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

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Regensburg

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

13 Feb 2024 → ongoing

Decision date (initial)

2023-09-19

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Chiesi GmbH, Germany

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis

To compare the relative bioavailability of two once-daily oral formulations of tacrolimus in kidney transplant recipients and show superiority of Envarsus® versus Advagraf™ in terms of C/D (concentration/dose) ratio measured at 12 weeks after organ transplantation. The parameter C/D ratio is used as an estimate of tacrolimus bioavailability.

Secondary objectives 2

1. To explore the relationship between the early C/D ratio measured at 12 weeks post-transplantation and later clinical outcomes measured until 3 years post-transplantation.
2. To compare the practicability (handling) of the two treatments in kidney transplant recipients in terms of ease of dosing and stability of blood trough level.

Conditions and MedDRA coding

Prophylaxis of transplant rejection in adult kidney 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. 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 16

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 active HCV, HBV or HIV infection
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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 31

1. Time to reach the first trough level in target range
2. Proportion of patients with trough levels lower, within, or higher than the target range at day 4, day 14, day 28 and week 12
3. Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels at day 4, day 14, day 28 and week 12
4. Mean daily dose of tacrolimus and inter-patient variability (range) of tacrolimus daily dose at day 4, day 14, day 28 and week 12
5. C/D ratio measured at day 4, day 14, day 28, and at 1, 2 and 3 years
6. Intra-patient variability of C/D ratio and daily dose over the time points: day 4, day 14, day 28 and week 12
7. Treatment failure rate, which is a composite endpoint of biopsy-proven acute rejection (BPAR), graft failure (defined as initiation of renal dialysis or re-transplantation) or death (from any cause), measured at 12 weeks and at 1, 2, 3 years
8. Time to treatment failure (composite endpoint of BPAR, graft failure2 or death) after transplantation
9. Incidence rate, severity and time to clinically-confirmed BPAR3 at 12 weeks and at 1, 2, 3 years
10. Incidence rate of graft failure (defined as initiation of renal dialysis or re-transplantation) at 12 weeks and at 1, 2, 3 years
11. Mortality rate (death from any cause) at 12 weeks and at 1, 2, 3 years
12. Graft function measured by eGFR (estimated glomerular filtration rate) calculated according to the CKD-EPI formula at day 4, day 14, day 28, week 12, and at 1, 2, 3 years
13. Incidence rate of for-cause biopsies at 12 weeks
14. Incidence rate of acute rejection episodes requiring treatment at 12 weeks
15. Incidence rate of steroid-resistant BPAR episodes at 12 weeks and at 1 year
16. Incidence rate of delayed graft function (DGF), defined as the need for more than one episode of dialysis after transplantation
17. Incidence rate of primary non-function (PNF) of the renal allograft, defined as the necessity for ongoing chronic dialysis
18. Incidence of hepatotoxicity (GPT or GOT levels ≥ 2.5 x upper limit of normal range) at 12 weeks and at 1, 2, 3 years
19. Incidence of CMV and BKV infection (including organ manifestation, if relevant) at 12 weeks and at 1 year
20. Incidence, type, severity and seriousness of adverse reactions (ARs) at 12 weeks and at 3 years
21. Blood pressure at 12 weeks and at 1, 2, 3 years
22. Incidence of de novo tremor (incidence and severity based on medical assessment by investigator) at 12 weeks and at 3 years
23. Incidence of gastrointestinal disorders requiring diagnostic investigation at 12 weeks and at 3 years
24. Incidence of new onset diabetes mellitus after transplantation (NODAT), defined as HbA1c ≥ 6.5% or 47.5 mmol/mol or fasting plasma glucose ≥ 126 mg/dl on two separate occasions, at 12 weeks and at 1, 2, 3 years
25. Recurrence of primary kidney disease at 12 weeks and at 3 years
26. Incidence of de novo DSA detected within 1 year post-transplantation
27. Patient-reported health-related quality-of-life measured using the Kidney Transplant Questionnaire-34 (KTQ-34) at 12 weeks and at 3 years
28. Doses and duration of glucocorticosteroid treatment at 12 weeks and at 1, 2, 3 years
29. Dose of mycophenolate (both formulations) at 12 weeks and at 1, 2, 3 years
30. Incidence and time to study treatment discontinuation
31. 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

Sponsor organisation

Universitaetsklinikum Regensburg

Address

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

City

Regensburg

Postcode

93053

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Regensburg

Contact name

coTrial Associates

Public contact point

Organisation

Universitaetsklinikum Regensburg

Contact name

coTrial Associates

Locations

1 EU/EEA country · 13 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 10 files

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

Application history

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