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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE3

Total Enrollment

145 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-07-28

Study Completion Date

2024-08-01

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Lung Transplant; Complications

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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de novo cohort, extended release tacrolimus

Group Type EXPERIMENTAL

Extended release tacrolimus

Intervention Type DRUG

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

de novo cohort, immediate release tacrolimus

Group Type ACTIVE_COMPARATOR

Immediate release tacrolimus

Intervention Type DRUG

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

conversion cohort, extended release tacrolimus

Group Type EXPERIMENTAL

Extended release tacrolimus

Intervention Type DRUG

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

conversion cohort, immediate release tacrolimus

Group Type ACTIVE_COMPARATOR

Immediate release tacrolimus

Intervention Type DRUG

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

Interventions

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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

Intervention Type 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

Intervention Type DRUG

Other Intervention Names

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LCP tacrolimus

Eligibility Criteria

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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)

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No