Clinical trial NCT06268769: Tacrolimus C:D Ratio Measured in Renal Transplant Recipients Treated With Once-daily Prolonged-release Drugs
Official title: Multicentre, Open-label, Randomised, Two-arm, Parallel-group, Superiority Trial to Assess Bioavailability and Practicability of Two Once-daily Tacrolimus Formulations, Envarsus® Compared With Advagraf™, Administered in Kidney Transplant Recipients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Immunosuppression
Keywords: Kidney transplantation
Tacrolimus
Concentration/dose ratio
Lead sponsor: University of Regensburg
Sponsor class: OTHER
Collaborators: name: Chiesi Pharmaceuticals GmbH
First posted: 2024-02-20
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A dynamic allocation technique assigns participants in a 1:1 ratio to one of two treatment arms: Envarsus tablets (test IMP) or Advagraf capsules (comparator IMP). Randomisation is stratified by two factors: a) trial site, in order to minimise systematic treatment bias at the level of the trial centre and reduce the influence of inter-centre variability, and b) participation in the optional pharmacokinetic sub-study, in order to ensure an equal representation of Envarsus- and Advagraf-treated patients in the sub-study.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated written informed consent
2. Adult (≥18 years old) male or female
3. Renal insufficiency necessitating kidney transplantation and approved to receive a first or second kidney allograft from a living or deceased organ donor
4. ABO blood type compatible with the donor kidney
5. Able to swallow an oral formulation of tacrolimus in tablet or capsule form

Exclusion Criteria:

1. Multi-organ transplantation
2. Any previous solid organ transplantation (other than a first kidney allograft)
3. For recipients of a second kidney transplant: loss of first kidney transplant within 2 years after transplantation owing to immunological reasons or recurrence of the underlying renal disease
4. Patient and/or donor is positive for HCV, HBV or HIV
5. History of any malignancy that could not be curatively treated
6. Ongoing abuse of drugs or alcohol
7. Signs of advanced liver disease or any signs of liver decompensation
8. Ongoing uncontrolled systemic infection
9. Severe diarrhoea, vomiting, active peptic ulcer, previous bariatric surgery, or any other gastrointestinal disorder that may affect absorption of tacrolimus
10. Planned or foreseeable use of cyclosporine, belatacept or any tacrolimus preparation other than Envarsus® or Advagraf™
11. Known contraindication or hypersensitivity to tacrolimus, and/or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics (SmPC) of both Envarsus® and Advagraf™, and/or to any other macrolides
12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
13. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless using a highly-effective method of contraception
14. Participation in another interventional clinical trial in the time period starting from 4 weeks prior to randomisation and throughout the entire trial period
15. Any condition or factor which, in the judgement of the investigator, would place the subject at undue risk, invalidate communication with the investigator or study team, or hamper compliance with the trial protocol or follow-up schedule
16. Inability to freely give informed consent (e.g. individuals under legal guardianship)

Primary outcomes:
measure: Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)
timeFrame: 12 weeks after kidney transplantation
Secondary outcomes:
measure: Time to reach the first trough level in target range
timeFrame: Time period measured in days, assessed within the first 2 weeks after kidney transplantation
measure: Proportion of patients with trough levels lower, within, or higher than the target range
timeFrame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
measure: Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels
timeFrame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
measure: Mean daily dose of tacrolimus and inter-patient variability (range) of tacrolimus daily dose
timeFrame: 4 days, 14 days, 28 days and 12 weeks after kidney transplantation
measure: Tacrolimus concentration/dose (C/D) ratio
timeFrame: 4 days, 14 days, 28 days and 1, 2, 3 years after kidney transplantation
measure: Intra-patient variability of C/D ratio and daily dose
timeFrame: Measured over the time points: day 4, day 14, day 28 and week 12
measure: Treatment failure rate
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Time to treatment failure after transplantation
timeFrame: Measured until 3 years after kidney transplantation
measure: Incidence rate, severity and time to clinically-confirmed biopsy-proven acute rejection
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Incidence rate of graft failure
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Mortality rate
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Graft function measured by eGFR (estimated glomerular filtration rate)
timeFrame: 4 days, 14 days, 28 days, 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Incidence rate of for-cause biopsies
timeFrame: 12 weeks after kidney transplantation
measure: Incidence rate of acute rejection episodes requiring treatment
timeFrame: 12 weeks after kidney transplantation
measure: Incidence rate of steroid-resistant episodes of biopsy-proven acute rejection
timeFrame: 12 weeks and 1 year after kidney transplantation
measure: Incidence rate of delayed graft function
timeFrame: Measurable within the first 2 weeks after kidney transplantation
measure: Incidence rate of primary non-function of the renal allograft
timeFrame: Measurable within the first 12 weeks after kidney transplantation
measure: Incidence of hepatotoxicity
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Incidence of CMV and BKV infection (including organ manifestation, if relevant)
timeFrame: 12 weeks and 1 year after kidney transplantation
measure: Incidence, type, severity and seriousness of adverse reactions (ARs)
timeFrame: 12 weeks and 3 years after kidney transplantation
measure: Blood pressure
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Incidence of de novo tremor
timeFrame: 12 weeks and 3 years after kidney transplantation
measure: Incidence of gastrointestinal disorders requiring diagnostic investigation
timeFrame: 12 weeks and 3 years after kidney transplantation
measure: Incidence of new onset diabetes mellitus after transplantation (NODAT)
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Recurrence of primary kidney disease
timeFrame: 12 weeks and 3 years after kidney transplantation
measure: Incidence of de novo DSA
timeFrame: Detected within the first year after kidney transplantation
measure: Patient-reported health-related quality-of-life measured using the Kidney Transplant Questionnaire-34 (KTQ-34)
timeFrame: 12 weeks and 3 years after kidney transplantation
measure: Doses and duration of glucocorticosteroid treatment
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Dose of mycophenolate
timeFrame: 12 weeks and 1, 2, 3 years after kidney transplantation
measure: Incidence and time to study treatment discontinuation
timeFrame: 3 years after kidney transplantation
measure: Incidence, time to and reason for patient withdrawal from study
timeFrame: 3 years after kidney transplantation
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: University Hospital Aachen, Department of General, Visceral and Transplant Surgery
city: Berlin
country: Germany
facility: Charité Universitätsmedizin, Department of Nephrology and Medical Intensive Care
city: Dresden
country: Germany
facility: University Hospital Dresden, Division of Nephrology
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf, Internal Medicine III (Nephrology, Rheumatology, Endocrinology)
city: Hannover
country: Germany
facility: Hannover Medical School, Department of General, Visceral and Transplant Surgery
city: Jena
country: Germany
facility: University Hospital Jena, Internal Medicine III, Nephrology
city: Mainz
country: Germany
facility: University Medical Center of the Johannes Gutenberg University Mainz, Medical Clinic I. (Nephrology)
city: Münster
country: Germany
facility: University Hospital Münster, Medical Clinic D
city: Regensburg
country: Germany
facility: University Hospital Regensburg, Department of Nephrology
Study officials:
affiliation: University Hospital Regensburg
name: Bernhard Banas, MD
role: PRINCIPAL_INVESTIGATOR
References: