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

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: Recruiting
• Conditions: Liver Transplantation; Neurotoxicity; Tremor; Tacrolimus; Immunosuppression
• Intervention / Treatment: Drug: Tacrolimus Extended Release Oral Tablet; Drug: Tacrolimus, Immediate Release, Oral

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: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Eric Yoshida, MD; Phone Number: 604-872-9858; Email: eric.yoshida@vch.ca
• Study Contact Backup: Name: Trana Hussaini; Phone Number: 6043284930; Email: trana.hussaini@vch.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Recruiting
      • Vancouver General Hospital
      • Contact: Trana Hussaini; Phone Number: 6043284930; Email: trana.hussaini@vch.ca
      • Contact: Jo-Ann Ford; Email: jo-ann.ford@vch.ca

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

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	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

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	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	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	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	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

Outcome Measure	Measure Description	Time Frame
Incidence of biopsy proven acute cellular rejection (BPAR)	Incidence of biopsy proven acute cellular rejection (BPAR) by Banff 97 criteria	3, 6 and 12 months post transplantation
Incidence and severity of AKI	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	Proportion of patients with eGFR (MDRD) < 45 mL/min and < 30 mL/min	6 & 12 months after transplant
Change in GFR	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)	Incidence of new onset diabetes after transplantation (NODAT)	6 and 12 months post transplant
Severity of tremors	Proportion of patients with mild, moderate and severe tremor	2, 4, 6 and 8 weeks after transplantation

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Paladin Labs Inc.
• Investigators: Principal Investigator: Trana Hussaini, Pharm D, University of British Columbia; Study Chair: Jo-Ann Ford, RN, University of British Columbia

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2023
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: October 8, 2021
• First Submitted That Met QC Criteria: October 20, 2021
• First Posted (Actual): October 22, 2021

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Immunosuppression; Tacrolimus; Tremor; Liver Transplant; Envarsus; LCP-TAC; Neurotoxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Neurologic Manifestations; Dyskinesias; Poisoning; Neurotoxicity Syndromes; Tremor; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID 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