The Vienna Prograf and Endothelial Progenitor Cell Extension Study (PEP-X)

Conversion of renal transplant recipients from either tacrolimus or cyclosporin A to tacrolimus modified release to investigate the effects of the MDR1/CYP450 genotype on the trough blood levels of tacrolimus with modified galenic (tacrolimus MR4; Advagraf®).

Study Overview

• Status: Completed
• Conditions: Renal Failure; Immunosuppression
• Intervention / Treatment: Drug: Tacrolimus

Detailed Description

The study concerns the conversion of immunosuppressive agents among participants in the clinical trial "The Vienna Prograf and Endothelial Progenitor Cell Study - The Vienna PEP Study" at the end of the study after 2 years in the extension study PEP-X.

The aim of the conversion is to investigate the effects of the multi-drug resistance (MDR1, gene symbol ABCB1) genotype on the trough blood levels of tacrolimus modified release (TAC MR4; Advagraf®). Analyzes of the effects of the genotype on the concentration/dose ratio ([ng/mL]/[mg/d]) will be carried out, as well as studies on existing polymorphisms in the MDR1 gene. The written informed consent to conversion of either tacrolimus (TAC; Prograf®) or cyclosporin A (CSA; Sandimmun Neoral®) to TAC MR4 will be obtained.

Upon completion of 24 months of study participation of the PEP-study, and consent to convert the immunosuppressant therapy of either TAC or CSA to TAC MR4, it will be used as indicated by the manufacturer. In patients treated with CSA, the initial dose will be 0.1-0.12 mg TAC MR4 per kg of body weight per day with oral morning administration. In patients who are already treated with TAC, the conversion to TAC MR4 will be performed in a 1:1 ratio.

The dosage data for the conversion of CSA to TAC MR4 are taken from the documents of the European Medicines Agency homepage (http://www.emea.europa.eu/index/ indexh1.htm, retrieved 26.09.2007), those on the safety and equivalence of the achieved areas under the curve (AUC) of both TAC formulations from Alloway et al. (Transplant Proc 2005; 37: 867-870).

The conversion will be performed by Univ. Prof. Dr. Gere Sunder-Plassmann, and Dr. Markus Riegersperger, respectively, both Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna. The desired trough level is set at 4.0-8.0ng/mL according to the usual clinical standards for long-term transplant patients at the investigators center. The trough level analyses are performed at the Medical University of Vienna, according to the following schedule: 1 week after conversion, 2 weeks after conversion, 4 weeks after conversion, 12 weeks and 12 months after conversion.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Any stable long-term kidney transplant recipient who participated in the Vienna Prograf and Endothelial-Progenitor Study (Vienna PEP Study; EudraCT identifier 2004-82 004209-98)
• Written informed consent to have the immunosuppression converted from either cyclosporin A or tacrolimus to tacrolimus modified-release

Exclusion Criteria:

• Graft failure
• Contraindication to receive immunosuppression

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Conversion from either CSA or TAC; Tacrolimus with modified galenic (tacrolimus MR4; Advagraf®) once daily. In patients treated with ciclosporin A, the initial dose will be 0.1 - 0.12 mg tacrolimus MR4 per kg of body weight per day with oral morning administration. In patients who are already treated with Prograf, the conversion to Advagraf will be performed in a 1:1 ratio.	Drug: Tacrolimus; Conversion from either cyclosporin or tacrolimus to tacrolimus modified release

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of the MDR1 genotype on the trough blood levels of tacrolimus with modified galenics (tacrolimus MR4; Advagraf®)	Effects of the genotype on the concentration/dose ratio ([ng/mL]/[mg/d])	12 months

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Publications and helpful links

General Publications

• Riegersperger M, Plischke M, Jallitsch-Halper A, Steinhauser C, Fodinger M, Winkelmayer WC, Dunkler D, Sunder-Plassmann G. A non-randomized trial of conversion from ciclosporin and tacrolimus to tacrolimus MR4 in stable long-term kidney transplant recipients: Graft function and influences of ABCB1 genotypes. PLoS One. 2019 Jul 2;14(7):e0218709. doi: 10.1371/journal.pone.0218709. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: November 9, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 23, 2018

Study Record Updates

• Last Update Posted (Actual): November 23, 2018
• Last Update Submitted That Met QC Criteria: November 20, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: Conversion; MDR-1; Tacrolimus modified release; Calcineurin inhibitors; Trough levels
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 1.05; 154/01/2008 (Other Identifier: Ethics Committee Medical University of Vienna)

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