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

Overview

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.

Interventions

• Drug Tacrolimus Pill
  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.
• Drug Tacrolimus capsule
  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.

Primary outcome measures

• Dose-normalised blood trough level of tacrolimus (concentration/dose ratio) [Time frame: 12 weeks after kidney transplantation]

Secondary outcome measures (12)

• Time to reach the first trough level in target range [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 [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 [Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation]
• Time to treatment failure after transplantation [Time frame: Measured until 3 years after kidney transplantation]
• Incidence rate, severity and time to clinically-confirmed biopsy-proven acute rejection [Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation]
• Incidence rate of graft failure [Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation]
• Mortality rate [Time frame: 12 weeks and 1, 2, 3 years after kidney transplantation]
• Graft function measured by eGFR (estimated glomerular filtration rate) [Time frame: 4 days, 14 days, 28 days, 12 weeks and 1, 2, 3 years after kidney transplantation]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• Multi-organ transplantation
• Any previous solid organ transplantation (other than a first kidney allograft)
• 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
• Patient and/or donor is positive for HCV, HBV or HIV
• History of any malignancy that could not be curatively treated
• Ongoing abuse of drugs or alcohol
• Signs of advanced liver disease or any signs of liver decompensation
• Ongoing uncontrolled systemic infection
• Severe diarrhoea, vomiting, active peptic ulcer, previous bariatric surgery, or any other gastrointestinal disorder that may affect absorption of tacrolimus
• Planned or foreseeable use of cyclosporine, belatacept or any tacrolimus preparation other than Envarsus® or Advagraf™
• 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
• 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
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless using a highly-effective method of contraception
• Participation in another interventional clinical trial in the time period starting from 4 weeks prior to randomisation and throughout the entire trial period
• 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
• Inability to freely give informed consent (e.g. individuals under legal guardianship)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

Germany · 9 centers

• University Hospital Aachen, Department of General, Visceral and Transplant Surgery — Aachen
• Charité Universitätsmedizin, Department of Nephrology and Medical Intensive Care — Berlin
• University Hospital Dresden, Division of Nephrology — Dresden
• University Medical Center Hamburg-Eppendorf, Internal Medicine III (Nephrology, Rheumatolo — Hamburg
• Hannover Medical School, Department of General, Visceral and Transplant Surgery — Hanover
• University Hospital Jena, Internal Medicine III, Nephrology — Jena
• University Medical Center of the Johannes Gutenberg University Mainz, Medical Clinic I. (N — Mainz
• University Hospital Münster, Medical Clinic D — Münster
• … and 1 more center

Identifiers

NCT: NCT06268769 · TaC:Drop · 2023-503531-18-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗