The goal of this clinical trial is to compare the bioavailability and practicability of two different formulations of tacrolimus in kidney transplant recipients. The main objective is to demonstrate that Envarsus® (test drug) has superior (higher) oral bioavailability compared with Advagraf™ (comparator drug) at 12 weeks after kidney transplantation. The trial also aims to compare the practicability (handling) of the two drugs using a series of pharmacokinetic parameters and to explore the relationship between drug bioavailability and long-term clinical outcomes, with a special focus on dose-dependent adverse reactions, measured until 3 years post-transplantation. The trial incorporates a pharmacokinetic sub-study designed to profile the peak tacrolimus blood concentration up to 6 hours after drug intake on the day of the 12-week study visit.
This clinical trial aims to compare the bioavailability and practicability of two alternative once-daily formulations of tacrolimus in patients who have received either a first or second kidney transplant and require prophylactic immunosuppressive treatment to prevent allograft rejection. Trial participants are randomised within 7 days prior to kidney transplantation surgery in a 1:1 ratio to two alternative treatment arms containing either Envarsus (test arm) or Advagraf (comparator arm) as first-line calcineurin inhibitor within a standard-of-care immunosuppressive regimen. Tacrolimus blood trough levels and drug doses are monitored at regular intervals to measure a dose-normalised trough level (concentration/dose, C/D ratio) as an estimate of tacrolimus bioavailability. The primary objective is to demonstrate that the C/D ratio of tacrolimus measured in kidney transplant recipients treated with Envarsus® (test drug) is superior to (higher than) the C/D ratio measured in patients treated with Advagraf™ (comparator drug) at 12 weeks post-transplantation. The trial also aims to compare the practicability (handling) of these two once-daily drug formulations using a series of pharmacokinetic parameters that will measure the speed with which therapeutic blood trough levels are attained and the ease with which stable blood trough levels are maintained over time. Secondarily, TaC:Drop aims to explore the relationship between the early C/D ratio measured at 12 weeks post-transplantation and later clinical outcomes measured until three years post-transplantation. The study aims to investigate whether a superior pharmacokinetic drug profile is associated with fewer and milder dose-dependent drug toxicities and superior kidney graft function, as measured by long-term safety and efficacy parameters. Drug pharmacokinetics will be explored in greater detail during a sub-study designed to profile the peak blood concentration of Envarsus® and Advagraf™ at 12 weeks post-transplantation in patients who volunteer to provide three additional blood samples at two-hour intervals after drug intake on the day of the 12-week trial visit. Participation in this sub-study is voluntary and available to all trial centres and all trial patients.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
300
Envarsus tablets dosed to achieve and maintain whole blood trough levels of tacrolimus within a therapeutic range of 5-12 ng/ml during the first 4 weeks post-transplantation, and 5-8 ng/ml thereafter.
Advagraf capsules dosed to achieve and maintain whole blood trough levels of tacrolimus within a therapeutic range of 5-12 ng/ml during the first 4 weeks post-transplantation, and 5-8 ng/ml thereafter.
University Hospital Aachen, Department of General, Visceral and Transplant Surgery
Aachen, Germany
NOT_YET_RECRUITINGCharité Universitätsmedizin, Department of Nephrology and Medical Intensive Care
Berlin, Germany
NOT_YET_RECRUITINGUniversity Hospital Dresden, Division of Nephrology
Dresden, Germany
RECRUITINGUniversity Medical Center Hamburg-Eppendorf, Internal Medicine III (Nephrology, Rheumatology, Endocrinology)
Hamburg, Germany
RECRUITINGHannover Medical School, Department of General, Visceral and Transplant Surgery
Hanover, Germany
RECRUITINGUniversity Hospital Jena, Internal Medicine III, Nephrology
Jena, Germany
RECRUITINGUniversity Medical Center of the Johannes Gutenberg University Mainz, Medical Clinic I. (Nephrology)
Mainz, Germany
NOT_YET_RECRUITINGUniversity Hospital Münster, Medical Clinic D
Münster, Germany
NOT_YET_RECRUITINGUniversity Hospital Regensburg, Department of Nephrology
Regensburg, Germany
RECRUITINGDose-normalised blood trough level of tacrolimus (concentration/dose ratio)
To calculate C/D ratio, "concentration" is the blood trough level of tacrolimus measured in a blood sample collected immediately prior to drug dosing on the day of the 12-week trial visit and "dose" is the daily dose taken by the patient on the day prior to the visit. C/D ratio is measured as a surrogate for tacrolimus bioavailability (i.e. systemic exposure per mg of drug). The primary endpoint uses a blood trough level reading that is measured in a central laboratory.
Time frame: 12 weeks after kidney transplantation
Time to reach the first trough level in target range
Reaching the target range is defined as two consecutive readings within the initial target range of 5-12 ng/ml; time is measured to the date of the first in-range reading
Time frame: Time period measured in days, assessed within the first 2 weeks after kidney transplantation
Proportion of patients with trough levels lower, within, or higher than the target range
Time frame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels
Time frame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
Mean daily dose of tacrolimus and inter-patient variability (range) of tacrolimus daily dose
Time frame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
Tacrolimus concentration/dose (C/D) ratio
The secondary endpoint using C/D ratio data takes a blood trough level reading that is measured in the local laboratory at the trial site.
Time frame: 4 days, 14 days, 28 days and 1, 2, 3 years after kidney transplantation
Intra-patient variability of C/D ratio and daily dose
Time frame: Measured over the time points: day 4, day 14, day 28 and week 12
Treatment failure rate
A composite endpoint of biopsy-proven acute rejection, graft failure (defined as initiation of renal dialysis or re-transplantation), or death (from any cause)
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Time to treatment failure after transplantation
Treatment failure is a composite endpoint of biopsy-proven acute rejection, graft failure (defined as initiation of renal dialysis or pre-emptive re-transplantation), or death (from any cause)
Time frame: Measured until 3 years after kidney transplantation
Incidence rate, severity and time to clinically-confirmed biopsy-proven acute rejection
Clinically-confirmed biopsy-proven acute rejection requires both a clinical diagnosis of rejection by an investigator and a histopathological diagnosis of rejection in a for-cause biopsy. Subclinical rejection diagnosed in a protocol biopsy is therefore excluded from this definition.
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence rate of graft failure
Graft failure is defined as initiation of renal dialysis or pre-emptive re-transplantation
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Mortality rate
Mortality rate measures death from any cause
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Graft function measured by eGFR (estimated glomerular filtration rate)
eGFR calculated according to the CKD-EPI formula
Time frame: 4 days, 14 days, 28 days, 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence rate of for-cause biopsies
Time frame: 12 weeks after kidney transplantation
Incidence rate of acute rejection episodes requiring treatment
Time frame: 12 weeks after kidney transplantation
Incidence rate of steroid-resistant episodes of biopsy-proven acute rejection
Time frame: 12 weeks and 1 year after kidney transplantation
Incidence rate of delayed graft function
Delayed graft function is defined as the need for more than one episode of dialysis after transplantation
Time frame: Measurable within the first 2 weeks after kidney transplantation
Incidence rate of primary non-function of the renal allograft
Primary non-function is defined as the necessity for ongoing chronic dialysis
Time frame: Measurable within the first 12 weeks after kidney transplantation
Incidence of hepatotoxicity
Hepatotoxicity is defined as GPT or GOT levels ≥ 2.5 x upper limit of normal range
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence of CMV and BKV infection (including organ manifestation, if relevant)
Time frame: 12 weeks and 1 year after kidney transplantation
Incidence, type, severity and seriousness of adverse reactions (ARs)
Time frame: 12 weeks and 3 years after kidney transplantation
Blood pressure
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence of de novo tremor
Incidence and severity of tremor based on medical assessment by the investigator
Time frame: 12 weeks and 3 years after kidney transplantation
Incidence of gastrointestinal disorders requiring diagnostic investigation
Time frame: 12 weeks and 3 years after kidney transplantation
Incidence of new onset diabetes mellitus after transplantation (NODAT)
NODAT is defined as HbA1c ≥ 6.5% or 47.5 mmol/mol or fasting plasma glucose ≥ 126 mg/dl on two separate occasions
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Recurrence of primary kidney disease
Time frame: 12 weeks and 3 years after kidney transplantation
Incidence of de novo DSA
Time frame: Detected within the first year after kidney transplantation
Patient-reported health-related quality-of-life measured using the Kidney Transplant Questionnaire-34 (KTQ-34)
The KTQ-34 is a renal transplantation-specific instrument that measures quality-of-life in five dimensions. It is a self-administered questionnaire that is completed in writing by the trial patients.
Time frame: 12 weeks and 3 years after kidney transplantation
Doses and duration of glucocorticosteroid treatment
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Dose of mycophenolate
Including both mycophenolate mofetil and mycophenolic acid
Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence and time to study treatment discontinuation
Time frame: 3 years after kidney transplantation
Incidence, time to and reason for patient withdrawal from study
Time frame: 3 years after kidney transplantation
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