Evaluation of Cognitive Function Post-Liver Transplantation: A Comparative Study of Once-Daily Versus Twice-Daily Tacrolimus Formulations

The primary objective of this study is to determine whether the once-daily formulation of **Tacrolimus** (Envarsus®) improves the subjective impression of attention and memory performance compared to the twice-daily formulation of Tacrolimus in patients with liver transplant status. This is clinically relevant as cognitive function is a critical aspect of post-transplant quality of life, and optimizing medication regimens could potentially enhance cognitive outcomes for these patients.

The clinical trial involves participants who are **liver transplant** recipients, specifically those who are between the ages of 20 and 75 years. Both male and female subjects are included in the study, and the population is not considered vulnerable. Participants are required to be at least 12 months post-transplantation and must have been on a twice-daily formulation of Tacrolimus for at least three months. Additionally, they should exhibit at least mild cognitive impairment. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is homogenous in terms of their post-transplant status and current immunosuppressive regimen, which is crucial for evaluating the trial's objective. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the impact of different formulations of **tacrolimus** on cognitive function in patients with liver transplant status. This is a Phase IV, randomized, double-blind, controlled trial comparing once-daily Envarsus prolonged-release tablets with twice-daily Prograf hard capsules. The trial aims to assess whether the once-daily formulation improves subjective impressions of attention and memory performance. The study is expected to last for approximately 12 months, with participant involvement spanning the same duration.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (20 to 75 years), post-transplantation status, and current immunosuppression regimen. Following the screening, participants will be randomized to receive either the test or comparator formulation. Subsequent visits will occur at 6 months and at the end of the study at 12 months. During these visits, primary and secondary endpoints will be assessed, including changes in quality of life (QoL) and cognitive function using validated tests such as the Trail Making Test and the SF36 questionnaire.

The expected length of participant involvement is 12 months, with conditions for early termination including the occurrence of serious adverse events or significant deviations from the study protocol. All adverse events and relevant laboratory parameters will be documented at each visit. The trial's primary endpoint is the change in subjective impression of QoL concerning attention and memory between the screening and the 6-month visit. Secondary endpoints include various cognitive assessments and QoL measures at specified intervals throughout the study.

The clinical trial involves the administration of several formulations of **tacrolimus**, a chemical immunosuppressant agent, to evaluate cognitive function post-liver transplantation. The experimental medication, **Envarsus**, is available in three different strengths: 4 mg, 1 mg, and 0.75 mg, all in the form of prolonged-release tablets. These tablets are manufactured by Chiesi Farmaceutici S.P.A. and are administered orally. The maximum daily dose for Envarsus is 0.13 mg/kg, with a total maximum dose of 47.45 mg/kg over a treatment period of up to 12 months. The prolonged-release formulation is designed for once-daily administration, aiming to improve patient compliance and potentially enhance cognitive outcomes.

The comparator treatment in the study is **Prograf**, available in hard capsule form with strengths of 5 mg, 1 mg, and 0.5 mg. Manufactured by Astellas Pharma GmbH, Prograf is also administered orally. The maximum daily dose for Prograf is 0.20 mg/kg, with a total maximum dose of 73 mg/kg over a 12-month treatment period. Prograf is typically administered twice daily, serving as the standard-of-care therapy against which the once-daily Envarsus is compared.

Both Envarsus and Prograf contain the active substance **tacrolimus**, classified under the ATC code L04AD02. The study monitors participant compliance through regular assessments to ensure adherence to the dosing schedule. The trial aims to determine whether the once-daily formulation of Envarsus offers superior cognitive benefits compared to the twice-daily Prograf regimen.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on the change in subjective impression of quality of life (QoL) concerning attention and memory. This will be evaluated using the FEDA, a self-report questionnaire on attention and memory, comparing results from the screening phase to those at visit 3, which occurs at 6 months.

Secondary endpoints include a comprehensive assessment of cognitive function using several validated tests: the Trail Making Test (TMT) for time criterion, the Adaptive Digit Ordering Test (DOT-A) for the number of correctly sorted digits, the Digit Symbol Test (DST) for the number of correctly sorted items, the Regensburg Stream of Speech Test (RWT) for the number of correct items, and the Victoria Stroop Test (VST) for time criterion. Quality of life will also be measured using the SF36 summary score, with assessments conducted during screening, and at 6 and 12 months. Everyday executive function will be evaluated using the BAFQ, which involves assessment by a close relative, partner, or care provider, at the same time points. Additionally, all serious adverse events, including clinically significant laboratory parameters and relevant liver and kidney functioning parameters, will be documented at each visit following baseline.