Investigation of Pharmacokinetic Variability of Tacrolimus Monohydrate and Mycophenolate Mofetil in Chronic Renal Failure Post-Kidney Transplantation

The primary objective of the ENIGMA study is to identify **staging biomarkers** of immunosuppressant pharmacokinetic variability, specifically focusing on **Tacrolimus** and **mycophenolate mofetil**, by examining the modulations in gut microbiota and physiological changes following kidney transplantation. This is clinically relevant as it aims to enhance the understanding of pharmacokinetic variability, which can significantly impact the efficacy and safety of immunosuppressant therapy in patients with **chronic renal failure**. No secondary objectives are provided in the data.

The clinical trial involves participants diagnosed with **chronic renal failure** who are scheduled for a kidney transplantation from a living donor. The study population includes both male and female subjects, aged between 18 and 75 years, with a body mass index (BMI) ranging from 18 to 35 kg/m². Participants are required to be under an immunosuppressive treatment regimen that includes Tacrolimus (Advagraft) and mycophenolate mofetil (Cellcept). The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are followed at Cliniques universitaires Saint-Luc, and no specific lifestyle considerations such as diet or physical activity are highlighted in the trial details.

The clinical trial is designed to investigate the pharmacokinetic variability of immunosuppressants, specifically **tacrolimus monohydrate** and **mycophenolate mofetil**, by examining gut microbiota modulations and physiological changes following kidney transplantation. This study is a low-intervention trial, as the medications involved are already authorized for market use and will be administered according to standard care procedures. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from February 2024 to December 2026, with participant involvement expected to last up to 5200 days, depending on individual treatment periods.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of chronic renal failure, planned kidney transplantation from a living donor, and an age range of 18 to 75 years. Follow-up visits will be scheduled to monitor the pharmacokinetic parameters of the immunosuppressive drugs, microbiota composition, and function, as well as antibiotic pharmacokinetics. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoints of the study. Conditions that may lead to early termination from the study include non-compliance with the study protocol or withdrawal of consent by the participant.

The trial aims to identify staging biomarkers of immunosuppressant pharmacokinetic variability, with primary endpoints focusing on the pharmacokinetic parameters of the drugs and microbiota analysis. The study will involve the collection of blood, plasma, feces, and urine samples, along with participant diaries, to gather comprehensive data. The trial is categorized as phase 6, with a justification for its low-intervention status due to the use of CE-marked medications under standard care conditions. Participants will be monitored closely throughout the trial to ensure safety and adherence to the study protocol.

The clinical trial involves the administration of **Tacrolimus Monohydrate**, an experimental medication used for the prophylaxis of acute transplant rejection. Tacrolimus Monohydrate is provided in the form of a hard capsule and is administered orally. The dosing regimen is based on body weight, with a maximum daily dose of 0.20 mg/kg and a maximum total dose of 0.30 mg/kg. The treatment period extends up to 5200 days. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to Tacrolimus Monohydrate, the study also includes the administration of **Mycophenolate Mofetil** as a non-experimental treatment. Mycophenolate Mofetil is also provided in the form of a hard capsule and is administered orally. The maximum daily dose for Mycophenolate Mofetil is 2 grams, with the same maximum total dose of 2 grams. The treatment period for Mycophenolate Mofetil is consistent with that of Tacrolimus Monohydrate, extending up to 5200 days. Compliance with the dosing schedule for Mycophenolate Mofetil is similarly monitored to ensure participant adherence.

Efficacy in this clinical trial will be assessed by evaluating the pharmacokinetic parameters of immunosuppressive drugs, specifically **tacrolimus** and mycophenolic acid, which is the active moiety of mycophenolate mofetil. The primary endpoints include the measurement of these pharmacokinetic parameters, as well as the composition and function of the gut microbiota and antibiotic pharmacokinetics. These assessments aim to identify staging biomarkers of immunosuppressant pharmacokinetic variability following kidney transplantation.

The trial will involve the collection of various biological samples, including blood, plasma, feces, and urine, to facilitate the analysis of these parameters. The study is designed to be a low-intervention trial, with the drugs being administered according to their market authorization and standard-of-care procedures. The trial is expected to run until December 31, 2026, with recruitment starting on February 1, 2024. The treatment period for participants is set at a maximum of 5200 days, during which the efficacy parameters will be systematically measured and analyzed.