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

Everolimus bAsed caLcineurin inhibiTor frEe immunosuppRession oNe Year AfTer lIver transplantatiON (ALTERNATION) - a Randomized, Prospective, Multicenter, Open-label, Controlled Phase III Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Diseases; Liver Transplantation; Liver Allograft
• Intervention / Treatment: Drug: Everolimus; Drug: Tacrolimus or Cyclosporine

Detailed Description

Randomized, prospective, multicenter, open-label, controlled trial in Liver allograft recipients beyond year one after transplantation (12-36 Months after liver transplantation) without graft dysfunction and with a surveillance biopsy without relevant subclinical graft injury.

The population of the trial will be adult LTR (≥18 and < 80 years at the study entry) beyond the first year after OLT, who are eligible for a svLBx. The aim of this study is to compare two regimens of a reduced IS in the first year after OLT. Therefore, patients with an increased rejection risk have to be excluded by relevant liver enzyme elevation (ALT, and ALP > 2 ULN) and by a svLBx showing relevant graft injury guided by the BANFFmini criteria. These thresholds have been safely used by several studies with a complete IS withdrawal and should be safe for the proposed study which rather aims for a moderate reduction of IS. Within our single center program for biopsy guided personalized immunosuppression an extension of this strict BANFFmini criteria was safe in patients with immunosuppression minimization but no complete withdrawal.

LTR with a putative intolerance of the increased IS after a rejection provoked by the study intervention (steroid boli or higher CNI doses) like older patients, pregnant woman or patients with advanced kidney failure (eGFR < 30 ml/min), ongoing infections or malignancies will also be excluded. We would not exclude per se LTR with autoimmune liver diseases as cause for OLT, because we did not observe any increased rejection risk in this patient population using a reduced IS with low dose CNI in our single center personalized IS program. Patients with an increased risk to be harmed by EVR, e.g. preexisting proteinuria, will be excluded as well. Screening of patients that are already on EVR/CNI combination therapy can be performed according to the judgement of participating centers. LTR on EVR/CNI because of reduced kidney function or because of recurrent viral infection, will not be harmed by the study, because both groups - intervention and SOC - will not lead to an increase in CNI dosage compared to the dosage before. Patients on EVR/CNI because of hepatocellular carcinoma: There is no prospective data showing an overall long-term survival benefit from a mTORI-based regimen and there is no prospective data showing a survival benefit between a mTORI containing regimen vs a low dose CNI regimen.

In contrast to previous studies on CNI-free mTORI-based IS, we will not focus exclusively on patients with a preexisting renal failure. Since we do not expect a relevantly increased rejection risk by the study intervention, the potential rejection risk has not to be balanced by a higher chance to benefit from renal protective IS as in previously performed trials. Therefore, it is ethically justifiable to include patients without significant renal impairment and thus to let them benefit from the possible benefit of the intervention.

The inclusion and exclusion criteria will select healthy LTR and more motivated patients that are willing to undergo a svLBx. However, the screening via a svLBx is essential considering the rate of BANFFmini in 30-40% of patients.

Patients in the intervention group will be switched to a mTORI-based immunosuppression (EVR 3-8ng/ml) with MMF (250-750 mg bid). CNI will be tapered stepwise in the 2 months lead-in phase.

Patients serving as control group need to fulfill the same inclusion criteria as the intervention group. Since they will also be eligible for minimization of IS guided by Banff criteria, after randomization IS will be provided based on a low dose CNI regime (Tac trough levels 2-4 ng/ml) with or without MMF (250 mg bid) as it is current standard of care. Patients, who have already been on low-dose CNI, will continue on their previous IS regime. According to recently published data showing reduced nephrotoxicity with a combined endpoint with new onset diabetes and new arterial hypertension with LCP-Tac Versus extended-released TAC, the preferred TAC in the study will be LCP-Tac. Only in case of intolerance, other tacrolimus preparations or CYS (trough level 50-80 ng/ml) should be used and discussion with the coordinating investigator may be advised.

In parallel for both study arms, a further minimization step to a low dose CNI therapy (control arm) or EVR low dose (trough level 3-6 ng/ml) both without MMF is advised after 14 months svLBx showing still no relevant graft injury.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sophia Heinrich, Doctor; Phone Number: 6619 +49-511-532; Email: heinrich.sophia@mh-hannover.de
• Study Contact Backup: Name: Esther Grahl; Phone Number: +49-176-1 532-7247; Email: grahl.esther@mh-hannover.de

Study Locations

• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • University Hospital Heidelberg; Department of Internal Medicine IV
    • Tübingen, Baden-Wurttemberg, Germany, 72076
      • University Hospital Tübingen, Department of Internal Medicine I
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • University Hospital Regensburg, Department of Surgery
    • Würzburg, Bavaria, Germany, 97080
      • University Hospital Würzburg, Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery
  • Free and Hanseatic City of Hamburg
    • Hamburg, Free and Hanseatic City of Hamburg, Germany, 20246
      • University Medical Center Hamburg, I. Department of Medicine, Department of Hepatobiliary and Transplantation Surgery
  • Lower Saxony
    • Hanover, Lower Saxony, Germany, 30625
      • Medical School Hannover, Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases
  • Mecklenburg-Vorpommern
    • Rostock, Mecklenburg-Vorpommern, Germany, 18057
      • University Medical Center Rostock, Interdisciplinary Transplant Center, Department of General, Visceral, Thoracic, Vascular, and Transplant Surgery
  • North Rhine-Westphalia
    • Aachen, North Rhine-Westphalia, Germany, 52074
      • RWTH Aachen University Hospital, Clinic for Gastroenterology, Metabolic Disorders, and Internal Intensive Medicine (Medical Clinic III)
    • Bonn, North Rhine-Westphalia, Germany, 53105
      • University Hospital Bonn, Department of General, Visceral, Transplant, and Vascular Surgery
    • Essen, North Rhine-Westphalia, Germany, 45147
      • University Hospital Essen, Department of Gastroenterology, Hepatology, and Transplant Medicine
    • Münster, North Rhine-Westphalia, Germany, 48149
      • University Hospital Münster, Department of Internal Medicine B Gastroenterology, Hepatology, Endocrinology, Clinical Infectious Diseases
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55131
      • University Medical Center of Johannes Gutenberg University Mainz, Department of Internal Medicine I
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany, 39120
      • Otto von Guericke University Magdeburg, Department of Visceral, Vascular, and Transplant Medicine
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Schleswig-Holstein University Hospital (UKSH), Department of General, Visceral, Thoracic, Transplant, and Pediatric Surgery, Campus Kiel
  • State of Berlin
    • Berlin, State of Berlin, Germany, 13353
      • Charité - University Hospital Berlin; Department of Surgery
  • Thuringia
    • Jena, Thuringia, Germany, 07747
      • University Hospital Jena, Department of General, Visceral, and Vascular Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Men**, women*, inter/diverse aged ≥ 18 or <80 years
2. Signed written informed consent from subject
3. Liver allograft recipients, either deceased or living donor liver transplant
4. Liver transplantation more than 12 months ago and less than 36 months ago
5. Recipients of single organ transplant only
6. LTR on CNI-based maintenance IS
7. Liver enzymes: ALT < 2x ULN and ALP< 2 ULN

8. *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
   • who are sexually active with fertile male partner, have two negative pregnancy tests with a sensitivity of at least 25 mIU/ml during screening (it is recommended that the second test be performed 8-10 days after the first test) and agree to use at least one highly *** from the time of screening until 8 weeks after completion of treatment (or even 90 days for males if MMF has been taken previously). Preferably, two complementary forms of contraception should be used simultaneously. Pregnancy tests should be repeated if clinically indicated (e.g. after a contraceptive failure has been reported).

Exclusion Criteria:

1. Previous CNI-free IS
2. Acute or chronic rejection within the 36 months prior to screening
3. Prednisolone intake due to another autoimmune disease for more than 8 weeks
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)
5. Need for chronic anti-coagulation that cannot be safely discontinued to perform a liver biopsy
6. Inability to participate in frequent monitoring of liver function (every 8 weeks) and clinical visits during the trial duration (38 months)
7. Malignancy or active infection including active, replicative viral hepatitis (chronic hepatitis does not belong to exclusion criteria)
8. Recurrence of underlying liver disease
9. Subjects who are pregnant or breastfeeding
10. Hypersensitivity or intolerance to any of the components of the medications used
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 Investigational Medicinal Product (IMP), whichever is longer)
12. Any medical condition which could compromise participation in the study according to the investigator's assessment.
13. Accommodation in an institution pursuant to a court or administrative order

14. Histological exclusion criteria in the baseline screening biopsy:

    1. more than mild portal tract inflammation, presence of interface hepatitis, more than mild lobular inflammation
    2. presence of biliary inflammation, endothelialitis, portal microvasculitis, central perivenulitis
    3. advanced fibrosis (≥2 in any scale of LAF score)
    4. evidence of acute or chronic rejection (T cell-mediated or antibody-mediated, plasma-cell-rich, chronic ductopenic rejection)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mTORI-based CNI-free IS; 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; Patients in the intervention group will be switched to CNI-free mTORI-based immunosuppression (EVR 3-8ng/ml) with MMF (250-750 mg bid); Other Names: mTORI
Active Comparator: Low dose CNI SOC; 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; 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); Other Names: low dose CNI SOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute liver graft rejection or liver graft loss until month 14	Biopsy proven acute rejection (BPAR) (yes/no) is defined as liver enzyme elevation above 2x upper limit of normal (ULN) and histological criteria according to the most recent BANFF consensus	14 months
Change from baseline to 38 months in the eGFR	Change in estimated glomerular filtration rate (eGFR (ml/min)) from baseline to end of follow-up (38 months)	38 months
Acute liver graft rejection or liver graft loss until month 38	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	38 months
Progression of chronic kidney disease	-Progression of chronic kidney disease to stage 4, 5 or requirement for renal replacement therapy (yes/no)	38 months
Liver-related mortality	-Incidence of liver-related mortality (yes/no)	38 months
-Progression of subclinical graft injury	Progression of subclinical graft injury (fibrosis) at rebiopsy at month 14, where progression in the svLBx is defined as reaching histological exclusion criteria from baseline biopsy (≥ 2 points)	14 months
-Progression of subclinical graft injury	Progression of subclinical graft injury (fibrosis) at rebiopsy at end of follow-up, where progression in the svLBx is defined as reaching histological exclusion criteria from baseline biopsy (≥ 2 points)	38 months
-Progression of subclinical inflammation	-Progression of subclinical inflammation at rebiopsy at month 14 (yes/no) where inflammation in the svLBx is defined as reaching exclusion criteria from baseline biopsy (≥ 2 points in any subscore)	14 months
-Progression of subclinical inflammation	-Progression of subclinical inflammation at rebiopsy at 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)	38 months
-Change in Quality of life measured with PROMIS	Quality of life measured as change from baseline to months 14	14 months
-Change in Quality of life measured with SF-36	Quality of life measured as change from baseline to months 14	14 months
-Change in Quality of life measured with PROMIS	Quality of life measured as change from baseline to end of follow-up	38 months
-Change in Quality of life measured with SF-36	Quality of life measured as change from baseline to end of follow-up	38 months
Donor Specific Antibodies	-De novo development of donor specific Human Leukocyte Antigen (HLA) antibodies (yes/no)	38 months
Liver Stiffness	-Increase in liver stiffness above 8,4 kilopascal (kPa) (yes/no)	38 months
Malignancy	-Incidence of malignancy (yes/no)	38 months
Infections	-Occurrence of infections requiring medical intervention or hospitalization (yes/no)	38 months
Comorbidities	-New onset of comorbidities including hypertension (yes/no), dyslipoproteinemia (yes/no) and diabetes mellitus (yes/no)	38 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients with elevated alanine aminotransferase (ALT)	Elevation of Alanine aminotransferase (ALT) > 2x upper limit of normal (yes/no)	38 months
Rate of patients with elevated aspartate aminotransferase (AST)	Elevation of aspartate aminotransferase (AST) > 2x upper limit of normal (yes/no)	38 months
Rate of patients with elevated alkaline phenyl phosphatase (ALP)	Elevation of alkaline phenyl phosphatase (ALP) > 2x upper limit of normal (yes/no)	38 months
Rate of patients with elevated gamma-glutamyltransferase (GGT)	Elevation of gamma-glutamyltransferase (GGT) > 2x upper limit of normal (yes/no)	38 months
Rate of patients with elevated international normalized ratio (INR)	Elevation of international normalized ratio (INR) > 2x upper limit of normal (yes/no)	38 months
Adverse Events of Special Interest (AESI)	The following events should be reported as AESI: Allograft dysfunction; Steroid-resistant rejection, defined as rejection requiring, at the discretion of the local principal investigators, an additional course of high-dose corticosteroids or treatment with antithymocyte globulin/thymoglobulin or a comparable lymphocyte-depleting therapy; Chronic rejection as defined by Banff Foundation; Increase ≥2 points in any Liver Allograft Fibrosis (LAF) component in any follow up liver biopsy in central pathology report; Reaching the exclusion criteria in the central pathology report in any follow up liver biopsy	38 months

Collaborators and Investigators

• Sponsor: Hannover Medical School
• Collaborators: Royal Infirmary of Edinburgh
• Investigators: Principal Investigator: Richard Taubert, Professor, Medical School Hannover

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): June 30, 2031

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 28, 2026
• First Posted (Actual): July 31, 2026

Study Record Updates

• Last Update Posted (Actual): July 31, 2026
• Last Update Submitted That Met QC Criteria: July 28, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Rejection; Everolimus; Liver Transplantation; Protocol biopsy; CNI withdrawal; Immunosuppression minimization; Liver allograft; mammilian target of rapamycin (mTOR) inhibitor; Surveillance biopsy
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Digestive System Diseases; Neurodegenerative Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Behavior; Social Behavior; Liver Diseases; Hereditary Sensory and Autonomic Neuropathies; Rejection, Psychology; Peptides; Amino Acids, Peptides, and Proteins; Organic Chemicals; Polycyclic Compounds; Macrolides; Lactones; Macrocyclic Compounds; Peptides, Cyclic; Sirolimus; Cyclosporins; Everolimus; Tacrolimus; Cyclosporine
• Other Study ID Numbers: ALTERNATION; 2025-524312-11-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No