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

NCT ID: NCT06268769

Last Updated: 2024-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-09
• Study Completion Date: 2029-09-30

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.

Conditions

Immunosuppression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Envarsus

Participants take prolonged-release tacrolimus tablets (Envarsus) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.

Group Type: EXPERIMENTAL

Tacrolimus Pill

Intervention Type: DRUG

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

Participants take prolonged-release tacrolimus capsules (Advagraf) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.

Group Type: ACTIVE_COMPARATOR

Tacrolimus capsule

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Envarsus; Advagraf

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chiesi Pharmaceuticals GmbH

INDUSTRY

Sponsor Role: collaborator

Edward Geissler

OTHER

Sponsor Role: lead

Responsible Party

Edward Geissler

Head of the Department of Experimental Surgery

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Bernhard Banas, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital Regensburg

Locations

University Hospital Aachen, Department of General, Visceral and Transplant Surgery

Aachen, , Germany

Site Status: NOT_YET_RECRUITING

Charité Universitätsmedizin, Department of Nephrology and Medical Intensive Care

Berlin, , Germany

Site Status: NOT_YET_RECRUITING

University Hospital Dresden, Division of Nephrology

Dresden, , Germany

Site Status: RECRUITING

University Medical Center Hamburg-Eppendorf, Internal Medicine III (Nephrology, Rheumatology, Endocrinology)

Hamburg, , Germany

Site Status: RECRUITING

Hannover Medical School, Department of General, Visceral and Transplant Surgery

Hanover, , Germany

Site Status: RECRUITING

University Hospital Jena, Internal Medicine III, Nephrology

Jena, , Germany

Site Status: RECRUITING

University Medical Center of the Johannes Gutenberg University Mainz, Medical Clinic I. (Nephrology)

Mainz, , Germany

Site Status: NOT_YET_RECRUITING

University Hospital Münster, Medical Clinic D

Münster, , Germany

Site Status: NOT_YET_RECRUITING

University Hospital Regensburg, Department of Nephrology

Regensburg, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Edward K. Geissler, PhD

Role: CONTACT

edward.geissler@ukr.de

+49 941 944 ext. 6961

Facility Contacts

Florian Vondran, Prof. Dr.

Role: primary

Klemens Budde, Prof. Dr.

Role: primary

Christian Hugo, Prof. Dr.

Role: primary

Malte A. Kluger, PD Dr.

Role: primary

Dennis Kleine-Döpke, Dr.

Role: primary

Mandy Schlosser, Dr.

Role: primary

Julia Weinmann-Menke, Prof. Dr.

Role: primary

Stefan Reuter, Prof. Dr.

Role: primary

Edward K. Geissler, PhD

Role: primary

edward.geissler@ukr.de

+49 941 944 ext. 6961

Bernhard Banas, MD, PhD

Role: backup

bernhard.banas@ukr.de

+49 941 944 ext. 7301

Other Identifiers

2023-503531-18-00

Identifier Type: OTHER

Identifier Source: secondary_id

TaC:Drop

Identifier Type: -

Identifier Source: org_study_id