Clinical trial NCT05089604: Tacrolimus Associated Tremors in Liver Transplantation: Immediate-Release Versus Extended-Release Formulations
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Liver Transplantation
Immunosuppression
Neurotoxicity
Tremor
Tacrolimus
Keywords: Liver Transplant
Tacrolimus
Immunosuppression
Tremor
Envarsus
LCP-TAC
Neurotoxicity
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Paladin Labs Inc.
First posted: 2021-10-22
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of patients with tacrolimus induced tremors or worsening tremors or tacrolimus discontinuation due to neurotoxicity at 8 weeks post transplantation
timeFrame: 8 weeks post transplantation
Secondary outcomes:
measure: Proportion of patients reaching the composite end point of death, graft loss or biopsy proven acute cellular rejection (BPAR) at 12 months post transplantation
timeFrame: 12 months post transplantation
measure: Tremor related quality of life satisfaction as assessed by the Quality of Life in Essential Tremor (QUEST) scale
timeFrame: 8 weeks post transplantation
measure: Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 8 weeks after transplant
timeFrame: 8 weeks post transplant
measure: Immunosuppression medication adherence as assessed by the Simplified Medication Adherence Questionnaire (SMAQ) at 12 months after transplant
timeFrame: 12 months post transplantation
Other outcomes:
measure: Incidence of biopsy proven acute cellular rejection (BPAR)
timeFrame: 3, 6 and 12 months post transplantation
measure: Incidence and severity of AKI
timeFrame: 1,3 and 6 months post transplant
measure: eGFR (MDRD) < 45 mL/min and < 30 mL/min
timeFrame: 6 & 12 months after transplant
measure: Change in GFR
timeFrame: 12 months after transplant
measure: Incidence of new onset diabetes after transplantation (NODAT)
timeFrame: 6 and 12 months post transplant
measure: Severity of tremors
timeFrame: 2, 4, 6 and 8 weeks after transplantation
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Trana Hussaini, Pharm D
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Jo-Ann Ford, RN
role: STUDY_CHAIR
References: