Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients (REVOLUTION)

Randomized Controlled Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients

Lung transplantation is a life-saving option in patients with end-stage lung disease. The introduction of calcineurin inhibitors has significantly improved long-term outcome in lung transplantation. The most frequently used calcineurin inhibitor as maintenance therapy is immediate release tacrolimus, dosed twice daily, which has shown to reduce both acute and chronic rejection. However, a drawback to the administration of tacrolimus is its toxicity. Especially progressive renal toxicity, new onset diabetes and hypertension contribute to the high cardiovascular burdon in this patient group. Since a few years an once daily extended release tacrolimus has been introduced in solid organ transplantation. The advantage of extended release tacrolimus is its prolonged release and higher bioavailability than other tacrolimus formulations. This result in lower peaks, more stable serum levels over 24 hours, and less fluctuation of blood concentrations.

Long-term toxicity outcome of extended release tacrolimus after lung transplantation has not been studied so far. Therefore the potential benefit of exteded release tacrolimus in de novo and stable post-lung transplant recipients should be investigated.

Study Overview

• Status: Recruiting
• Conditions: Lung Transplant; Complications
• Intervention / Treatment: Drug: Extended release tacrolimus; Drug: Immediate release tacrolimus

Detailed Description

Lung transplantation is a life-saving option in patients with end-stage lung disease. The introduction of calcineurin inhibitors (CNI) has significantly improved long-term outcome in lung transplantation. The most frequently used CNI as maintenance therapy is immediate release tacrolimus, dosed twice daily, which has shown to reduce both acute and chronic rejection. However, a drawback to the administration of tacrolimus is its toxicity. Especially progressive renal toxicity, new onset diabetes and hypertension contribute to the high cardiovascular burdon in this patient group. In lung transplant recipients the incidence of severe renal impairment, new onset of diabetes mellitus, hypertension and dyslipidemia is 53,9%, 40%, 80% and 40,3% post lung transplantation. Tremor is one of the most common CNI induced neurological toxic effect, besides polyneuropathy, headaches, insomnia, vertigo, dysesthesia and reduced cognitive ability. These complications are, among others, attributed to high peak serum tacrolimuslevels, whereas the effectiveness of the drug is determined by the area under the curve. In general lung transplant recipients have higher peak and trough levels when compared to other solid organ transplant recipients and therefore potentially experience more severe toxic side effects.

Since a few years an once daily extended release tacrolimus has been introduced in solid organ transplantation. The advantage of extended release tacrolimus is its prolonged release and higher bioavailability than other tacrolimus formulations. This result in lower peaks, more stable serum levels over 24 hours, and less fluctuation of blood concentrations. In addition, for an equal overall systemic tacrolimus exposure a 30% lower dosage is needed for extended release tacrolimus when compared to other formulations. In kidney and liver transplantation, extended release tacrolimus is safe and effective. Langone et al demonstrated in an enriched population of kidney transplant patients with tremor, that extended release tacrolimus improved hand tremor compared to immediate release tacrolimus.

Long-term toxicity outcome of extended release tacrolimus after lung transplantation has not been studied so far. Therefore the potential benefit of exteded release tacrolimus in de novo and stable post-lung transplant recipients should be investigated.

• Study Type: Interventional
• Enrollment (Anticipated): 145
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Heleen Grootjans; Phone Number: 0031503616161; Email: h.grootjans@umcg.nl
• Study Contact Backup: Name: Tji Gan; Phone Number: 0031503616161; Email: c.t.gan@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: Heleen Grootjans; Phone Number: 0031503616161
    • Principal Investigator: Tji Gan
    • Sub-Investigator: Heleen Grootjans
    • Sub-Investigator: Erik Verschuuren
    • Sub-Investigator: Stefan Berger
    • Sub-Investigator: Daan Touw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• Single or bilateral lung transplantation
• On twice daily tacrolimus with stable trough levels in target range
• Participant in the TransplantLines biobank study in the UMCG

Additional criteria for Conversion cohort:

• At least one year after lung transplantation with a stable clinical course and lung function
• eGFR >30ml/min*1.73m2 calculated with the CKD-EPI formula

Exclusion Criteria:

• Administration of mTOR inhibitors; everolimus, sirolimus
• Quadruple immunosuppression
• Renal transplantation
• The subject has any disease or condition that might interfere with completion of this study or reaching the primary endpoint (e.g., life expectancy of <3 years, renal replacement therapy at start study)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: de novo cohort, extended release tacrolimus	Drug: Extended release tacrolimus; de novo cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus direct post-lung transplantation Conversion cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus when >1 year post-lungtransplantation and with stable graft function; Other Names: LCP tacrolimus
Active Comparator: de novo cohort, immediate release tacrolimus	Drug: Immediate release tacrolimus; de novo cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus direct post-lung transplantation Conversion cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus when >1 year post-lungtransplantation and with stable graft function
Experimental: conversion cohort, extended release tacrolimus	Drug: Extended release tacrolimus; de novo cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus direct post-lung transplantation Conversion cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus when >1 year post-lungtransplantation and with stable graft function; Other Names: LCP tacrolimus
Active Comparator: conversion cohort, immediate release tacrolimus	Drug: Immediate release tacrolimus; de novo cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus direct post-lung transplantation Conversion cohort: participants are randomised for extended release tacrolimus or immediate release tacrolimus when >1 year post-lungtransplantation and with stable graft function

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
renal function: absolute change in eGFR	absolute change in eGFR absolute change in eGFR change in eGFR at 2 years	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
graft function	Acute graft dysfunction is a clinical diagnoses, with or without histological confirmation, and indictation for rejection treatment such as methylprednisolon. Chronic graft dysfunction is defined according to the ISHLT guidelines, as a persistent decline (≥20%) in measured FEV1 value from baseline.	2 years
renal function: 40% eGFR reduction	40% eGFR reduction	2 years
renal function: 50% eGFR reduction	50% eGFR reduction	2 years
renal function:end stage kidney disease	end stage kidney disease	2 years
hypertension	Incidence of inadequate regulated or new onset of hypertension	2 years
diabetes mellitus	Incidence of inadequate glycemic control of preexisting diabetes mellitus or new onset diabetes after transplantation (NODAT)	2 years
Infections	Incidence of infections	2 years
Malignancies	Incidence of malignancies	2 years
neurological function: tremor	Incidence of or change in pre-existing hand tremor by using the validated Fahn-Tolosa-Martin (FTM) tremor rating scale (grades of tremor 0-4, in which 0 indicated no tremor and 4 severe tremor)	2 years
neurological function: polyneuropathy	Incidence of or change in pre-existing polyneuropathy	2 years
neurological function: sleep quality	Incidence of or change in sleep quality by using validated questionnaire: Pittsburg Sleep Quality Index (PSQI)	2 years
neurological function: cognitive functioning	Incidence of or change in cognitive functioning by using validated questionnaire: the Cognitive Functioning Questionnaire (CFQ)	2 years
quality of life score	change in SF36 score	2 years
pharmacogenetic	explorative endpoints: effects of well known variances in CYP3A4, CYP3A5 and ABCB1 transporter function on tacrolimus metabolism (resulting in so-called slow and fast tacrolimus metabolisers) on long-term tacrolimus renal toxicity by using absolute eGFR change	2 years
pharmacogenetic	explorative endpoints: effects of well known variances in CYP3A4, CYP3A5 and ABCB1 transporter function on tacrolimus metabolism (resulting in so-called slow and fast tacrolimus metabolisers) on long-term tacrolimus neurological toxicity: change in incidence of or change in pre-existing hand tremor by using the validated Fahn-Tolosa-Martin tremor rating scale	2 years

Collaborators and Investigators

• Sponsor: Heleen Grootjans
• Collaborators: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Tji Gan, University Medical Center Groningen

Publications and helpful links

General Publications

• Sintes H, Saez-Gimenez B, Berastegui C, Lopez-Meseguer M, Monforte V, Bravo C, Vima J, Gomez-Olles S, Roman A. Pharmacokinetic Study of Conversion Between 2 Formulations of Once-daily Extended-release Tacrolimus in Stable Lung Transplant Patients. Transplantation. 2018 Oct;102(10):e439-e446. doi: 10.1097/TP.0000000000002348.
• Mendez A, Berastegui C, Lopez-Meseguer M, Monforte V, Bravo C, Blanco A, Camos S, Pou L, Roman A. Pharmacokinetic study of conversion from tacrolimus twice-daily to tacrolimus once-daily in stable lung transplantation. Transplantation. 2014 Feb 15;97(3):358-62. doi: 10.1097/01.TP.0000435699.69266.66.
• TruneCka P, Klempnauer J, Bechstein WO, Pirenne J, Friman S, Zhao A, Isoniemi H, Rostaing L, Settmacher U, Monch C, Brown M, Undre N, Tisone G; DIAMONDdagger study group. Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study. Am J Transplant. 2015 Jul;15(7):1843-54. doi: 10.1111/ajt.13182. Epub 2015 Feb 23.
• Sanchez Fructuoso A, Ruiz JC, Franco A, Diekmann F, Redondo D, Calvino J, Serra N, Aladren MJ, Cigarran S, Manonelles A, Ramos A, Gomez G, Gonzalez Posada JM, Andres A, Beneyto I, Muniz AL, Perello M, Lauzurica R. Effectiveness and safety of the conversion to MeltDose(R) extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study. Clin Transplant. 2020 Jan;34(1):e13767. doi: 10.1111/ctr.13767. Epub 2019 Dec 31.

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2020
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: July 1, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 11, 2021

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: cardiovascular disease; chronic kidney disease; lung transplantation; extended release tacrolimus; LCP tacrolimus; immediate release tacrolimus
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 202000134

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No