Multicentre, open-label, randomised, two-arm, parallel-group, superiority study to assess bioavailability and practicability of Envarsus® compared with Advagraf® in de novo liver transplant recipients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Regensburg AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Immune system processes [G12]

Trial duration

27 Nov 2020 → ongoing

Decision date (initial)

2024-10-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Chiesi GmbH, Germany

External identifiers

EU CT number

2024-518033-28-00

EudraCT number

2020-000796-20

ClinicalTrials.gov

NCT04720326

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

To compare the bioavailability of two once-daily tacrolimus formulations in de novo liver transplant recipients and show superiority of Envarsus® versus Advagraf® in terms of C/D (concentration/dose) ratio after 12 weeks of therapy. The recently identified and postulated parameter C/D ratio is used as an estimate of tacrolimus bioavailability.

Secondary objectives 2

1. To compare the practicability (handling) of the two treatments in de novo liver transplant recipients in terms of ease of dosing and stability of blood trough level.
2. To measure the efficacy and safety of both treatments.

Conditions and MedDRA coding

Prophylaxis of transplant rejection in adult liver allograft recipients

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Signed and dated written informed consent
2. Adult (≥18 years old) male or female
3. Recipient of a whole liver transplant from a deceased donor or a split liver transplant from a deceased or living donor
4. ABO blood type compatible with the organ donor
5. Able to swallow an oral formulation of tacrolimus in tablet or capsule form

Exclusion criteria 16

1. Multi-organ transplantation
2. Any previous organ allograft transplantation
3. Biopsy-proven acute rejection that is ongoing at the time of randomisation
4. Occurrence of post-transplant thrombosis, occlusion or stent placement in any major hepatic arteries, hepatic veins, portal vein or inferior vena cava
5. History of extra-hepatic malignancy that could not be curatively treated
6. Hepatocellular carcinoma with extra-hepatic spread or macrovascular invasion
7. Uncontrolled systemic infection
8. Requirement of life support measures such as ventilation or vasopressor agents (>20 μg/kg BW/h) at the time of randomisation
9. 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
10. Ongoing, planned or foreseeable use of cyclosporine or any tacrolimus preparation other than Envarsus® or Advagraf® (except for immediate-release formulations administered before randomisation)
11. Any prolonged-release tacrolimus treatment prior to randomisation
12. Pregnant or nursing (lactating) female, 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. Female of child-bearing potential, defined as physiologically capable of becoming pregnant, unless using a reliable method* of contraception
14. Participation in another interventional clinical trial during the time period from randomisation to study end, if the trial is testing an IMP (AMG study**) or if the intervention and/or follow-up requirements of the trial impede or interfere with either the objectives of EnGraft or the treatment / follow-up requirements of EnGraft
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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Dose-normalised trough level (C/D ratio) measured at 12 weeks

Secondary endpoints 29

1. Number of IMP dose adjustments until 12 weeks
2. Time to reach the first defined range in target trough level
3. Number of measurements above and below the first defined range in target trough level
4. Dose-normalised trough level (C/D ratio) measured at 1, 2 and 3 years
5. Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at 1, 2, 4 and 12 weeks
6. Inter-patient variability (range) of tacrolimus total daily dose until 12 weeks
7. Proportion of patients with trough levels lower, within, or higher than the standard reference range at 1, 2, 4 and 12 weeks
8. Incidence and severity (BANFF criteria) of clinically-confirmed BPAR2 at 12 weeks and 1, 2, 3 years
9. Incidence of graft failure (defined as necessity for re-transplantation) at 12 weeks and 1, 2, 3 years
10. Incidence of death (for any reason) at 12 weeks and 1, 2, 3 years
11. Treatment failure rate (composite endpoint of BPAR, graft failure or death) at 12 weeks and 1, 2, 3 years
12. Time to treatment failure (composite endpoint of BPAR, graft failure3 or death) after randomisation
13. Incidence of acute rejections requiring treatment at 12 weeks
14. Incidence of multiple rejection episodes at 12 weeks
15. Laboratory measures at 12 weeks and 1, 2, 3 years: liver function, metabolic profile, renal function
16. Malignancies at 1, 2 and 3 years
17. Infections (HCV, HBV, CMV, EBV) at 1, 2 and 3 years
18. Degree of liver fibrosis (fibroscan4 or biopsy) at 12 weeks and 1, 2, 3 years
19. Incidence, type, severity, seriousness and causality of adverse events (AEs)
20. Change vs. baseline in vital signs (heart rate, blood pressure) and body weight
21. Incidence of de novo occurrence of tremor or vision impairments
22. Incidence of post-transplant diabetes mellitus and post-transplant hyperglycaemia at 12 weeks and 1, 2, 3 years
23. Dose-normalised trough level (C/D ratio) 12 weeks after transplantation
24. Number and doses of immunosuppressive medications (incl. other tacrolimus formulations) at 12 weeks and after 12 weeks (if applicable)
25. Recurrence of primary hepatic disease
26. Incidence of DSA up to 12 weeks and at 1, 2 and 3 years (optional)
27. Continuation rate at 12 weeks
28. Incidence and time to study treatment discontinuation
29. Incidence, time to and reason for patient withdrawal from study

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 4

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Regensburg AöR

Sponsor organisation

Universitaetsklinikum Regensburg AöR

Address

Franz-Josef-Strauss-Allee 11, Grass-Oberisling Grass-Oberisling

City

Regensburg

Postcode

93053

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Regensburg AöR

Contact name

coTrial Associates

Public contact point

Organisation

Universitaetsklinikum Regensburg AöR

Contact name

coTrial Associates

Third parties 1

Locations

1 EU/EEA country · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications