Everolimus bAsed caLcineurin inhibiTor frEe immunosuppRession oNe Year AfTer lIver transplantatiON (ALTERNATION)

NCT07739914 | Not Yet Recruiting Phase 3 DMC

• 2 other identifiers: ALTERNATION2025-524312-11-00
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 16

Brief Summary

The overall aim of this study is nephroprotection based on a calcineurin inhibitor (CNI)-free therapy beyond year one after orthotopic liver transplantation (OLT) in highly pre-selected patients with low rejection risk.

Conditions

Liver Allograft; Liver Diseases; Liver Transplantation

Keywords

Liver allograft; Liver Transplantation; Everolimus; Rejection; mammilian target of rapamycin (mTOR) inhibitor; CNI withdrawal; Immunosuppression minimization; Surveillance biopsy; Protocol biopsy

Outcome Measures

Primary Outcomes (1)

• Change from baseline to 14 months in the eGFR between CNI-free and SOC group

  The primary endpoint is change from baseline (CFB) to 14 months in the eGFR (ml/min) between the CNI-free and SOC group, where treatment effect is calculated by CFB-CNI-free minus CFB-SOC. The primary analysis will be performed in the Intention to Treat (ITT) population, i.e. all study subjects will be analyzed as randomized. The eGFR will be calculated using the new CKD-EPI Creatinine equation according to the national kidney foundation, 2021

  14 months

Secondary Outcomes (18)

• Acute liver graft rejection or liver graft loss until month 14

  14 months

• Change from baseline to 38 months in the eGFR

  38 months

• Acute liver graft rejection or liver graft loss until month 38

  38 months

• Progression of chronic kidney disease

  38 months

• Liver-related mortality

  38 months

Other Outcomes (6)

• Rate of patients with elevated alanine aminotransferase (ALT)

  38 months

• Rate of patients with elevated aspartate aminotransferase (AST)

  38 months

• Rate of patients with elevated alkaline phenyl phosphatase (ALP)

  38 months

Study Arms (2)

mTORI-based CNI-free IS

EXPERIMENTAL

CNI-free IS with EVR (trough level 3-8 ng/ml) in combination with MMF (250-750 mg bid) with a second minimization step to EVR monotherapy depending on the 14 months (2 months lead in, 12 months full intervention) surveillance biopsy (svLbx)

Drug: Everolimus

Low dose CNI SOC

ACTIVE COMPARATOR

Standard of care meaning IS with CNI (TAC trough level 2-4 ng/ml or CYS trough level 50-80 ng/ml) with or without low dose MMF (250 mg bid) with a second minimization step to CNI monotherapy (if not already performed) depending on the 14 months (2 months lead in, 12 months full intervention) svLbx

Drug: Tacrolimus or Cyclosporine

Interventions

Everolimus DRUG

Patients in the intervention group will be switched to CNI-free mTORI-based immunosuppression (EVR 3-8ng/ml) with MMF (250-750 mg bid)

Also known as: mTORI

mTORI-based CNI-free IS

Tacrolimus or Cyclosporine DRUG

Patients in the comparator group will be switched to a low dose CNI therapy (TAC trough level 2-4 ng/ml; CYS trough level 50-80 ng/ml) with or without low dose MMF 250 mg bid)

Also known as: low dose CNI SOC

Low dose CNI SOC

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men\*\*, women\*, inter/diverse aged ≥ 18 or \<80 years
• Signed written informed consent from subject
• Liver allograft recipients, either deceased or living donor liver transplant
• Liver transplantation more than 12 months ago and less than 36 months ago
• Recipients of single organ transplant only
• LTR on CNI-based maintenance IS
• Liver enzymes: ALT \< 2x ULN and ALP\< 2 ULN
• \*Women without childbearing potential defined as follows:
• at least 6 weeks after surgical sterilization by bilateral tubal ligation 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:
• who are practicing sexual abstinence (periodic abstinence and withdrawal are not acceptable) or
• who have sexual relationships with female partners only and/or with sterile male partners or

You may not qualify if:

• Previous CNI-free IS
• Acute or chronic rejection within the 36 months prior to screening
• Prednisolone intake due to another autoimmune disease for more than 8 weeks
• 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)
• Need for chronic anti-coagulation that cannot be safely discontinued to perform a liver biopsy
• Inability to participate in frequent monitoring of liver function (every 8 weeks) and clinical visits during the trial duration (38 months)
• Recurrence of underlying liver disease
• Subjects who are pregnant or breastfeeding
• Hypersensitivity or intolerance to any of the components of the medications used
• 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 Investigational Medicinal Product (IMP), whichever is longer)
• Any medical condition which could compromise participation in the study according to the investigator's assessment.
• Accommodation in an institution pursuant to a court or administrative order
• more than mild portal tract inflammation, presence of interface hepatitis, more than mild lobular inflammation
• presence of biliary inflammation, endothelialitis, portal microvasculitis, central perivenulitis
• advanced fibrosis (≥2 in any scale of LAF score)

Sponsors & Collaborators

• Hannover Medical School: lead
• Royal Infirmary of Edinburgh: collaborator

Study Sites (16)

University Hospital Heidelberg; Department of Internal Medicine IV

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

University Hospital Tübingen, Department of Internal Medicine I

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

University Hospital Regensburg, Department of Surgery

Regensburg, Bavaria, 93053, Germany

Location

University Hospital Würzburg, Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery

Würzburg, Bavaria, 97080, Germany

Location

University Medical Center Hamburg, I. Department of Medicine, Department of Hepatobiliary and Transplantation Surgery

Hamburg, Free and Hanseatic City of Hamburg, 20246, Germany

Location

Medical School Hannover, Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases

Hanover, Lower Saxony, 30625, Germany

Location

University Medical Center Rostock, Interdisciplinary Transplant Center, Department of General, Visceral, Thoracic, Vascular, and Transplant Surgery

Rostock, Mecklenburg-Vorpommern, 18057, Germany

Location

RWTH Aachen University Hospital, Clinic for Gastroenterology, Metabolic Disorders, and Internal Intensive Medicine (Medical Clinic III)

Aachen, North Rhine-Westphalia, 52074, Germany

Location

University Hospital Bonn, Department of General, Visceral, Transplant, and Vascular Surgery

Bonn, North Rhine-Westphalia, 53105, Germany

Location

University Hospital Essen, Department of Gastroenterology, Hepatology, and Transplant Medicine

Essen, North Rhine-Westphalia, 45147, Germany

Location

University Hospital Münster, Department of Internal Medicine B Gastroenterology, Hepatology, Endocrinology, Clinical Infectious Diseases

Münster, North Rhine-Westphalia, 48149, Germany

Location

University Medical Center of Johannes Gutenberg University Mainz, Department of Internal Medicine I

Mainz, Rhineland-Palatinate, 55131, Germany

Location

Otto von Guericke University Magdeburg, Department of Visceral, Vascular, and Transplant Medicine

Magdeburg, Saxony-Anhalt, 39120, Germany

Location

Schleswig-Holstein University Hospital (UKSH), Department of General, Visceral, Thoracic, Transplant, and Pediatric Surgery, Campus Kiel

Kiel, Schleswig-Holstein, 24105, Germany

Location

Charité - University Hospital Berlin; Department of Surgery

Berlin, State of Berlin, 13353, Germany

Location

University Hospital Jena, Department of General, Visceral, and Vascular Surgery

Jena, Thuringia, 07747, Germany

Location

MeSH Terms

Conditions

Liver Diseases; Rejection, Psychology; Hereditary Sensory and Autonomic Neuropathies

Interventions

Everolimus; Tacrolimus; Cyclosporine

Condition Hierarchy (Ancestors)

Digestive System Diseases; Social Behavior; Behavior; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Richard Taubert, Professor

  Medical School Hannover

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sophia Heinrich, Doctor

CONTACT

+49-511-532; heinrich.sophia@mh-hannover.de

Esther Grahl

CONTACT

+49-176-1 532-7247; grahl.esther@mh-hannover.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, prospective, multicenter, open-label, controlled parallel-group design

Study Record Dates

• First Submitted: July 15, 2026
• First Posted: July 31, 2026
• Study Start: June 30, 2026
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): June 30, 2031
• Last Updated: July 31, 2026

Record last verified: 2026-07

Locations

DE (16)