
Universitaire Ziekenhuizen Leuven
Investigators
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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 automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: J.S.F. Sanders, principal investigator, head of renal transplant program UMCG, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03797196    
Other Study ID Numbers: OPTIMIZE
First Posted: January 9, 2019    Key Record Dates
Last Update Posted: April 27, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Mycophenolic Acid
Everolimus
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents