OPTIMIZE Trial: Prevention of Over-Immunosuppression in Elderly Transplant Recipients

Elderly patients are an increasing sector of both the dialysis and kidney transplant population. In the Netherlands, 30% of the newly kidney transplanted kidney transplant recipients in 2019 were >65 years of age, as were more than 60% of the dialysis population.

Compared with younger kidney transplant recipients, risk profiles among the elderly population are different. In younger recipients, graft loss is due primarily to the loss of transplant; in elderly recipients, graft loss is associated with the patient’s death with a functioning transplant. Thus, death-censored graft loss among elderly transplant recipients is relatively rare.

According to researchers, led by S. E. de Boer, there are two explanations that account for the difference. First, the incidence of rejection in elderly kidney transplant recipients is lower, due to the aging immune system. Second, there is a higher competing incidence of death in the elderly kidney transplant recipient population, attributable to increased risks of mortality associated with cardiovascular complications, infection, and malignancy.

In a report online in BMC Nephrology [doi.org/10.1186/s12882-021-02409-8], the researchers described the 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 patients) trial. The trial is designed to test the hypothesis that reduced calcineurin inhibitor (CNI) exposure in combination with everolimus will lead to improved kidney transplant function, a reduction in the incidence of complications, and improvements in health-related quality of life for kidney transplant recipients ≥65 years of age, compared with standard immunosuppression.

The trial will include two strata of kidney transplant recipients: (1) those who received kidneys from older deceased donors (≥65 years of age) (stratum 1)and (2) those who received kidneys from living donors of all ages and younger (<65 years of age) deceased donors (stratum 2). The comparator will be the standard CNI exposure in combination with mycophenolate mofetil.

The study will (1) examine the impact of transplantation and adapted immunosuppression on frailty and health-related quality of life in elderly Dutch and Belgian kidney transplant recipients; (2) monitor the function of the aging immune system following transplantation and the effect of low CNI exposure in combination with everolimus on parameters of immunosuppression compared with standard, tacrolimus-based immunosuppression; and (3) identify immunologic biomarkers that may serve as biomarkers of immunosenescence for future clinical application.

The study is an investigator-driven, randomized, multicenter, open-label, intervention trial that will include 374 patients. Six transplant centers in the Netherlands and one in Belgium will participate.

At the time of transplantation, patients will be randomized in a 1:1 ratio to receive either standard quadruple immunosuppression regimen with tacrolimus and mycophenolate mofetil (the tacrolimus, mycophenolate mofetil, prednisolone group [TMP group], or a low exposure tacrolimus regimen in combination with everolimus (the tacrolimus, everolimus, prednisone group [TEP group]).

Patients in the TMP group will receive a starting dose of 7 mg Envarsus® once daily (or an equivalent dose of Advagraf®), with an initial target trough concentration of 8-12 ng/mL tapered to 6-10 from 3 months onward, and 5-8 mg/mL from 6 months after transplant. Patients in the TMP group will receive mycophenolate mofetil throughout the trial. Patients in the TEP group will receive a starting dose of 5 mg Envarsus once daily (or an equivalent dose of Advagraf) with an initial target trough concentration of 5-7 tapered to 3-4 ng/mL from 3 months onward, and 1.5-4 ng/mL from 6 months after transplant. Everolimus will be started at an initial dose of 1.5 mg twice a day with a target trough concentration of 3-6 ng/mL throughout the trial.

The trial’s primary end point will be successful transplantation, defined as survival with a functioning allograft with an estimated glomerular filtration rate >30 mL/min/1.73 m² in stratum 1 and >45 mL/min/1.73 m² in stratum 2 at 2 years post-transplantation.  Secondary end points include the primary end point analyzed separately per stratum and the incidence of biopsy-proven rejection, the presence of and changes in immunosenescence, frailty and comorbidities, and assessment of and changes in health-related quality of life as a patient-reported outcome.

Safety objectives include standard assessments of serious adverse events, including drug-related adverse events and drug-related discontinuation of the study medication, and specific objectives regarding clinically relevant infections, post-transplantation diabetes, malignancy, and cardiovascular events. Immunosenescence will be examined by assessment of the immunological phenotype pre-transplant and identification of T cell aging characteristics associated with the risk for acute rejection and infection following kidney transplant. The study will also assess immunological aging within a 2-year period following kidney transplantation in relation to the two immunosuppressive regimens.

There will be nine study visits: baseline, 7 days, 4 weeks, 3, 6, 9, 12, 18, and 24 months post-transplant. At most of the visits, vital signs, and blood and urine analysis will be examined. Some of the visits will involve additional tests and/or questionnaires. At baseline and 6, 12, and 24 months post-transplant, extra blood samples will be drawn from 250 study participants and stored in a biobank to allow the collection of isolated Peripheral Blood Mononuclear Cells (PBMCs) for examination of immunosenescence.

Frailty, cognitive and physical functioning, health-related quality of life, illness perceptions, symptom burden, and adherence to immunosuppressive medications will be monitored using several instruments, both objective and subjective. All study data will be entered into the secured OPTIMIZE project database.

Safety assessment will be based on the frequency of adverse events, including all serious adverse events. Adverse events will be summarized by presenting the number and percentage of patients experiencing any adverse event.

The study began in July 2019. As of the first quarter 2021, all centers had started and 116 patients were included (64 in stratum 1 and 52 in stratum 2). A total inclusion time of 4 years was initially projected; however, due to the COVID-19 pandemic, study inclusion will be delayed.

In summary, the researchers said, “The OPTIMIZE study is a unique clinical trial; it is the first randomized clinical trial to extensively examine the effect of a low exposure tacrolimus regimen in combination with everolimus specifically in de novo elderly kidney transplant recipients. The study also pays attention to the quality of life, cognitive and physical functioning of the participants. The unique character of the study in combination with the data it will yield will position the OPTIMIZE study to have profound impact on future kidney transplant practice in elderly recipients.”

Takeaway Points

1. Researchers describe the OPTIMIZE trial that will compare 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.
2. The primary endpoint will be successful transplantation, defined as survival with a functioning allograft with an estimated glomerular filtration rate >30 mL/min/1.73 m² (stratum 1) or eGFR >45 mL/min/1.73 m² (stratum 2).
3. Secondary end points are the primary end point analyzed separately per stratum and assessment at months 12 and 24 of death, graft loss, and eGFR below 30 or 45 mL/min/1.73 m².