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

Abstract

Background In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. Methods This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is ‘successful transplantation’, defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. Conclusions The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. Trial registration ClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Enhanced Humoral Immune Response After COVID-19 Vaccination in Elderly Kidney Transplant Recipients on Everolimus Versus Mycophenolate Mofetil–containing Immunosuppressive Regimens

“…The design of this study has been described in detail before. 9 In short, the OPTIMIZE trial is an open-label, randomized, multicenter, clinical trial that includes the elderly (≥65 y), de novo KTRs. KTRs are randomized to an immunosuppressive regimen with standard-exposure calcineurin inhibitor (CNI), MMF, and prednisolone (the MMF group) or a regimen with low dose CNI, EVR, and prednisolone (the EVR group).…”

Kidney Transplantation Improves Health-Related Quality of Life in Older Recipients

“…This randomized-controlled trial showed that KTR treated with belatacept, which has generally less side-effects, had better HRQoL compared to calcineurin inhibitors-treated controls at several timepoints after transplantation [ 31 ]. We therefore hypothesize that alterations in the immunosuppressive regimen of older KTR may help to further improve their HRQoL, and this will be assessed in the ongoing OPTIMIZE-trial [ 37 ].…”

Clinical and Molecular Profiling to Develop a Potential Prediction Model for the Response to Alemtuzumab Therapy for Acute Kidney Transplant Rejection

“…Another limitation is that the heterogeneity of the patient cohort made it difficult to define treatment response. The eGFR cutoff we used has been used previously 50 . Despite not being ideal, this definition was considered as the most optimal for the study purpose The criterion “at least once” and the relatively early time point at 6 months, were chosen to guard against nonrelated adverse events that influence kidney function that would possibly lead to an incorrect conclusion of nonresponse to alemtuzumab.…”