Randomized Controlled Trial Comparing Immediate Versus Extended Release Tacrolimus; Reducing Calcineurin Inhibitor Related Toxicity in Lung Transplantation Patients
Overview
- Phase
- Phase 3
- Intervention
- Extended release tacrolimus
- Conditions
- Lung Transplant; Complications
- Sponsor
- Heleen Grootjans
- Enrollment
- 145
- Locations
- 1
- Primary Endpoint
- renal function: absolute change in eGFR
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
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.
Investigators
Heleen Grootjans
Drs. Heleen Grootjans, internist-nephrologist
University Medical Center Groningen
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)
Arms & Interventions
de novo cohort, extended release tacrolimus
de novo cohort, extended release tacrolimus
Intervention: Extended release tacrolimus
de novo cohort, immediate release tacrolimus
de novo cohort, immediate release tacrolimus
Intervention: Immediate release tacrolimus
conversion cohort, extended release tacrolimus
conversion cohort, extended release tacrolimus
Intervention: Extended release tacrolimus
conversion cohort, immediate release tacrolimus
conversion cohort, immediate release tacrolimus
Intervention: Immediate release tacrolimus
Outcomes
Primary Outcomes
renal function: absolute change in eGFR
Time Frame: 2 years
absolute change in eGFR absolute change in eGFR change in eGFR at 2 years
Secondary Outcomes
- renal function: 50% eGFR reduction(2 years)
- hypertension(2 years)
- renal function:end stage kidney disease(2 years)
- diabetes mellitus(2 years)
- Infections(2 years)
- Malignancies(2 years)
- neurological function: tremor(2 years)
- neurological function: polyneuropathy(2 years)
- neurological function: sleep quality(2 years)
- quality of life score(2 years)
- pharmacogenetic(2 years)
- graft function(2 years)
- renal function: 40% eGFR reduction(2 years)
- neurological function: cognitive functioning(2 years)