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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Lung Transplant; Complications

Intervention / Treatment
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* Drug: Extended release tacrolimus
* Drug: Immediate release tacrolimus


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: De novo cohort, 2 arms: de novo lung transplant recipients. Conversion cohort, 2 arms: stable lung transplant recipients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: de novo cohort, extended release tacrolimus<br>de novo cohort, extended release tacrolimus | Drug: Extended release tacrolimus<br>* 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<br>* Other names: LCP tacrolimus;|
| Active Comparator: de novo cohort, immediate release tacrolimus<br>de novo cohort, immediate release tacrolimus | Drug: Immediate release tacrolimus<br>* 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<br>|
| Experimental: conversion cohort, extended release tacrolimus<br>conversion cohort, extended release tacrolimus | Drug: Extended release tacrolimus<br>* 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<br>* Other names: LCP tacrolimus;|
| Active Comparator: conversion cohort, immediate release tacrolimus<br>conversion cohort, immediate release tacrolimus | Drug: Immediate release tacrolimus<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung transplantation, chronic kidney disease, cardiovascular disease, extended release tacrolimus, LCP tacrolimus, immediate release tacrolimus