Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients
- Conditions
- Lung Transplant; Complications
- Interventions
- Drug: Extended release tacrolimusDrug: Immediate release tacrolimus
- Registration Number
- NCT05001074
- Lead Sponsor
- Heleen Grootjans
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 145
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description de novo cohort, extended release tacrolimus Extended release tacrolimus de novo cohort, extended release tacrolimus de novo cohort, immediate release tacrolimus Immediate release tacrolimus de novo cohort, immediate release tacrolimus conversion cohort, extended release tacrolimus Extended release tacrolimus conversion cohort, extended release tacrolimus conversion cohort, immediate release tacrolimus Immediate release tacrolimus conversion cohort, immediate release tacrolimus
- Primary Outcome Measures
Name Time Method 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
Name Time Method renal function: 50% eGFR reduction 2 years 50% eGFR reduction
hypertension 2 years Incidence of inadequate regulated or new onset of hypertension
renal function:end stage kidney disease 2 years end stage kidney disease
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)
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 neurological toxicity: change in incidence of or change in pre-existing hand tremor by using the validated Fahn-Tolosa-Martin tremor rating scale
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
neurological function: cognitive functioning 2 years Incidence of or change in cognitive functioning by using validated questionnaire: the Cognitive Functioning Questionnaire (CFQ)
Trial Locations
- Locations (1)
University medical center Groningen
🇳🇱Groningen, Netherlands