Tacrolimus C:D Ratio Measured in Renal Transplant Recipients Treated With Once-daily Prolonged-release Drugs (TaC:Drop)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Immunosuppression
• Intervention / Treatment: Drug: Tacrolimus Pill; Drug: Tacrolimus capsule

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.

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Edward K. Geissler, PhD; Phone Number: 6961 +49 941 944; Email: edward.geissler@ukr.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Not yet recruiting
    • Charité Universitätsmedizin, Department of Nephrology and Medical Intensive Care
    • Contact: Klemens Budde, Prof. Dr.
  • Dresden, Germany, 01307
    • Recruiting
    • University Hospital Dresden, Division of Nephrology
    • Contact: Christian Hugo, Prof. Dr.
  • Hamburg, Germany, 20251
    • Not yet recruiting
    • University Medical Center Hamburg-Eppendorf, Internal Medicine III (Nephrology, Rheumatology, Endocrinology)
    • Contact: Malte A. Kluger, PD Dr.
  • Mainz, Germany, 55131
    • Not yet recruiting
    • University Medical Center of the Johannes Gutenberg University Mainz, Medical Clinic I. (Nephrology)
    • Contact: Julia Weinmann-Menke, Prof. Dr.
  • Regensburg, Germany, 93053
    • Recruiting
    • University Hospital Regensburg, Department of Nephrology
    • Contact: Edward K. Geissler, PhD; Phone Number: 6961 +49 941 944; Email: edward.geissler@ukr.de
    • Contact: Bernhard Banas, MD, PhD; Phone Number: 7301 +49 941 944; Email: bernhard.banas@ukr.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Envarsus; Participants take prolonged-release tacrolimus tablets (Envarsus) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.	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.; Other Names: Envarsus
Active Comparator: Advagraf; Participants take prolonged-release tacrolimus capsules (Advagraf) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.	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.; Other Names: Advagraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-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.	12 weeks after kidney transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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		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		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		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.	4 days, 14 days, 28 days and 1, 2, 3 years after kidney transplantation
Intra-patient variability of C/D ratio and daily dose		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)	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)	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.	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	12 weeks and 1, 2, 3 years after kidney transplantation
Mortality rate	Mortality rate measures death from any cause	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	4 days, 14 days, 28 days, 12 weeks and 1, 2, 3 years after kidney transplantation
Incidence rate of for-cause biopsies		12 weeks after kidney transplantation
Incidence rate of acute rejection episodes requiring treatment		12 weeks after kidney transplantation
Incidence rate of steroid-resistant episodes of biopsy-proven acute rejection		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	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	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	12 weeks and 1, 2, 3 years after kidney transplantation
Incidence of CMV and BKV infection (including organ manifestation, if relevant)		12 weeks and 1 year after kidney transplantation
Incidence, type, severity and seriousness of adverse reactions (ARs)		12 weeks and 3 years after kidney transplantation
Blood pressure		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	12 weeks and 3 years after kidney transplantation
Incidence of gastrointestinal disorders requiring diagnostic investigation		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	12 weeks and 1, 2, 3 years after kidney transplantation
Recurrence of primary kidney disease		12 weeks and 3 years after kidney transplantation
Incidence of de novo DSA		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.	12 weeks and 3 years after kidney transplantation
Doses and duration of glucocorticosteroid treatment		12 weeks and 1, 2, 3 years after kidney transplantation
Dose of mycophenolate	Including both mycophenolate mofetil and mycophenolic acid	12 weeks and 1, 2, 3 years after kidney transplantation
Incidence and time to study treatment discontinuation		3 years after kidney transplantation
Incidence, time to and reason for patient withdrawal from study		3 years after kidney transplantation

Collaborators and Investigators

• Sponsor: Edward Geissler
• Collaborators: Chiesi Pharmaceuticals GmbH
• Investigators: Principal Investigator: Bernhard Banas, MD, University Hospital Regensburg

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: February 12, 2024
• First Submitted That Met QC Criteria: February 12, 2024
• First Posted (Actual): February 20, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Tacrolimus; Kidney transplantation; Concentration/dose ratio
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: TaC:Drop; 2023-503531-18-00 (Other Identifier: EUCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No