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

May 9, 2023 updated by: Heleen Grootjans

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

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
145

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • Recruiting
        • University Medical Center Groningen
        • Contact:
          • Heleen Grootjans
          • Phone Number: 0031503616161
        • Principal Investigator:
          • Tji Gan
        • Sub-Investigator:
          • Heleen Grootjans
        • Sub-Investigator:
          • Erik Verschuuren
        • Sub-Investigator:
          • Stefan Berger
        • Sub-Investigator:
          • Daan Touw

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: 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
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
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
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

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
renal function: absolute change in eGFR
Time Frame: 2 years
absolute change in eGFR absolute change in eGFR change in eGFR at 2 years
2 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
graft function
Time Frame: 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.
2 years
renal function: 40% eGFR reduction
Time Frame: 2 years
40% eGFR reduction
2 years
renal function: 50% eGFR reduction
Time Frame: 2 years
50% eGFR reduction
2 years
renal function:end stage kidney disease
Time Frame: 2 years
end stage kidney disease
2 years
hypertension
Time Frame: 2 years
Incidence of inadequate regulated or new onset of hypertension
2 years
diabetes mellitus
Time Frame: 2 years
Incidence of inadequate glycemic control of preexisting diabetes mellitus or new onset diabetes after transplantation (NODAT)
2 years
Infections
Time Frame: 2 years
Incidence of infections
2 years
Malignancies
Time Frame: 2 years
Incidence of malignancies
2 years
neurological function: tremor
Time Frame: 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)
2 years
neurological function: polyneuropathy
Time Frame: 2 years
Incidence of or change in pre-existing polyneuropathy
2 years
neurological function: sleep quality
Time Frame: 2 years
Incidence of or change in sleep quality by using validated questionnaire: Pittsburg Sleep Quality Index (PSQI)
2 years
neurological function: cognitive functioning
Time Frame: 2 years
Incidence of or change in cognitive functioning by using validated questionnaire: the Cognitive Functioning Questionnaire (CFQ)
2 years
quality of life score
Time Frame: 2 years
change in SF36 score
2 years
pharmacogenetic
Time Frame: 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
2 years
pharmacogenetic
Time Frame: 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
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Heleen Grootjans

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Chiesi Farmaceutici S.p.A.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Tji Gan, University Medical Center Groningen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 28, 2020

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2024

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 1, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 3, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 11, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 10, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 9, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 202000134

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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