A Randomized Controlled Trial to Evaluate Efficacy and Safety of Early Conversion to a Low-Dose Calcineurin Inhibitor Combined with Sirolimus in Renal Transplant Patients
Renal transplantation remains the most effective treatment for end-stage renal disease. Despite significant advancements in immunosuppressive therapies, the long-term prognosis of renal grafts has not seen substantial improvement. The calcineurin inhibitor (CNI)-based immunosuppressive regimen, while effective in reducing acute rejection (AR) rates, is associated with nephrotoxicity, which is a major risk factor for chronic renal graft dysfunction. Sirolimus (SRL), a mammalian target of rapamycin inhibitor (mTORi), has been used in clinical practice for over two decades and is known for its lack of nephrotoxic effects. However, the optimal regimen and timing for SRL application post-transplantation remain controversial, with limited clinical data and few multicenter prospective randomized controlled studies available.
This study aims to evaluate the efficacy and safety of early conversion to a low-dose CNI combined with SRL in renal transplant patients. The trial is designed as a multicenter prospective randomized controlled study conducted across multiple transplant centers in China. Patients who have received a standard CNI + mycophenolic acid (MPA) + glucocorticoid regimen for four weeks post-transplantation are eligible for inclusion. At the fifth week post-operation, patients in the experimental group will receive SRL, a reduction in CNI dosage, withdrawal of MPA, and continued glucocorticoid therapy. The control group will maintain the standard CNI + MPA + glucocorticoid regimen.
The primary endpoint of the study is the change in estimated glomerular filtration rate (eGFR) from baseline to week 104 post-operation. Secondary endpoints include changes in renal function, incidence of AR, graft loss rate, 24-hour urine protein levels, Banff score, Chronic Allograft Damage Index (CADI) score, and rates of BK virus (BKV) and cytomegalovirus (CMV) infections at various time points post-conversion.
The study protocol has been approved by the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University, and follows the Declaration of Helsinki guidelines. Informed consent is obtained from all participants, and the study is registered with the Chinese Clinical Trial Registry (ChiCTR1800017277).
The inclusion criteria for the study are as follows: voluntary signing of the informed consent form, age between 18 and 70 years, end-stage renal disease patients prepared to accept organ donation, preoperative panel reactive antibody (PRA) ≤10%, renal transplantation-naïve patients, and a glomerular filtration rate ≥45 mL/min. Exclusion criteria include severe systemic or local active infection, chest X-ray findings of infiltration, cavitation, or consolidation, primary disease of the recipient diagnosed as focal segmental glomerulosclerosis or membranous proliferative glomerulonephritis, multiple organ transplantation, triglycerides ≥400 mg/dL (≥4.6 mmol/L) and total cholesterol ≥300 mg/dL (≥7.8 mmol/L), 24-hour urine protein >500 mg/day, biopsy-confirmed AR within four weeks prior to enrollment, intolerance to MMF 1.5 g/day within four weeks prior to enrollment, delayed graft function (DGF) and glomerular filtration rate <45 mL/min within four weeks prior to enrollment, active hepatitis B or C, HIV positivity, usage of other investigational drugs within four weeks prior to enrollment, history of a tumor within three years prior to inclusion (except for well-treated basal cell skin cancer and squamous cell skin cancer), renal graft from monozygotic twins, readiness to use substances known to have strong interactions with SRL, women in pregnancy, preparation for pregnancy or lactation, and other factors determined by the investigator as unsuitable for investigational drugs.
Patients are randomized into two groups: the control group (Group A) and the experimental group (Group B). Group A continues with the standard CNI + MPA + glucocorticoid regimen, with gradual reduction in CNI dosage over the first and second years post-transplantation. Group B receives a reduced CNI dosage combined with SRL, with different regimens based on patient conditions. Regimen 1 involves a 1/3 dose reduction for tacrolimus (TAC) or a 1/2 dose reduction for cyclosporin (CsA) at week 5 post-operation, with SRL initiated at 2 to 3 mg/day and MPA reduced to 0.5 to 1 g/day. From day 3 at week 5 to year 1 post-operation, CNI dosage is further reduced, and MPA is withdrawn. From year 1 to year 2 post-operation, CNI dosage is further reduced, and SRL is maintained at 2 to 3 mg/day with a plasma concentration of 5 to 8 ng/mL. Regimen 2 involves a similar reduction in CNI dosage and maintenance of SRL from day 3 at week 5 to year 1 post-operation, with further dosage adjustments from year 1 to year 2 post-operation.
The study involves six follow-up visits at weeks 12, 24, 36, 48, 72, and 104 post-operation. During these visits, vital signs, routine blood and urine tests, blood biochemistry, serum creatinine levels, BKV/CMV tests, and trough concentrations of CNI drugs and SRL are recorded. Patient survival, graft survival, and eGFR are calculated, and concomitant medications and adverse events (AEs) are documented.
The sample size calculation is based on previous literature reports, with an estimated eGFR of 51.0 and 50.5 mL/min/1.73m² for the experimental and control groups, respectively. Assuming a 10% dropout rate, the study requires 500 patients in the experimental group and 250 patients in the control group, totaling 750 patients.
Data collection involves recording and entering data twice, with any missing values verified for accuracy. Withdrawals and AEs are recorded promptly. The efficacy analysis is performed according to the intent-to-treat population and the per-protocol population. Demographic data and baseline characteristics are summarized using descriptive statistics. The t-test/rank-sum test is used for qualitative data, and the chi-square test is used for rates. Safety analysis is performed according to the safety set, which includes all subjects who receive at least some doses of the study drugs. Correlation analysis is performed using the Pearson or Spearman test. Continuous variables are described using means with standard deviations and analyzed using the independent samples t-test. Categorical variables are analyzed using the chi-squared test or Fisher exact test. All analyses are performed using SPSS software V24, with a confidence interval of 95% and P < 0.05 considered statistically significant.
The discussion highlights the challenges in renal transplantation, including AR, DGF, chronic renal allograft dysfunction, and side effects of nonspecific immunosuppressive agents. CNI drugs, while effective in reducing AR, are associated with nephrotoxicity, which is a major risk factor for poor long-term prognosis. SRL, with its unique immunosuppressive effects and lack of nephrotoxicity, is considered an ideal therapeutic drug to replace CNIs. However, the increased risk of AR after conversion to SRL remains a significant issue. Studies suggest that early conversion to SRL can reduce CNI-related nephrotoxicity and improve renal graft function, but the optimal regimen and timing for SRL application remain controversial.
The study aims to provide valuable data on the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients. The results will contribute to the development of optimal immune maintenance regimens, improving renal graft function and long-term prognosis for transplant recipients.
doi.org/10.1097/CM9.0000000000001866
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