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

Sponsor

University of British Columbia (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05089604

Collaborator

Paladin Labs Inc. (Other)

124

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Transplantation Immunosuppression Neurotoxicity Tremor Tacrolimus	Drug: Tacrolimus, Immediate Release, Oral Drug: Tacrolimus Extended Release Oral Tablet	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

124 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Dec 1, 2021

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

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: Tacrolimus, Sandoz Prograf

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:

Tacrolimus, Sandoz

Prograf

Outcome Measures

Primary Outcome Measures

Proportion of patients with tacrolimus induced tremors or worsening tremors or tacrolimus discontinuation due to neurotoxicity at 8 weeks post transplantation [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).

Secondary Outcome Measures

Proportion of patients reaching the composite end point of death, graft loss or biopsy proven acute cellular rejection (BPAR) at 12 months post transplantation [12 months post transplantation]
The proportion of patients reaching the composite end point of death, graft loss or biopsy proven acute cellular rejection (BPAR)
Tremor related quality of life satisfaction as assessed by the Quality of Life in Essential Tremor (QUEST) scale [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.
Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 8 weeks after transplant [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.
Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 12 months after transplant [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.

Other Outcome Measures

Incidence of biopsy proven acute cellular rejection (BPAR) [3, 6 and 12 months post transplantation]
Incidence of biopsy proven acute cellular rejection (BPAR) by Banff 97 criteria
Incidence and severity of AKI [1,3 and 6 months post transplant]
Incidence and severity of AKI based on KDIGO classification
eGFR (MDRD) < 45 mL/min and < 30 mL/min [6 & 12 months after transplant]
Proportion of patients with eGFR (MDRD) < 45 mL/min and < 30 mL/min
Change in GFR [12 months after transplant]
Change in GFR from month 1 (day 28) to month 12 (day 364)
Incidence of new onset diabetes after transplantation (NODAT) [6 and 12 months post transplant]
Incidence of new onset diabetes after transplantation (NODAT)
Severity of tremors [2, 4, 6 and 8 weeks after transplantation]
Proportion of patients with mild, moderate and severe tremor

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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