Clinical trial NCT05001074: Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients
Official title: Randomized Controlled Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Lung Transplant; Complications
Keywords: lung transplantation
chronic kidney disease
cardiovascular disease
extended release tacrolimus
LCP tacrolimus
immediate release tacrolimus
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Chiesi Farmaceutici S.p.A.
First posted: 2021-08-11
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: De novo cohort, 2 arms: de novo lung transplant recipients. Conversion cohort, 2 arms: stable lung transplant recipients
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: renal function: absolute change in eGFR
timeFrame: 2 years
Secondary outcomes:
measure: graft function
timeFrame: 2 years
measure: renal function: 40% eGFR reduction
timeFrame: 2 years
measure: renal function: 50% eGFR reduction
timeFrame: 2 years
measure: renal function:end stage kidney disease
timeFrame: 2 years
measure: hypertension
timeFrame: 2 years
measure: diabetes mellitus
timeFrame: 2 years
measure: Infections
timeFrame: 2 years
measure: Malignancies
timeFrame: 2 years
measure: neurological function: tremor
timeFrame: 2 years
measure: neurological function: polyneuropathy
timeFrame: 2 years
measure: neurological function: sleep quality
timeFrame: 2 years
measure: neurological function: cognitive functioning
timeFrame: 2 years
measure: quality of life score
timeFrame: 2 years
measure: pharmacogenetic
timeFrame: 2 years
measure: pharmacogenetic
timeFrame: 2 years
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University medical center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Tji Gan
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.