ALTERNATION Trial: A Clinical Trial Evaluating Everolimus-Based, Calcineurin Inhibitor-Free Immunosuppression One Year After Liver Transplantation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medizinische Hochschule Hannover

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Decision date (initial)

2026-06-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

DFG (Deutsche Forschungsgemeinschaft; German Research Foundation)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

The primary objective is to demonstrate that Calcineurin-inhibitor (CNI)-free immunosuppression (IS) is superior in sparing kidney function (measured as change from baseline to 14 months in estimated glomerular filtration rate (eGFR)) beyond year one after liver transplantation compared to standard therapy with CNI-based IS regimen in liver allograft recipients without relevant subclinical graft injury.

Secondary objectives 1

1. The key-secondary objective is to demonstrate that CNI-free IS is non-inferior in biopsy-proven acute liver graft rejection rate or liver graft loss (whichever occurs first) until month 14 compared to standard therapy in liver allograft recipients without relevant subclinical graft injury.

Conditions and MedDRA coding

Patients after the first year following liver transplantation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Men**, women* (biological sex), aged ≥ 18 or <80 years; *Women without childbearing potential defined as follows: • at least 6 weeks after surgical sterilization by salpingectomy or bilateral oophorectomy or • hysterectomy or uterine agenesis or • ≥ 50 years and in postmenopausal state > 1 year or • < 50 years and in postmenopausal state > 1 year with serum FSH > 40 IU/l and serum estrogen < 30 ng/l or a negative estrogen test, both at screening or *Women of childbearing potential: • Must have a negative pregnancy test at screening with a sensitivity of at least 25 mIU/ml. A repeat negative pregnancy test is required immediately prior to treatment initiation at baseline to confirm non-pregnancy status. • Must agree to undergo additional pregnancy testing as specified in section 6.2, or when clinically indicated (e.g., following a reported contraceptive failure). • Must agree to use at least one highly effective method of contraception (as defined in section 3.2.1) from the time of screening until 8 weeks after completion of studytreatment. • For participants using hormonal contraception, a barrier method (preferably a male condom) must be used in addition to the primary method from screening until 8 weeks after the end of treatment, to minimize the risk of reduced contraceptive efficacy **Sexually active and fertile male study subjects • Must use a condom from screening, during treatment with mycophenolate mofetil (MMF) and for at least 90 days after discontinuation of treatment. • If the male participant has a female partner of childbearing potential who is not pregnant, additional contraceptive measures should be considered for the partner. • The requirement for condom use may be waived provided that a highly effective method of contraception is consistently used by the female partner of childbearing potential.
2. 2. Signed written informed consent from subject
3. 3. Liver allograft recipients, either deceased or living donor liver transplant
4. 4. Liver transplantation more than 12 months ago and less than 36 months ago
5. 5. Recipients of single organ transplant only
6. 6. Liver Transplant Recipient (LTR) on CNI-based maintenance IS
7. 7. Liver enzymes: alanine aminotransferase (ALT) < 2x upper limit of normal (ULN) and ALP < 2xULN

Exclusion criteria 15

1. 1. Previous CNI-free IS
2. 10. Hypersensitivity or intolerance to any of the components of the medications used
3. 11. Participation in another clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior enrolment or within five half-lives of the IMP, whichever is longer)
4. 12. Any medical condition which could compromise participation in the study according to the investigator’s assessment.
5. 13. Accommodation in an institution pursuant to a court or administrative order
6. 14. Histological exclusion criteria in the baseline screening biopsy: a. more than mild portal tract inflammation, presence of interface hepatitis, more than mild lobular inflammation b. presence of biliary inflammation, endothelialitis, portal microvasculitis, central perivenulitis c. advanced fibrosis (≥2 in any scale of LAF score) d. evidence of acute or chronic rejection (T cellmediated or antibody-mediated, plasma-cell-rich, chronic ductopenic rejection)
7. 2. Acute or chronic rejection within the 36 months prior to screening
8. 3. Prednisolone intake due to another autoimmune disease for no longer than 8 weeks
9. 4. eGFR <30ml/min and/or proteinuria >0.5g/l (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI might be required and proteinuria as a contraindication for mTORI-based therapy)
10. 5. Need for chronic anti-coagulation that cannot be safely discontinued to perform a liver biopsy
11. 6. Inability to participate in frequent monitoring of liver function (every 8 weeks) and clinical visits during the trial duration (38 months)
12. 7. Malignancy or active infection including active, replicative viral hepatitis (chronic hepatitis does not belong to exclusion criteria)
13. 8. Recurrence of underlying liver disease
14. 9. Subjects who are pregnant or breastfeeding
15. 15. The use of any prohibited medication specified in section 5.2 is not permitted, unless the patient can be safely transitioned to an alternative medication at least 5 half-lives prior to the start of study-specific treatment (baseline).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in estimated glomerular filtration rate (eGFR (ml/min)) from baseline to 14 months after randomization – eGFR will be calculated using the CKD-EPI Creatinine equation according to the national kidney foundation, 2021.(1)

Secondary endpoints 13

1. Biopsy-proven acute liver graft rejection or liver graft loss (whichever occurs first) until month 14. Biopsy proven acute rejection (BPAR) (yes/no) is defined as liver enzyme elevation above 2xULN and histological criteria according to the most recent BANFF consensus.(2)
2. Change in estimated glomerular filtration rate (eGFR (ml/min)) from baseline to end of follow-up (38 months)
3. Biopsy- proven acute liver graft rejection or liver graft loss (whichever occurs first) until month 38
4. Progression of chronic kidney disease to stage 4, 5 or requirement for renal replacement therapy (yes/no)
5. Incidence of liver-related mortality (yes/no)
6. Progression of subclinical graft injury (fibrosis) at rebiopsy at month 14 and end of follow-up, where progression in the svLBx is defined as reaching histological exclusion criteria from baseline biopsy (≥ 2 points)
7. Progression of subclinical inflammation at rebiopsy at month 14 (yes/no) and end of follow-up (yes/no), where inflammation in the svLBx is defined as reaching exclusion criteria from baseline biopsy (≥ 2 points in any subscore)
8. Quality of life: change from baseline to months 14 and end of follow-up (measured with PROMIS and SF-36)
9. De novo development of donor specific HLA antibodies (yes/no)
10. Increase in liver stiffness above 8,4 kPa (yes/no)
11. Incidence of malignancy (yes/no)
12. Occurrence of infections requiring medical intervention or hospitalization (yes/no)
13. New onset of comorbidities including hypertension (yes/no), dyslipoproteinemia (yes/no) and diabetes mellitus (yes/no)

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medizinische Hochschule Hannover

Sponsor organisation

Medizinische Hochschule Hannover

Address

Carl-Neuberg-Strasse 1, Gross Buchholz Gross Buchholz

City

Hanover

Postcode

30625

Country

Germany

Scientific contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie

Public contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie

Third parties 3

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Results and documents

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

Documents 8 files

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

Application history

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