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

Sponsor

Heleen Grootjans (Other)

Overall Status

Recruiting

CT.gov ID

NCT05001074

Collaborator

Chiesi Farmaceutici S.p.A. (Industry)

145

Enrollment

Location

Arms

48.1

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lung Transplant; Complications	Drug: Extended release tacrolimus Drug: Immediate release tacrolimus	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

145 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

De novo cohort, 2 arms: de novo lung transplant recipients. Conversion cohort, 2 arms: stable lung transplant recipientsDe novo cohort, 2 arms: de novo lung transplant recipients. Conversion cohort, 2 arms: stable lung transplant recipients

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 28, 2020

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: de novo cohort, extended release tacrolimus 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 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 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 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

Outcome Measures

Primary Outcome Measures

renal function: absolute change in eGFR [2 years]
absolute change in eGFR absolute change in eGFR change in eGFR at 2 years

Secondary Outcome Measures

graft function [2 years]
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.
renal function: 40% eGFR reduction [2 years]
40% eGFR reduction
renal function: 50% eGFR reduction [2 years]
50% eGFR reduction
renal function:end stage kidney disease [2 years]
end stage kidney disease
hypertension [2 years]
Incidence of inadequate regulated or new onset of hypertension
diabetes mellitus [2 years]
Incidence of inadequate glycemic control of preexisting diabetes mellitus or new onset diabetes after transplantation (NODAT)
Infections [2 years]
Incidence of infections
Malignancies [2 years]
Incidence of malignancies
neurological function: tremor [2 years]
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)
neurological function: polyneuropathy [2 years]
Incidence of or change in pre-existing polyneuropathy
neurological function: sleep quality [2 years]
Incidence of or change in sleep quality by using validated questionnaire: Pittsburg Sleep Quality Index (PSQI)
neurological function: cognitive functioning [2 years]
Incidence of or change in cognitive functioning by using validated questionnaire: the Cognitive Functioning Questionnaire (CFQ)
quality of life score [2 years]
change in SF36 score
pharmacogenetic [2 years]
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
pharmacogenetic [2 years]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)