Tacrolimus Associated Tremors in Liver Transplantation: Immediate-Release Versus Extended-Release Formulations (LCP-TAC)

December 27, 2023 updated by: Trana Hussaini, University of British Columbia

Tacrolimus Associated Tremors in Liver Transplant Recipients: a Randomized Open Label Trial Comparing De Novo Extended-release Once Daily (LCP-TAC) and Twice Daily Immediate-release (IR-TAC) Tacrolimus Formulations

This is a randomized open label study in de novo liver transplant recipients that aims to compare the risk of tacrolimus induced tremors with once daily extended-release formulation, Envarsus, versus the twice daily immediate-release formulation. Both formulations of tacrolimus are currently approved for the prevention of rejection in liver transplant patients.

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: This study is designed to evaluate the incidence and severity of tremors with two different tacrolimus formulations (LCPT versus IR-TAC) when administered in combination with mycophenolate and short term corticosteroids in de novo liver transplant (LT) recipients.

Hypothesis: In de novo liver transplant recipients, an LCPT-based immunosuppression regimen, in combination with mycophenolate and short term steroids offers improved neurotoxicity profile as evidenced by lower incidence and severity of tremors and treatment discontinuation when compared to an identical regimen using twice-daily immediate-release tacrolimus.

Rationale: Tacrolimus is the first line immunosuppressive agent in all organ transplantation and its use is associated with improved patient and graft outcomes. Neurotoxicity including headaches and tremors are amongst common dose limiting toxicities associated with tacrolimus early after liver transplantation. Mitigation strategies include dosage reduction or switch to CSA, both of which can put patient at risk of rejection and other toxicities. LCPT is a new extended release formulation with improved PK parameters and evidence of improved tolerability (lower risk of tremors) in renal transplant population. In this study, we will compare the incidence and severity of tremors associated with IR-TAC, which is currently standard of care at our institution, with LCPT, which is a new dosage form added to the hospital formulary. We will be using wearable sensors to assess the severity of tremors. Furthermore, the objective and systematic documentation of tremor severity during the first 8 weeks after transplantation will provide granular data that will elucidate the natural history of tacrolimus induced tremors early post liver transplantation.

Research design: This is a single centre, prospective, randomized, open label, parallel group trial in adult de novo liver transplant recipients. Patients will be randomized (1:1) to either LCPT or IR-TAC, both groups will receive mycophenolate and short term steroids according to the standard of care protocol. This is a superiority study.

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.
124

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
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1M9

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:

  1. Adults aged 18 years or older
  2. Recipients of a first-time liver transplant
  3. eGFR more than 30 ml/min on the day of tacrolimus initiation
  4. All patients who are eligible to initiate Tacrolimus within 7 days post-liver transplant
  5. Informed consent

Exclusion Criteria:

  1. Recipients of prior organ transplant
  2. Need for hemodialysis either prior or following liver transplantation
  3. Recipients of living donor liver or split deceased donor liver allografts
  4. Recipients of combined liver/kidney transplants
  5. Recipients receiving liver allografts from donors with HCV viremia (detected through nucleic acid testing or other means)
  6. Patients with a history of tremor prior to transplantation including essential tremors, Parkinson's or Parkinsonian syndromes
  7. Patients receiving concomitant medications known to induce tremors such as dopamine blocking agents
  8. Baseline TSH, T3, T4 indicating hyperthyroidism

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: LCPT
Drug: Tacrolimus Extended Release Oral Tablet
Once Daily Tacrolimus
Other Names:
  • Envarsus
Active Comparator: IR-TAC
Drug: Tacrolimus, Immediate Release, Oral
Twice Daily Tacrolimus
Other Names:
  • Prograf
  • Tacrolimus, Sandoz

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
Proportion of patients with tacrolimus induced tremors or worsening tremors or tacrolimus discontinuation due to neurotoxicity at 8 weeks post transplantation
Time Frame: 8 weeks post transplantation
Composite end point of proportion of patients with new tremor as defined by Kinesia One average score of 1 or greater or an increase from baseline of greater than or equal to 1 point at week 8 after transplantation, or tacrolimus discontinuation due to neurotoxicity (tremor, headaches, seizure or dysarthria).
8 weeks post transplantation

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
Proportion of patients reaching the composite end point of death, graft loss or biopsy proven acute cellular rejection (BPAR) at 12 months post transplantation
Time Frame: 12 months post transplantation
The proportion of patients reaching the composite end point of death, graft loss or biopsy proven acute cellular rejection (BPAR)
12 months post transplantation
Tremor related quality of life satisfaction as assessed by the Quality of Life in Essential Tremor (QUEST) scale
Time Frame: 8 weeks post transplantation
The Quality of Life in Essential Tremor (QUEST) is a 30 item scale rated on five-point scale (0-4), corresponding to the frequency (never, rarely, sometimes, frequently, always) with scores ranging from 0 to 120. Higher scores indicate greater dissatisfaction or disability.
8 weeks post transplantation
Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 8 weeks after transplant
Time Frame: 8 weeks post transplant

Simplified Medication Adherence Questionnaire (SMAQ) consists of six questions evaluating different aspects of patient adherence, such as forgetfulness, routine and adverse events. SMAQ is a self-reported questionnaire that has been validated in transplant population. Patients are considered adherent if they reply to all questions with an adherent answer in all six SMAQ items. (ie 1-"yes" , 2-4 - "no", not having missed more than 2 doses during last week or having failed to take the medication on not more than 2 days during the last 3 months.

We are measuring SMAQ twice for this study (at 8 weeks and again at 12 months). Based on the literature, transplant patients are more likely to be adherent early after transplantation but they become progressively less adherent with time after transplant. We would like to determine if once daily tacrolimus has any impact on adherence.
8 weeks post transplant
Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 12 months after transplant
Time Frame: 12 months post transplantation

Simplified Medication Adherence Questionnaire (SMAQ) consists of six questions evaluating different aspects of patient adherence, such as forgetfulness, routine and adverse events. SMAQ is a self-reported questionnaire that has been validated in transplant population. Patients are considered adherent if they reply to all questions with an adherent answer in all six SMAQ items. (ie 1-"yes" , 2-4 - "no", not having missed more than 2 doses during last week or having failed to take the medication on not more than 2 days during the last 3 months.

We are measuring SMAQ twice for this study (at 8 weeks and again at 12 months). Based on the literature, transplant patients are more likely to be adherent early after transplantation but they become progressively less adherent with time after transplant. We would like to determine if once daily tacrolimus has any impact on adherence.
12 months post transplantation

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of biopsy proven acute cellular rejection (BPAR)
Time Frame: 3, 6 and 12 months post transplantation
Incidence of biopsy proven acute cellular rejection (BPAR) by Banff 97 criteria
3, 6 and 12 months post transplantation
Incidence and severity of AKI
Time Frame: 1,3 and 6 months post transplant
Incidence and severity of AKI based on KDIGO classification
1,3 and 6 months post transplant
eGFR (MDRD) < 45 mL/min and < 30 mL/min
Time Frame: 6 & 12 months after transplant
Proportion of patients with eGFR (MDRD) < 45 mL/min and < 30 mL/min
6 & 12 months after transplant
Change in GFR
Time Frame: 12 months after transplant
Change in GFR from month 1 (day 28) to month 12 (day 364)
12 months after transplant
Incidence of new onset diabetes after transplantation (NODAT)
Time Frame: 6 and 12 months post transplant
Incidence of new onset diabetes after transplantation (NODAT)
6 and 12 months post transplant
Severity of tremors
Time Frame: 2, 4, 6 and 8 weeks after transplantation
Proportion of patients with mild, moderate and severe tremor
2, 4, 6 and 8 weeks after transplantation

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 British Columbia

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.
Paladin Labs Inc.

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: Trana Hussaini, Pharm D, University of British Columbia
  • Study Chair: Jo-Ann Ford, RN, University of British Columbia

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.
January 9, 2023

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.
January 1, 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.
December 31, 2026

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).
October 8, 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.
October 20, 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.
October 22, 2021

Study Record Updates

Last Update Posted (Estimated)

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.
January 1, 2024

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.
December 27, 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.
December 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.
  • H20-01688

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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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