Extended-Release Tacrolimus Following Liver Transplantation

September 10, 2026 updated by: University of Alberta

Feasibility, Efficacy And Safety Of De Novo Extended-Release Tacrolimus Following Liver Transplantation

Medications used after transplant to prevent rejection are associated with many side effects. Tacrolimus side effects include kidney dysfunction; tremor, headaches, difficulty sleeping, change in sensation (legs), seizure, or confusion; high blood pressure; anemia, or low blood cell counts; diabetes; abnormal cholesterol and weight gain. The investigators want to use a new, approved, formulation of the standard medication (Envarsus) as they believe it may be associated with reduced side effects. The investigators would like to assess how safe it is to use this medication and how well it works in comparison to currently used formulations. The investigators will study if there are less side effects and will study clinical outcomes (including how well the liver does and if there is need for hospitalizations after transplant).

The investigators hope that this information will improve the care provided to and outcomes in patients following liver transplant.

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

PURPOSE

To assess the impact of Envarsus on toxicity and clinical outcomes in participants following liver transplant. Tacrolimus-based immunosuppression is the standard of care following liver transplantation (LT). This medication is associated with significant toxicity including renal dysfunction, increased risk of diabetes and neurotoxicity. Of note, both nephrotoxicity and neurotoxicity occur at elevated peak serum tacrolimus blood concentrations and improve when the dose is reduced or discontinued. Envarsus does not have the high peak seen with initial dosing in the other formulations. This may be one of the reasons Envarsus use improves tremor associated with tacrolimus use.

HYPOTHESES

Use of extended-release tacrolimus following LT will be: 1. Effective and safe. 2. Without any difference in rejection. 3. Less nephrotoxic with reduced incidence of renal impairment. 4. Better with regard to features of metabolic syndrome including myosteatosis. 5. Less neurotoxic. 6. Better with regard to both graft and patient survival when compared to immediate-release tacrolimus (Prograf®).

JUSTIFICATION

Tacrolimus-associated toxicity, especially renal dysfunction is common following LT (up to 25%) and is associated with increased mortality. Showing extended-release tacrolimus (Envarsus) is safe and efficacious will lead to broader use in the post-transplant setting. Use of this regimen leads to decreased maximum concentration and in some studies has shown benefit with regards to renal function. Such benefit will no doubt translate into improved long-term outcomes including survival and reduced healthcare costs.

OBJECTIVES/AIMS

The aim of this study is to assess the feasibility, safety and efficacy of using Envarsus in comparison to the immediate-release tacrolimus (Prograf®) following LT. Additional objectives include impact on renal function, metabolic syndrome, myosteatosis (fatty infiltration of skeletal muscle; reflects poor quality and function and correlated with poor outcomes), cardiovascular events, neurotoxicity, graft and patient survival.

METHODS

Basic study design

This will be a randomized control trial where participants will be randomized 1:1 to two groups: i) Prograf (dose 0.10 - 0.15mg/Kg daily; divided into BID dosing), ii) Envarsus (0.11 - 0.13 mg/Kg/day); both groups will be on mycophenolate (dose 1g BID) and will receive basiliximab (dose 20 mg) for induction at POD 0 and 4. Participants will be enrolled prior to transplant or up to 90 days following LT. The first dose will be administered within 90 days of LT. Randomization will be done at the first post-transplant outpatient visit (30-90 days post-transplant). Randomization will be stratified according to gender, bilirubin (< 50 and ≥ 50 umol/L), albumin (<30 and ≥ 30 g/L) and diagnosis of diabetes and renal function (according to the category of estimated GFR (45 to <60 ml, or 60 to <90 ml per minute per 1.73 m2)) to ensure that all groups are homogeneous. Tacrolimus will be taken orally with water, twice daily in the immediate-release group and once daily in the extended-release group for the duration of the study. Participants will take tacrolimus at approximately the same time each day (1 hour before meals). Participants will be instructed to swallow the tablet whole (no chewing, dividing, or crushing the tablet).

All participants who have received a liver transplant at the University of Alberta in Edmonton, Canada who are at least 18 years of age will be eligible for enrollment (18 month period following study initiation).

The primary analysis will be at 1-year, however, there will be a 10 year period of follow up off-trial. This will include participant outcomes (hospitalizations, complications of rejection, diabetes, renal dysfunction, cardiovascular events, graft and participant survival). The study will be carried out in compliance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice.

Covariates of interest

Baseline participant characteristics - Participant demographics; height, weight, BMI and waist circumference; etiology of cirrhosis; co-morbidities including diabetes, dyslipidemia, hypertension, smoking status and cardiovascular disease. History of malignancies at the time of transplant evaluation will also be noted. Immunosuppression (IS) following LT (at discharge, 1-, 3-, 6-, 12-, 60-months following LT and at end of follow up) and levels and dose of IS will also be recorded. Any changes, or adverse events including neurotoxicity due to IS will also be recorded. Finally, any episodes of rejection (based on biopsy) will be recorded. Biopsy will be obtained if clinically indicated at any time during the post-transplant course based on the participants presentation (persistently elevated liver enzymes or liver function tests, or abnormal FibroScan (liver stiffness > 9 kPa)). FibroScan will be done at one year, two years post-transplant and then every 2-years until end of follow up.

Biochemistry - serum creatinine, INR, sodium and bilirubin will be acquired. Data on albumin, transaminases, GGT, electrolytes, and CBC will also be collected. Values for lipid profiles, random and fasting blood glucose, insulin levels, and hemoglobin A1C will be recorded.

Analysis plan

Safety and efficacy - will be assessed descriptively. All participants who received at least one dose of Envarsus® will be included for analysis in the Envarsus® group. Only treatment related adverse events will be analyzed (complications following surgery such as bile leak, vascular thrombus, etc. will not be reported). The difference between the groups with regards to number of adverse events will be determined using poisson regression.

Incidence of acute rejection will be reported; Cox regression will be used to determine if there is a difference between the 2 study groups.

Impact of extended-release tacrolimus on secondary endpoints:

Impact on renal function - Proportion of participants with renal impairment (change in GFR 10%), number of episodes of AKI, incidence of AKI and CKD will be reported. The investigators will use Cox regression to determine if there is a difference between the 2 study groups with regards to renal function. Participants will be analyzed according to the treatment group to which they were randomized and not based on medication taken during the course of the study.

Incidence of diabetes, metabolic syndrome, and neurotoxicity will be reported. Rates of hospitalization, incidence of myosteatosis and patient and graft survival will be reported. Cox regression will be used to determine if there is a difference between the 2 study groups with regards to neurotoxicity and development of myosteatosis. The investigators will use poisson regression to determine difference between groups with regards to hospitalization rates. The investigators will use ANCOVA to determine if there is a difference between groups with regards to features of metabolic syndrome (diabetes, glycemic control, dyslipidemia, weight gain and hypertension). Difference in LOS between groups will be determined using linear regression. The investigators will use Kaplan Meier curves and log-rank test to determine if there is a difference in graft survival or mortality between the two arms (p-value will be provided).

Sample size calculation

This is a feasibility study thus no sample size calculation was required. The investigators will aim to enroll 94 participants over a 18 month period. Recruitment should not be a problem as approximately 90-100 LT are done each year at the University of Alberta.

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 (Estimated)

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.
94

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 4

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

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G 2R3
        • Recruiting
        • Univerity of Alberta
        • Contact:
        • Principal Investigator:
          • Rahima Bhanji, MD

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

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

- Adult individuals transplanted at the University of Alberta

Exclusion Criteria:

  • Individuals with congenital long QT syndrome
  • Patients with elevated bilirubin > 100 umol/L post-LT (at day 3)
  • Patients with chronic kidney disease (eGFR < 45 ml per minute per 1.73 m2)
  • Patients with acute kidney injury requiring discontinuation of calcineurin inhibitors.
  • Patients who have hepatocellular carcinoma, require a re-transplant, or receive multi-visceral transplant

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.
Active Comparator: Envarsus
Envarsus tablet Dose 0.11 - 0.13 mg/Kg/day Frequency: once per day
Drug: Envarsus Oral Product
as described in arm/group description
Other: Prograf (SOC)
Prograf tablet Dose 0.10 - 0.15mg/Kg daily Frequency: 2 doses per day (dose above split in half for each dose)
Drug: Prograf (SOC)
Prograf (SOC)

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
Safety of Envarsus as indicated by adverse events
Time Frame: 1 year
Adverse events include frequency of transplant rejection, and changes from baseline in clinical laboratory parameters
1 year

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
Incidence of renal impairment
Time Frame: 1-10 years
We will consider participants with >10% decline in GFR to represent a group with renal impairment. We will define acute kidney injury (AKI) as at least a 50% and/or a 26.5 µmol/L (0.3 mg/dL) increase in serum creatinine level relative to the baseline reference value as per Kidney Disease: Improving Global Outcomes (KDIGO) criteria (11) in participants without pre-existing CKD. CKD will be defined as eGFR <60 ml/min for more than 3 months, according to the KDIGO criteria (13), evidence of intrinsic renal disease or requiring renal replacement therapy. Acute on CKD will be defined as at least a 50% and/or a 26.5 µmol/L (0.3 mg/dL) increase in serum creatinine level relative to the baseline reference value as per KDIGO criteria (11) in participants with pre-existing CKD. The baseline creatinine will be defined as the minimum of all values available within 3 months of LT.
1-10 years
Number of patients with metabolic syndromes [diabetes]
Time Frame: 1-10 years

Diabetes will be diagnosed based on an elevated fasting plasma glucose (≥7.0 mmol/l) or an elevated 2-hour plasma glucose (≥11.1 mmol/l) during an oral glucose tolerance test or an elevated random plasma glucose (≥11.1 mmol/l).

Glycemic control will be measured by fasting blood glucose and hemoglobin A1C (at 3-, 6-, 12, 60-months following LT and at end of follow up). Change in hemoglobin A1C at 1 year post LT from baseline will be used as a measure of glycemic control. Hemoglobin A1C value within 3 months of LT will be used as the baseline value.
1-10 years
Incidence of neurotoxicity
Time Frame: 1 years
adverse events including tremor, headache, insomnia, dysesthesia, or mood disturbance will be recorded. Severe events including akinetic mutism, seizures, cortical blindness, focal neurological deficits, encephalopathy, decreased cognitive ability and psychosis will be monitored and recorded
1 years
Length of stay in hospitalized patients
Time Frame: 1-10 years
From time of admission for surgery to time of discharge.
1-10 years
Incidence of Intensive Care Unit (ICU) admission
Time Frame: 1-10 years
Looking at if the patient is admitted to the ICU post transplant
1-10 years
Length of Intensive Care Unit admission
Time Frame: 1-10 years
Length of stay in the intensive care unit if admitted post transplant
1-10 years
Incidence of hospitalizations
Time Frame: 1-10 years
how many patients are hospitalized post transplant
1-10 years
Patient Survival
Time Frame: 1-10 years
Liver-related versus all-cause mortality will be documented.
1-10 years
Graft Survival
Time Frame: 1-10 years
Any re-transplants will be recorded.
1-10 years
Impact on quality of life (QOL) - Chronic Liver Disease Questionnaire
Time Frame: 1 year

Using the Chronic Liver Disease Questionnaire (CLDQ) which is a disease specific questionnaire. This will be administered twice during the study period; at the start and after 12 months of study enrollment.

Minimum score: 1 Maximum score: 7

The higher score indicates a better outcome
1 year
Impact on quality of life (QOL) - EuroQuol-5Dimensions-5 Levels Questionnaire
Time Frame: 1 year

EuroQuol-5Dimensions-5Levels (EQ-5D-5L)

Description System section Maximum score 1 Minimum score 5

A higher score indicates a lower assessment for quality of life
1 year
Muscularity assessment
Time Frame: 1 year
mean muscle attenuation in Hounsfield units will be calculated for the entire muscle area at the third lumbar (L3) vertebra. Myosteatosis will be defined as <41 mean Hounsfield units in patients with a BMI up to 24.9, and <33 mean Hounsfield units in those with a BMI ≥25. These cut-off values have been used previously in patients with cirrhosis and have been shown to be associated with mortality (17). We will use CT L3 skeletal muscle index (L3 SMI) expressed as cross sectional muscle area/height2, and cutoffs for sarcopenia will be based on values for cirrhotic patients (L3 SMI: < 39 cm2/m2 for women and < 50 cm2/m2 for men). CT will be obtained at 1 year post-LT.
1 year
Impact on quality of life (QOL) - EuroQuol Visual Analogue Scale (VAS)
Time Frame: 1 year

EuroQuol Visual Analogue Scale (VAS) Max score 100 Minimum score 0

A higher score indicates a higher quality of life
1 year

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.
University of Alberta

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.
May 15, 2022

Primary Completion (Estimated)

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.
December 15, 2026

Study Completion (Estimated)

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.
February 15, 2034

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).
January 19, 2022

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.
February 15, 2022

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.
February 16, 2022

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.
September 15, 2026

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.
September 10, 2026

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.
September 1, 2026

More Information

Terms related to this study

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.
  • Pro00105029

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Potential to share de-identified data if requested from other researchers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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