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

Lung Transplant; Complications Clinical Trial

— REVOLUTION  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05001074
• Other study ID #: 202000134
• Status: Recruiting
• Phase: Phase 3
• Start date: July 28, 2020
• Est. completion date: August 1, 2024

Study information

• Verified date: May 2023
• Source: University Medical Center Groningen
• Contact: Heleen Grootjans
• Phone: 0031503616161
• Email: h.grootjans[@]umcg.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 145
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Lung Transplant; Complications

Intervention

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
• 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

Locations

Country	Name	City	State
Netherlands	University medical center Groningen	Groningen

Sponsors (2)

Lead Sponsor	Collaborator
Heleen Grootjans	Chiesi Farmaceutici S.p.A.

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

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):3 — View 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 conversio — View 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. Transpl — View 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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	renal function: absolute change in eGFR	absolute change in eGFR absolute change in eGFR change in eGFR at 2 years	2 years
Secondary	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
Secondary	renal function: 40% eGFR reduction	40% eGFR reduction	2 years
Secondary	renal function: 50% eGFR reduction	50% eGFR reduction	2 years
Secondary	renal function:end stage kidney disease	end stage kidney disease	2 years
Secondary	hypertension	Incidence of inadequate regulated or new onset of hypertension	2 years
Secondary	diabetes mellitus	Incidence of inadequate glycemic control of preexisting diabetes mellitus or new onset diabetes after transplantation (NODAT)	2 years
Secondary	Infections	Incidence of infections	2 years
Secondary	Malignancies	Incidence of malignancies	2 years
Secondary	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
Secondary	neurological function: polyneuropathy	Incidence of or change in pre-existing polyneuropathy	2 years
Secondary	neurological function: sleep quality	Incidence of or change in sleep quality by using validated questionnaire: Pittsburg Sleep Quality Index (PSQI)	2 years
Secondary	neurological function: cognitive functioning	Incidence of or change in cognitive functioning by using validated questionnaire: the Cognitive Functioning Questionnaire (CFQ)	2 years
Secondary	quality of life score	change in SF36 score	2 years
Secondary	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
Secondary	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