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

28. července 2026 aktualizováno: Hannover Medical School

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.

Přehled studie

Postavení

Zatím nenabíráme

Podmínky

Intervence / Léčba

Detailní popis

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.

Typ studie

Intervenční

Zápis (Odhadovaný)

150

Fáze

  • Fáze 3

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní kontakt

Studijní záloha kontaktů

Studijní místa

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

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

  • Dospělý
  • Starší dospělý

Přijímá zdravé dobrovolníky

Ne

Popis

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)

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: Randomizované
  • Intervenční model: Paralelní přiřazení
  • Maskování: Žádné (otevřený štítek)

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Experimentální: 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)
Lék: 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)
Ostatní jména:
  • mTORI
Aktivní komparátor: 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
Lék: 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)
Ostatní jména:
  • low dose CNI SOC

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Change from baseline to 14 months in the eGFR between CNI-free and SOC group
Časové okno: 14 months

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

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Acute liver graft rejection or liver graft loss until month 14
Časové okno: 14 months
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
Časové okno: 38 months
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
Časové okno: 38 months
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
Časové okno: 38 months
-Progression of chronic kidney disease to stage 4, 5 or requirement for renal replacement therapy (yes/no)
38 months
Liver-related mortality
Časové okno: 38 months
-Incidence of liver-related mortality (yes/no)
38 months
-Progression of subclinical graft injury
Časové okno: 14 months
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
Časové okno: 38 months
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
Časové okno: 14 months
-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
Časové okno: 38 months
-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
Časové okno: 14 months
Quality of life measured as change from baseline to months 14
14 months
-Change in Quality of life measured with SF-36
Časové okno: 14 months
Quality of life measured as change from baseline to months 14
14 months
-Change in Quality of life measured with PROMIS
Časové okno: 38 months
Quality of life measured as change from baseline to end of follow-up
38 months
-Change in Quality of life measured with SF-36
Časové okno: 38 months
Quality of life measured as change from baseline to end of follow-up
38 months
Donor Specific Antibodies
Časové okno: 38 months
-De novo development of donor specific Human Leukocyte Antigen (HLA) antibodies (yes/no)
38 months
Liver Stiffness
Časové okno: 38 months
-Increase in liver stiffness above 8,4 kilopascal (kPa) (yes/no)
38 months
Malignancy
Časové okno: 38 months
-Incidence of malignancy (yes/no)
38 months
Infections
Časové okno: 38 months
-Occurrence of infections requiring medical intervention or hospitalization (yes/no)
38 months
Comorbidities
Časové okno: 38 months
-New onset of comorbidities including hypertension (yes/no), dyslipoproteinemia (yes/no) and diabetes mellitus (yes/no)
38 months

Další výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Rate of patients with elevated alanine aminotransferase (ALT)
Časové okno: 38 months
Elevation of Alanine aminotransferase (ALT) > 2x upper limit of normal (yes/no)
38 months
Rate of patients with elevated aspartate aminotransferase (AST)
Časové okno: 38 months
Elevation of aspartate aminotransferase (AST) > 2x upper limit of normal (yes/no)
38 months
Rate of patients with elevated alkaline phenyl phosphatase (ALP)
Časové okno: 38 months
Elevation of alkaline phenyl phosphatase (ALP) > 2x upper limit of normal (yes/no)
38 months
Rate of patients with elevated gamma-glutamyltransferase (GGT)
Časové okno: 38 months
Elevation of gamma-glutamyltransferase (GGT) > 2x upper limit of normal (yes/no)
38 months
Rate of patients with elevated international normalized ratio (INR)
Časové okno: 38 months
Elevation of international normalized ratio (INR) > 2x upper limit of normal (yes/no)
38 months
Adverse Events of Special Interest (AESI)
Časové okno: 38 months

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

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Hannover Medical School

Spolupracovníci

Royal Infirmary of Edinburgh

Vyšetřovatelé

  • Vrchní vyšetřovatel: Richard Taubert, Professor, Medical School Hannover

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia (Odhadovaný)

30. června 2026

Primární dokončení (Odhadovaný)

30. června 2029

Dokončení studie (Odhadovaný)

30. června 2031

Termíny zápisu do studia

První předloženo

15. července 2026

První předloženo, které splnilo kritéria kontroly kvality

28. července 2026

První zveřejněno (Aktuální)

31. července 2026

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

31. července 2026

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

28. července 2026

Naposledy ověřeno

1. července 2026

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • ALTERNATION
  • 2025-524312-11-00 (Ctis)

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Studuje produkt zařízení regulovaný americkým úřadem FDA

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