Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52)
<p>Patients’ disposition. IS: Immunosuppression; OGT: Oral glucose tolerance test. PKD-1: Autosomal Dominant Polycystic Kidney Disease type I; GN: Glomerulonephritis.</p> "> Figure 2
<p>Distribution of glucose metabolism abnormalities at the end of the study in each group. Prediabetes: Impaired Fasting Glucose and Impaired Glucose Tolerance, isolated or combined. (<b>A</b>): All patients; (<b>B</b>): Excluding patients with acute rejection or a baseline BMI < 22 Kg/m<sup>2</sup>. IR-Tac: Immediate-release tacrolimus; LCPT: LCP Tacrolimus.</p> ">
Abstract
:1. Introduction
2. Material and Methods
2.1. Study Design
2.2. Study Population
2.3. Randomization, Groups, and Interventions
- Group 1: IR-Tac: 0.1 mg/kg/day in 2 divided doses to maintain tacrolimus trough levels at between 8–12 ng/mL for the first month. A single dose of 0.05 mg/kg or 0.10 mg/kg (in expanded criteria or standard donor, respectively) was administered before surgery.
- Group 2: LCPT tacrolimus: 0.1 mg/kg/day in a single dose starting within the first 24 h after transplantation to maintain tacrolimus trough levels at between 8–12 ng/mL for the first month.
- Mycophenolate mofetil (MMF) 2 g/day or mycophenolic acid (EC-MFA) 1.44 g/day during the first month, then reduced to 1 g/day or 720 mg/day, respectively.
- Corticosteroids at reduced exposure as previously described, with slight modifications [16]: intravenous methylprednisolone 0.25 g intraoperatively and 60 mg on day 1; oral prednisone starting on day 3 with 20 mg/day, progressively reduced to 5 mg/day from day 42 until the end of the study.
- Induction was based on basiliximab, 20 mg intravenously on days 0 and 4. For grafts at high risk of delayed graft function (e.g., donation after cardiac death or prolonged cold ischemia time), a transient reduction of tacrolimus doses or delayed initiation (maximum of 5 days) plus induction with rabbit ATG was performed.
2.4. Assessment of Glucose Metabolism Alterations
2.5. Analytical and Other Determinations
2.6. Efficacy Variables
2.7. Statistical Analysis
2.8. Sample Size
2.9. Safety
3. Results
3.1. Patient Disposition
3.2. Baseline Demographics of Recipients and Donors
3.3. Post-Transplant Evolution and Other Outcomes at the End of the Study
3.4. Tacrolimus Exposure
3.5. Primary and Secondary Efficacy Endpoints
3.6. Sensitivity Analysis
3.7. Adverse Events
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variable | IR-TAC | LCPT | p-Value |
---|---|---|---|
(n = 27) | (n = 25) | ||
Recipient Age (years) | 64 (50.6–68.2) | 63.52 (46.53–69.66) | 0.7 |
Sex (% Males) | 17/27 (63%) | 19/25 (76%) | 0.31 |
Race (% Caucasians) | 26/27 (96.3%) | 23/25 (92%) | 0.58 |
BMI (Kg/m2) | 28.61 ± 4.43 | 25.53 ± 4.19 | 0.013 |
Family history of Diabetes | 7/24 (29.2%) | 9/23 (39.1%) | 0.47 |
Polycystic kidney disease | 5/27 (18.5%) | 6/25 (24%) | 0.63 |
Peritoneal dialysis | 7/26 (26.9%) | 12/25 (48%) | 0.12 |
Time on dialysis (months) | 21.9 (15.2–32) | 23.4 (9.7–28.6) | 0.8 |
Total Cholesterol (mg/dL) | 152.92 ± 38.84 (n = 26) | 158.59 ± 37.27 (n = 22) | 0.61 |
HDL cholesterol (mg/dL) | 43.62 ± 13.32 (n = 21) | 44.10 ± 11.42 (n = 21) | 0.90 |
LDL cholesterol (mg/dL) | 75 (56–99) (n = 19) | 67 (60–98.5) (n = 21) | 0.9 |
Triglycerides (mg/dL) | 143 (102–167.8) (n = 26) | 145 (103.5–181.5) (n = 22) | 0.7 |
Tobacco (former or current smoker) | 8/26 (30.8%) | 13/25 (52%) | 0.30 |
Statin treatment | 19/26 (73.1%) | 17/25 (68%) | 0.70 |
Fasting glucose (mg/dL) | 90.3 (83–96) | 91 (83.5–94.5) | 0.8 |
HbA1c (%) | 5.19 ± 0.41 (n = 18) | 5.22 ± 0.29 (n = 17) | 0.85 |
Donor age (years) | 56.70 ± 10.67 | 55.24 ± 13.40 | 0.66 |
Donor Sex (% Males) | 17/27 (63%) | 20/25 (80%) | 0.18 |
Cold Ischemia Time (hours) | 11.42 (6.54–18.67) | 10.12 (7.66–16.58) | 0.99 |
Donation after cardiac death | 8/27 (29.6%) | 6/25 (24%) | 0.65 |
Delayed graft function | 10/27 (37%) | 2/25 (8%) | 0.02 |
Variable | IR-TAC | LCTP | p-Value |
---|---|---|---|
(n = 27) | (n = 25) | ||
BMI (Kg/m2) | 28.34 ± 4.64 | 26.02 ± 3.71 | 0.06 |
Weight increase (Kg) | −0.99 ± 4.1 | 0.92 ± 4.7 | 0.1 |
Total Cholesterol (mg/dL) | 192.63 ± 38.52 (n = 24) | 176.96 ± 40.17 (n = 23) | 0.18 |
HDL cholesterol (mg/dL) | 52.04 ± 15.24 (n = 23) | 53.87 ± 16.92 (n = 23) | 0.70 |
LDL cholesterol (mg/dL) | 109.45 ± 32.16 (n = 20) | 99.64 ± 33.63 (n = 22) | 0.34 |
Triglycerides (mg/dL) | 132 (101–170) | 116 (100.50–143.50) | 0.36 |
Statin therapy | 9/26 (34.6%) | 12/25 (48%) | 0.33 |
Magnesium (1 week) | 1.96 ± 0.3 | 1.9 ± 0.3 | 0.4 |
Magnesium (1 month) | 1.55 ± 0.3 | 1.5 ± 0.15 | 0.7 |
Magnesium (2 months) | 1.6 ± 0.16 | 1.6 ± 0.17 | 0.9 |
CNI-related acute nephrotoxicity (%) | 0/27 (0%) | 2/25 (8%) | 0.2 |
Acute Rejection (%) | 3/27 (11.1%) | 0/25 (0%) | 0.2 |
Cumulative corticosteroid dose (mg) | 1321.25 (1189.38–1561.25) | 1195 (1173.75–1270) | 0.05 |
CMV Infection (%) | 2/27 (9.4%) | 2/25 (8%) | 1 |
BKV Infection (%) | 0% | 1/25 (4%) | 0.8 |
Awake SPB (ABPM) (mmHg) | 129.60 ± 12.55 (n = 25) | 129.84 ± 12.78 (n = 25) | 0.95 |
Asleep SBP (ABPM) (mmHg) | 124.68 ± 13.19 (n = 25) | 129.48 ± 16.92 (n = 25) | 0.27 |
Awake DBP (ABPM) (mmHg) | 79.92 ± 8.11 (n = 25) | 80.48 ± 8.61 (n = 25) | 0.81 |
Asleep DBP (ABPM) (mmHg) | 75.32 ± 8.46 (n = 25) | 77.80 ± 8.75 (n = 25) | 0.31 |
Creatinine (mg/dL) | |||
1 month | 1.77 (1.48–2.48) | 1.52 (1.28–1.75) | 0.07 |
2 months | 1.65 (1.43–1.95) | 1.46 (1.2–1.85) | 0.1 |
3 months | 1.6 (1.36–1.86) | 1.42 (1.14–1.87) | 0.36 |
eGFR (mL/mn/1.73 m2) | |||
1 month | 39.23 ± 16.57 | 49.16 ± 15.74 | 0.03 |
2 months | 41.16 ± 14.36 | 48.92 ± 13.95 | 0.05 |
3 months | 44.68 ± 13.99 | 51.28 ± 15.48 | 0.11 |
Measured GFR 3 months (mL/mn) | 49.2 ± 17.3 (n = 26) | 55.4 ± 18.2 (n = 23) | 0.2 |
Proteinuria 3 months (mg/gr creatinine) | 154.2 (133.2–244.2) | 152.8 (139.7–271.2) | 0.90 |
Whole-Blood Tacrolimus Levels (ng/mL) | IR-Tacrolimus | LCPT | p-Value |
---|---|---|---|
(n = 27) | (n = 25) | ||
1 week | 9.5 (7.1–12.9) | 10.5 (9.4–14.5) | 0.1 |
1 month | 9.5 (7.5–11.2) | 9.8 (7.6–11.7) | 1 |
2 months | 9.6 (7–12) | 10.7 (8.3–13) | 0.2 |
3 months | 8.3 (6.9–9.2) | 9.4 (7.4–11.4) | 0.05 |
Variables | IR-TAC | LCPT | p-Value |
---|---|---|---|
(n = 27) | (n = 25) | ||
Fasting Glucose (mg/dL): | |||
Pre-Transplantation | 90.3 (83–96) | 91 (83.5–94.5) | 0.77 |
1 week | 102 (92–116) | 99 (93–116) | 0.88 |
1 month | 90 (83–98) | 92 (86–104) | 0.69 |
2 months | 95 (86–108) | 92 (85.25–105) | 0.68 |
3 months | 92 (86–102) | 88 (81–97.5) | 0.24 |
Oral Glucose Tolerance Test (3 months) | |||
Baseline Fasting Glycemia (mg/dL) | 92 (86–102) | 88 (81–97.5) | 0.24 |
Glycemia at 30 min (mg/dL) | 157 (138–178.50) (n = 18) | 139 (125–154.5) (n = 21) | 0.02 |
Glycemia at 120 mn (mg/dL) | 131 (111–167) (n = 27) | 120 (97–181) (n = 23) | 0.53 |
Baseline Insulin (mcU/mL) | 7.9 (4.8–10.2) (n = 23) | 7 (5.5–10) (n = 23) | 0.84 |
Insulin at 30 min (mcU/mL) | 25.35 (13.95–41.23) (n = 18) | 22.9 (9–43.6) (n = 21) | 0.67 |
Insulin at 120 min (mcU/mL) | 32.35 (16.1–49) (n = 22) | 27.90 (7.1–44.5) (n = 23) | 0.32 |
Insulin Sensitivity Index (ISI) | 7.4 (5.7–8.8) (n = 22) | 8.5 (6.6–9.8) (n = 23) | 0.2 |
Insulinogenic Index | 43.7 (20.7–66.4) (n = 16) | 38.4 (22.7–147.2) (n = 19) | 0.7 |
DISTRIBUTION OF GLUCOSE METABOLIC ALTERATIONS AT THE END OF STUDY | |||
Normal Tolerance | 11/27 (40.7%) (95%CI: 24.5–59%) | 14/25 (56%) (95%CI: 37.1–73.3%) | 0.4 |
Isolated impaired fasting glucose (IFG) | 3/27 (11.1%) (95%CI: 3.85–28.1%) | 1/25 (4%) (95%CI: 0.7–19.5%) | 0.6 |
Impaired Glucose Tolerance (IGT) | 8/27 (29.6%) (95%CI: 15.9–48.5%) | 4/25 (16%) (95%CI: 6.4–34.7%) | 0.3 |
Post-transplant diabetes | 5/27 (18.5%) (95%CI: 8.2–36.7%) | 6/25 (24%) (95%CI: 11.5–43.4%) | 0.7 |
Prediabetes (IFG + IGT) | 11/27 (40.7%) (95%CI: 25–59%) | 5/25 (20%) (95%CI: 9–39%) | 0.1 |
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Torres, A.; Rodríguez-Adanero, C.; Fernández-Rivera, C.; Marrero-Miranda, D.; de Bonis-Redondo, E.; Rodríguez-Hernández, A.P.; Pérez-Tamajón, L.; González-Rinne, A.; Álvarez-Sosa, D.; Álvarez-González, A.; et al. Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52). J. Clin. Med. 2024, 13, 7802. https://doi.org/10.3390/jcm13247802
Torres A, Rodríguez-Adanero C, Fernández-Rivera C, Marrero-Miranda D, de Bonis-Redondo E, Rodríguez-Hernández AP, Pérez-Tamajón L, González-Rinne A, Álvarez-Sosa D, Álvarez-González A, et al. Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52). Journal of Clinical Medicine. 2024; 13(24):7802. https://doi.org/10.3390/jcm13247802
Chicago/Turabian StyleTorres, Armando, Concepción Rodríguez-Adanero, Constantino Fernández-Rivera, Domingo Marrero-Miranda, Eduardo de Bonis-Redondo, Aurelio P. Rodríguez-Hernández, Lourdes Pérez-Tamajón, Ana González-Rinne, Diego Álvarez-Sosa, Alejandra Álvarez-González, and et al. 2024. "Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52)" Journal of Clinical Medicine 13, no. 24: 7802. https://doi.org/10.3390/jcm13247802
APA StyleTorres, A., Rodríguez-Adanero, C., Fernández-Rivera, C., Marrero-Miranda, D., de Bonis-Redondo, E., Rodríguez-Hernández, A. P., Pérez-Tamajón, L., González-Rinne, A., Álvarez-Sosa, D., Álvarez-González, A., Sanchez-Dorta, N., Pérez-Carreño, E., Díaz-Martín, L., Luis-Lima, S., Rodríguez-Rodríguez, A. E., Vera González, A. M. d., Romero-Delgado, C., Calvo-Rodríguez, M., Seijo-Bestilleiro, R., ... Porrini, E. (2024). Efficacy of the Once-Daily Tacrolimus Formulation LCPT Compared to the Immediate-Release Formulation in Preventing Early Post-Transplant Diabetes in High-Risk Kidney Transplant Patients: A Randomized, Controlled, Open-Label Pilot Study (EUDRACT: 2017-000718-52). Journal of Clinical Medicine, 13(24), 7802. https://doi.org/10.3390/jcm13247802