Clinical trial NCT05655273: Conversion of Maintenance Prograf to Envarsus in Liver Transplant Recipients
Official title: Prograf/Envarsus Conversion Study in Liver Transplant Recipients to Improve Side Effects, Adherence and Quality of Life: a Single-centre Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Liver Transplant Rejection
Immune System Suppression
Keywords: liver transplant
tacrolimus toxicity
drug conversion
tacrolimus
prograf
envarsus
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Paladin Labs Inc.
First posted: 2022-12-19
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: conversion v. control
Primary purpose: TREATMENT

Brief summary: Prograf and Envarsus are two different formulations of Tacrolimus which is used as an immunosuppressant in liver transplant (LT) patients. Prograf is currently used as part of the standard immunosuppression regimen for LT recipients at UHN. This study will compare the use of Prograf and Envarsus and their effects on liver and renal function, trough tacrolimus levels, drug-related adverse effects, and patient adherence. Trial design is a pilot randomized trial. The study aims to recruit 40 patients from UHN's LT program and they will be randomized 1:1 to either stay on their current dose of Prograf or be converted to a once-daily equivalent dose of Envarsus. Both groups of patients will be followed for 48 weeks. This study will compare the change from baseline to week 48 in liver and renal function, tacrolimus-related side effects and patient reported outcomes between the two study groups.

Detailed description: Tacrolimus (Prograf ©) has become part of the standard of care for patients receiving solid organ transplants and is part of the immunosuppressive protocol (along with prednisone and mycophenolate mofetil \[CellCept ©\]) used by liver transplant recipients at University Health Network (UHN). Tacrolimus is associated with several toxicities including renal injury, tremor, pancreatic islet β-cell injury (leading to diabetes) and hyperlipidemia. As a result of these potential toxicities, careful therapeutic drug monitoring of tacrolimus is a key component of post-transplant management. Tacrolimus trough levels are known to correlate with total tacrolimus exposure, as shown from formal pharmacokinetic assessments. Accordingly, trough serum concentrations of tacrolimus are measured routinely in all recipients and are used to guide dosing. The Prograf formulation of tacrolimus has a short serum half-life and must be dosed twice daily to maintain therapeutic serum concentrations. Further, Prograf administration results in a high peak tacrolimus level. Peak tacrolimus levels have been shown to correlate with toxicity; thus, avoidance of high peaks may be desirable to minimize tacrolimus toxicity.

Envarsus is an extended-release formulation of tacrolimus that provides similar drug exposure to tacrolimus at a 30% lower dose but with a once daily dosing regimen. Envarsus dosing also results in a lower peak tacrolimus level compared to Prograf. In this way, it is hoped that Envarsus may provide similar therapeutic efficacy as Prograf but with fewer adverse effects. In addition, the simpler dosing regimen is expected to enhance patient adherence and quality of life.

The present study is aimed at evaluating the impact of a switch from Prograf to Envarsus on liver and renal function, trough tacrolimus levels, drug-related adverse effects and adherence. It hypothesizes that once daily Envarsus can be substituted at reduced daily dose for twice daily Prograf in stable liver transplant recipients without clinically meaningful changes in liver allograft function while reducing tacrolimus side effects, reducing cumulative daily dose of the drug and increasing adherence to treatment and quality of life.The results of this study have the potential to change current practice. Trial design is a pilot randomized trial. The study aims to recruit 40 patients from UHN's LT program and they will be randomized 1:1 to either stay on their current dose of Prograf or be converted to a once-daily equivalent dose of Envarsus. Both groups of patients will be followed for 48 weeks. This study will compare the change from baseline to week 48 in liver and renal function, tacrolimus-related side effects and patient reported outcomes between the two study groups.

Eligibility criteria: Inclusion Criteria:

* Adult (\>18 years) prevalent liver transplant recipient
* \>12 months after liver transplant
* Prograf-based maintenance immunosuppression with targeted tacrolimus trough level of 5-10 ug/L
* Stable liver allograft function (defined as ASL \& ALT \<30, Bilirubin \<20 \& ALP\<150 at baseline visit or within 4 weeks of baseline visit)
* Stable renal function (creatinine \< 180 µmol/l and eGFR \> 40 ml/min) at baseline visit (or within 4 weeks of baseline visit)
* No episode of acute rejection within 6 months of baseline visit
* Elevated creatinine (defined as \>ULN) OR Significant symptoms (by patient self-report) potentially associated with tacrolimus (eg. tremor, difficulty to concentrate, insomnia) OR difficulty to adhere to a twice daily regimen

Exclusion Criteria:

* Multiorgan transplant;
* severe intercurrent illness;
* severe cognitive impairment (all as determined by clinical team);
* unwilling to consent.

Primary outcomes:
measure: Change in AST levels
timeFrame: Baseline to week 12
measure: Change in ALT levels
timeFrame: Baseline to week 12
measure: Change in ALP levels
timeFrame: Baseline to week 12
measure: Change in Bilirubin blood levels
timeFrame: Baseline to week 12
measure: Change in tacrolimus trough levels
timeFrame: Baseline to week 12
measure: Change in overall daily dose of tacrolimus
timeFrame: Baseline to week 12
Secondary outcomes:
measure: Change in Systolic Blood Pressure
timeFrame: Baseline to week 24 and week 48
measure: Change in Diastolic Blood Pressure
timeFrame: Baseline to week 24 and week 48
measure: Change in Renal function (eGFR)
timeFrame: Baseline to week 24 and week 48
measure: Change in tremor severity (for subset of patients who report significant tremor at baseline)
timeFrame: Baseline to week 24 and week 48
measure: Change in glycemic control (HbA1c)
timeFrame: Baseline to week 24 and week 48
measure: Change in lipid profile
timeFrame: Baseline to week 24 and baseline to week 48
measure: Change in Patient-Reported Outcomes Measurement Information Systems' Pain Interference Bank 2.0
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Sleep Disturbance Bank 1.0
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Anxiety Bank 1.0
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Depression Bank 1.0
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Global Health Scale version 1.2
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Fatigue bank 1.0
timeFrame: Baseline to Week 48 (inclusive)
measure: Change in Patient-Reported Outcomes Measurement Information Systems' (PROMIS) Ability to Participate in Social Roles and Activities
timeFrame: Baseline to Week 48 (inclusive)
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Nazia Selzner, MD
role: PRINCIPAL_INVESTIGATOR
References: