Optimum Immunosuppression in Renal Transplant Recipients.New Onset Diabetes After Transplantation (01-DMPT)

Optimum Immunosuppression in Renal Transplant Recipients at High Risk of Developing New Onset Diabetes After Transplantation: A Multicenter, Prospective, Controlled and Randomized Trial.

New onset diabetes after renal transplantation (NODAT) is a common and severe complication negatively influencing graft and patient survival. Cyclosporine (CsA) and Tacrolimus are the basis of modern immunosuppression. Tacrolimus is superior to CsA in terms of acute rejection and graft function. However, Tacrolimus increases 2 times the risk of NODAT as compared to CsA.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Adult-Onset
• Intervention / Treatment: Drug: Tacrolimus with rapid steroid withdrawal; Drug: Tacrolimus with steroids minimization; Drug: CsA with steroid minimization

Detailed Description

New onset diabetes after renal transplantation (NODAT) is a common and severe complication negatively influencing graft and patient survival. CsA and Tacrolimus are the basis of modern immunosuppression. Tacrolimus is superior to CsA in terms of acute rejection and graft function. However, increases 2 times the risk of NODAT as compared to CsA. Objectives: a) To compare the incidence of NODAT and glucose intolerance with 3 different regimes: Tacrolimus with rapid steroid withdrawal; Tacrolimus with steroids minimization; and CsA with steroid minimization; b) To compare acute rejection rate, renal function and graft and patient survival between different regimes; and c) to investigate the influence of different regimes on subclinical atheromatosis. A total of 210 patients will be randomized. The primary efficacy variable will be NODAT or glucose intolerance at 1 year; secondary efficacy variables will be acute rejection, renal function, and changes of carotid intima-media thickness over time.

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Las Palmas de Gran Canaria, Spain, 35010
    • Roberto Gallego
  • Valencia, Spain, 46017
    • Luis Pallardo
  • Andalucía
    • Granada, Andalucía, Spain, 18014
      • Antonio Osuna
    • Málaga, Andalucía, Spain, 29010
      • Domingo Hernández
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Carmen Díaz Corte
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Carlos Gómez Alamillo
  • Cataluña
    • Barcelona, Cataluña, Spain, 08025
      • Juan Manuel Díaz
    • Barcelona, Cataluña, Spain, 08035
      • Francisco Moreso
  • Galicia
    • La Coruña, Galicia, Spain, 15006
      • Francisco Valdés
  • S/C De Tenerife
    • La Laguna, S/C De Tenerife, Spain, 38320
      • Armando Torres Ramírez

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Primary renal transplant recipients with end stage renal disease
• No prior history of diabetes mellitus before transplant
• Absence of Immunologic risk defined by the investigator criterion and Panel Reactive Antibody (PRA) < 50%
• Absence of severe infection and hepatitis C or B infection
• Efficient contraception in women during the study

Additionally must meet one of these "Metabolic Criteria

• Recipient age >or =60 or
• Recipient age between 45 and 59 years and at least one of the following metabolic criteria: Prior to transplantation Triglycerides (TGS) >200mg/dl or the combination of a body mass index (BMI)> 27 and Triglycerides>150 mg/dl or the combination of HDL-cholesterol<40 mg/dl for men or <50 mg/dl for women and Triglycerides >150 mg/dl.

Exclusion Criteria:

• Patients with type I or II diabetes prior to transplantation defined by the American Diabetes Association (ADA) criteria
• Recipient age under 45
• Patients receiving a second renal transplant
• Patients with high immunological risk or PRA (panel reactive antibody level) >or =50%
• Severe infection or hepatitis C or B infection.
• Dual renal transplant or double transplant with any other organ.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus with rapid steroid withdrawal; Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week.	Drug: Tacrolimus with rapid steroid withdrawal; Basiliximab induction (4 mg i.v., days 0 and 4).; Corticosteroids: 0.5 gr of i.v. Methylprednisolone (MP) intraoperatively and 125 mg on the first day, followed by oral doses of prednisone rapidly tapered from 30 mg/day to complete discontinuation by postoperative day 7.; Tacrolimus: 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month and then 5-8 ng/ml.; Mycophenolate mofetil 1 gr b.i.d. for the first month and then 500 mg b.i.d.; Other Names: Simulect; Dacortin; Prograf/Advagraf; Cellcept/Myfortic.
Active Comparator: Tacrolimus with steroids minimization; Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal	Drug: Tacrolimus with steroids minimization; Basiliximab induction (4 mg i.v., days 0 an 4); Corticosteroids: 0.5 gr of i.v. MP intraoperatively and 60 mg on the first day, followed by oral doses of prednisone starting with 0.3 mg/Kg/day, and gradual weekly tapering to complete discontinuation over 6 months.; Tacrolimus 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month and then 5-8 ng/ml.; Mycophenolate mofetil 1 gr b.i.d. for the first month and then 500 mg b.i.d.; Other Names: Simulect; Dacortin; Prograf/Advagraf; Cellcept/Myfortic.
Experimental: CsA with steroid minimization; Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal	Drug: CsA with steroid minimization; Basiliximab induction (4 mg i.v., days 0 an 4); Corticosteroids: 0.5 gr of i.v. MP intraoperatively and 60 mg on the first day, followed by oral doses of prednisone starting with 0.3 mg/Kg/day, and gradual weekly tapering to complete discontinuation over 6 months.; CsA 5 mg/Kg/day to achieve target trough of 150-200 ng/ml the first month and then 100-150 ng/ml.; Mycophenolate mofetil 1 gr b.i.d; Other Names: Simulect; Dacortin; Sandimmun Neoral; Cellcept/Myfortic.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome Measure "New Onset Diabetes After Renal Transplantation" (NODAT)	American Diabetes Association criteria (ADA) including an oral glucose tolerance test.	1 year
Patients Treated With Insulin or Oral Antidiabetic Drugs		1 year
Primary Outcome Measure (Glucose Intolerance)	Glycemia >=140 and <200 mg/dl, 2 hours after a standard oral glucose tolerance test. Measured values: glucose intolerance at 1 year defined by ADA criteria.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rejection	Biopsy proven acute rejection. Measured variable: Rate of Biopsy proven acute rejection.	1 year
Renal Function	Estimated Glomerular Filtration Rate (ml/min/1.73 m^2)	1 year
Proteinuria		1 year
Blood Pressure	Systolic pressure (mmHg)	1 year
Blood Pressure	Diastolic pressure (mmHg)	1 year
Number of Antihypertensive Drugs Patients Reported Taking.		1 year
Lipidic Profile (Triglycerides)		1 year
Lipidic Profile (Cholesterol)	Lipidic Profile (total cholesterol)	1 year
Lipidic Profile (HDL-c)		1 year
Lipidic Profile (LDL-c)		1 year
Percentage of Patients Using Statins		1 year
Changes of Carotid Intima-media Thickness Over Time	absolute difference between carotid intima-media thickness at study end versus baseline.	1 year
Percentage of Patients Using Acetylsalicylic Acid (ASA)		1 year

Collaborators and Investigators

• Sponsor: Armando Torres Ramírez
• Investigators: Study Director: Armando Torres, PhD, Fundación Canaria para la Investigación Biomédica Rafael Clavijo

Publications and helpful links

General Publications

• Porrini E, Gomez MD, Alvarez A, Cobo M, Gonzalez-Posada JM, Perez L, Hortal L, Garcia JJ, Dolores Checa M, Morales A, Hernandez D, Torres A. Glycated haemoglobin levels are related to chronic subclinical inflammation in renal transplant recipients without pre-existing or new onset diabetes. Nephrol Dial Transplant. 2007 Jul;22(7):1994-9. doi: 10.1093/ndt/gfm067. Epub 2007 Mar 29.
• Alvarez A, Fernandez J, Porrini E, Delgado P, Pitti S, Vega MJ, Gonzalez-Posada JM, Rodriguez A, Perez L, Marrero D, Luis D, Velazquez S, Hernandez D, Salido E, Torres A. Carotid atheromatosis in nondiabetic renal transplant recipients: the role of prediabetic glucose homeostasis alterations. Transplantation. 2007 Oct 15;84(7):870-5. doi: 10.1097/01.tp.0000284462.70064.ae.
• Hernandez D, Miquel R, Porrini E, Fernandez A, Gonzalez-Posada JM, Hortal L, Checa MD, Rodriguez A, Garcia JJ, Rufino M, Torres A. Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression. Transplantation. 2007 Sep 27;84(6):706-14. doi: 10.1097/01.tp.0000282872.17024.b7.
• Porrini E, Delgado P, Alvarez A, Cobo M, Perez L, Gonzalez-Posada JM, Hortal L, Gallego R, Garcia JJ, Checa M, Morales A, Salido E, Hernandez D, Torres A. The combined effect of pre-transplant triglyceride levels and the type of calcineurin inhibitor in predicting the risk of new onset diabetes after renal transplantation. Nephrol Dial Transplant. 2008 Apr;23(4):1436-41. doi: 10.1093/ndt/gfm762. Epub 2007 Nov 19.
• Porrini E, Moreno JM, Osuna A, Benitez R, Lampreabe I, Diaz JM, Silva I, Dominguez R, Gonzalez-Cotorruelo J, Bayes B, Lauzurica R, Ibernon M, Moreso F, Delgado P, Torres A. Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study. Transplantation. 2008 Apr 27;85(8):1133-8. doi: 10.1097/TP.0b013e31816b16bd.
• Bayes B, Moreso F, Benitez R, Torres A, Diaz JM, Granada ML, Lauzurica R, Pastor MC, Teixido J. [Post-transplant diabetes mellitus depending on the pre-transplant dialysis technique]. Nefrologia. 2008;28 Suppl 6:97-102. Spanish.
• Porrini E, Bayes B, Diaz JM, Ibernon M, Benitez R, Dominguez R, Moreno JM, Delgado P, Lauzurica R, Silva I, Moreso F, Lampreabe I, Arias M, Osuna A, Torres A. Hyperinsulinemia and hyperfiltration in renal transplantation. Transplantation. 2009 Jan 27;87(2):274-9. doi: 10.1097/TP.0b013e318191a7d5.
• Porrini EL, Diaz JM, Moreso F, Delgado Mallen PI, Silva Torres I, Ibernon M, Bayes-Genis B, Benitez-Ruiz R, Lampreabe I, Lauzurrica R, Osorio JM, Osuna A, Dominguez-Rollan R, Ruiz JC, Jimenez-Sosa A, Gonzalez-Rinne A, Marrero-Miranda D, Macia M, Garcia J, Torres A. Clinical evolution of post-transplant diabetes mellitus. Nephrol Dial Transplant. 2016 Mar;31(3):495-505. doi: 10.1093/ndt/gfv368. Epub 2015 Nov 3.
• Rodriguez-Rodriguez AE, Trinanes J, Porrini E, Velazquez-Garcia S, Fumero C, Vega-Prieto MJ, Diez-Fuentes ML, Luis Lima S, Salido E, Torres A. Glucose homeostasis changes and pancreatic beta-cell proliferation after switching to cyclosporin in tacrolimus-induced diabetes mellitus. Nefrologia. 2015;35(3):264-72. doi: 10.1016/j.nefro.2015.05.007. Epub 2015 Jun 27. English, Spanish.
• Rodriguez-Rodriguez AE, Trinanes J, Velazquez-Garcia S, Porrini E, Vega Prieto MJ, Diez Fuentes ML, Arevalo M, Salido Ruiz E, Torres A. The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats. Am J Transplant. 2013 Jul;13(7):1665-75. doi: 10.1111/ajt.12236. Epub 2013 May 7.
• Delgado P, Diaz JM, Silva I, Osorio JM, Osuna A, Bayes B, Lauzurica R, Arellano E, Campistol JM, Dominguez R, Gomez-Alamillo C, Ibernon M, Moreso F, Benitez R, Lampreave I, Porrini E, Torres A. Unmasking glucose metabolism alterations in stable renal transplant recipients: a multicenter study. Clin J Am Soc Nephrol. 2008 May;3(3):808-13. doi: 10.2215/CJN.04921107. Epub 2008 Mar 5.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: October 26, 2009
• First Submitted That Met QC Criteria: October 26, 2009
• First Posted (Estimated): October 27, 2009

Study Record Updates

• Last Update Posted (Actual): October 22, 2024
• Last Update Submitted That Met QC Criteria: September 28, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus, Type 2; Diabetes Mellitus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Dermatologic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Basiliximab; Prednisone; Mycophenolic Acid; Tacrolimus; Cyclosporine
• Other Study ID Numbers: FundacionRC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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