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Everolimus-Based Calcineurin-Inhibitor-Free Immunosuppression with Drug Combination in Patients One Year After Liver Transplantation

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study involves people who have had a liver transplantation at least one year ago. After a transplant, patients need medicines to keep the new liver working and to protect other organs, especially the kidneys. The trial tests a new approach that uses everolimus together with other medicines but avoids drugs known as calcineurin inhibitors such as tacrolimus or cyclosporin. In the standard group, patients continue the usual regimen that includes those calcineurin inhibitors, often combined with mycophenolate mofetil.

The purpose of the study is to determine whether the calcineurin‑inhibitor‑free regimen can better preserve kidney function compared with the standard treatment. Participants will be randomly assigned to one of the two groups and will take the assigned medicines for about a year, with regular clinic visits, blood tests, and occasional imaging. Kidney health will be checked using a blood test called estimated glomerular filtration rate, which estimates how well the kidneys filter waste.

Throughout the trial, doctors will also look for signs that the transplanted liver is still healthy by performing a small tissue sample test called a biopsy and by monitoring for any serious problems such as rejection, infection, or the development of chronic kidney disease. Quality of life will be assessed with questionnaires, and any new health issues, including high blood pressure or diabetes, will be recorded. The study will continue follow‑up for several years to see long‑term effects.

The research process

The trial runs in 10 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization into treatment group

    After enrollment, the patient is assigned by the study to one of two treatment groups using a random process.

  2. Step 2

    Baseline assessments

    The patient undergoes initial evaluations that include blood tests to measure kidney function, a liver biopsy to assess graft condition, and completion of quality‑of‑life questionnaires.

  3. Step 3

    Initiation of medication regimen

    If assigned to the everolimus‑based arm, the patient starts oral everolimus 2 mg once daily together with oral mycophenolate mofetil 1500 mg daily.

    If assigned to the standard calcineurin‑inhibitor arm, the patient starts either oral tacrolimus 0.13 mg per kilogram of body weight daily or oral ciclosporin 12 mg per kilogram of body weight daily, according to the investigator’s choice.

  4. Step 4

    Daily medication intake

    The patient takes the prescribed medication(s) by mouth each day at the same time, following the dosage instructions provided.

  5. Step 5

    Regular study visits for monitoring

    The patient attends scheduled clinic visits at approximately month 1, month 3, month 6, month 12, month 14, month 24, and month 38 after randomization.

    Each visit includes a review of medication adherence, measurement of blood pressure, and collection of blood samples.

  6. Step 6

    Kidney function testing

    At every study visit, the patient has a kidney function test (estimated glomerular filtration rate, eGFR) performed to track changes over time.

  7. Step 7

    Liver biopsy procedures

    The patient undergoes a repeat liver biopsy at month 14 and again at month 38 to evaluate graft health.

  8. Step 8

    Quality‑of‑life questionnaires

    The patient completes standardized quality‑of‑life questionnaires at month 14 and month 38 to assess overall well‑being.

  9. Step 9

    Continuation of medication

    The prescribed medication(s) are continued for the duration of the trial, up to month 38, unless the investigator decides to stop treatment because of safety concerns.

  10. Step 10

    Final assessment

    At month 38, the patient undergoes the final study procedures, including blood tests, a liver biopsy, and completion of the quality‑of‑life questionnaire, after which the trial participation ends.

Who can join the trial?

9 criteria

  • Be a man or woman who is at least 18 years old but younger than 80 years.
  • If you are a woman who could become pregnant, you must have a negative pregnancy test and agree to use a reliable method of birth control (such as hormonal contraception plus a condom) from the screening visit until 8 weeks after the study ends; women who cannot become pregnant (for example after removal of the uterus or ovaries, after menopause, or age 50+ with menopause) do not need birth control.
  • If you are a man who can father children, you must use a condom while taking the study medication and for at least 90 days after stopping it; if your partner could become pregnant, she must also use reliable birth control.
  • Sign a written informed consent form agreeing to take part in the study.
  • Have received a liver transplant (from a deceased or living donor).
  • Your transplant must have been performed more than 12 months ago but less than 36 months ago.
  • Have received only a single organ transplant (no other organ transplants).
  • Currently be on a maintenance regimen that includes a calcineurin inhibitor (a type of medication that suppresses the immune system to prevent organ rejection).
  • Your liver enzyme levels must be within safe limits: alanine aminotransferase (ALT) and alkaline phosphatase (ALP) must each be less than twice the upper normal range.

Who cannot join the trial?

18 criteria

  • Having already used a calcineurin‑inhibitor‑free immunosuppression (CNI‑free IS) regimen before the study.
  • Needing long‑term anticoagulation (blood‑thinning medication) that cannot be safely stopped to allow a liver biopsy.
  • Being unable to attend regular check‑ups of liver function every 8 weeks and clinic visits for the 38‑month study period.
  • Having cancer (malignancy) or an active infection, including a virus that is actively replicating in the liver (such as active viral hepatitis).
  • Experiencing a return of the original liver disease that led to the transplant.
  • Being currently pregnant or breastfeeding.
  • Using any medication that the study lists as prohibited, unless it can be safely switched to another drug at least five drug half‑lives before the study starts (the time it takes for half of the drug to leave the body).
  • Having an allergy or intolerance to any of the medicines that will be used in the trial.
  • Being enrolled in another clinical trial or having taken other investigational drugs or devices within the past 30 days or within five drug half‑lives, whichever is longer.
  • Having any other medical problem that the investigator believes could make participation unsafe.
  • Living in a facility because of a court or administrative order.
  • Showing certain findings on the initial liver biopsy, such as:
    • More than mild inflammation in the liver tissue (portal tract inflammation, interface hepatitis, or lobular inflammation).
    • Inflammation of the bile ducts or small blood vessels (biliary inflammation, endothelialitis, portal microvasculitis, central perivenulitis).
    • Advanced scarring (fibrosis) at stage 2 or higher on any fibrosis scoring system.
    • Evidence of the body rejecting the transplanted liver (acute or chronic rejection, including T‑cell‑mediated, antibody‑mediated, plasma‑cell‑rich, or chronic duct‑openic rejection).
    • Having had an episode of acute or chronic rejection of the liver transplant within the 36 months before screening.
    • Taking prednisolone (a steroid medication) for another autoimmune disease for more than 8 weeks.
    • Having an estimated kidney function (eGFR) lower than 30 ml/min and/or urine protein loss greater than 0.5 g/L (proteinuria), which could increase the risk of kidney problems.
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Investigated drugs

  • Everolimus

    is a medication that works by blocking a pathway in immune cells, helping to prevent the body from attacking a new liver. In this study it is used instead of the usual drugs that can harm the kidneys, with the goal of protecting kidney function while still stopping rejection of the transplanted liver.

  • Tacrolimus

    is a commonly used drug that suppresses the immune system by inhibiting a protein called calcineurin. It is part of the standard treatment for liver transplant patients and helps keep the new liver from being rejected, but it can sometimes reduce kidney function over time.

  • Ciclosporin

    is another calcineurin‑inhibiting medicine that is often used to prevent rejection after a liver transplant. Like tacrolimus, it is effective at controlling the immune response but may also have side effects that affect the kidneys.

  • Mycophenolate mofetil

    is an immune‑modulating drug that works by stopping certain immune cells from multiplying. It is given together with other medicines in the trial to provide additional protection against liver rejection while allowing the researchers to test whether reducing calcineurin‑inhibitor use can improve kidney health.

What is already known about the treatment

  • EVEROLIMUS

    This medication is taken by mouth as a tablet and works by attaching to a protein called FKBP12, which then blocks a key cell‑growth pathway known as mTOR, reducing the activity of immune cells that can harm a transplanted liver. Everolimus is an approved and widely used drug for preventing organ rejection and for certain cancers, and it is well described in medical research. Its main use is as an immunosuppressant to help patients after liver transplantation keep the new organ healthy. It belongs to the class of mTOR inhibitors, a type of immunosuppressive therapy.

  • TACROLIMUS

    Tacrolimus is given orally as a capsule and works by binding to FKBP12, which then stops an enzyme called calcineurin from activating immune cells that produce the signaling molecule IL‑2. It is an established, FDA‑approved drug for preventing rejection of transplanted organs and is extensively covered in the medical literature. The drug is primarily used to protect liver, kidney, and heart transplants from immune attack. It is classified as a calcineurin inhibitor and an immunosuppressant.

  • CICLOSPORIN

    This drug is taken by mouth in capsule form and attaches to a protein called cyclophilin, which together block calcineurin and lower the production of IL‑2, thus calming the immune system’s response to a new liver. Ciclosporin has been approved for many years to prevent organ rejection and has a large body of research supporting its use. Its main indication is as an immunosuppressive agent for liver transplant recipients. It belongs to the calcineurin inhibitor class of immunosuppressants.

  • MYCOPHENOLATE MOFETIL

    Mycophenolate mofetil is an oral tablet that is converted in the body to mycophenolic acid, which stops an enzyme called IMPDH needed for making DNA building blocks, thereby reducing the growth of T and B immune cells. This medication is approved and widely used to prevent rejection after organ transplants and is well documented in clinical studies. Its primary role is as an immunosuppressant to help maintain the health of a transplanted liver. It is classified as an antimetabolite immunosuppressive drug.

Investigated diseases

  • Acute liver graft rejection

    This is a sudden immune response where the body attacks the transplanted liver. It typically appears weeks to months after the transplant. Liver enzymes rise, indicating damage. If the response continues, the transplanted tissue can become scarred. Over time, the liver may lose its ability to function properly.

  • Chronic kidney disease

    This condition involves a gradual loss of kidney function over years. It often starts with mild reductions in filtering ability. As it progresses, waste products build up in the blood. The disease is staged, with higher stages indicating more severe loss. Eventually, kidney function may become very low.

  • Hypertension

    High blood pressure means the force of blood against artery walls is consistently elevated. It can develop slowly without obvious symptoms. Over time, the arteries may become stiffer. The heart works harder to pump blood. Persistent high pressure can affect many organs.

  • Dyslipidemia

    This disorder refers to abnormal levels of fats in the blood, such as cholesterol or triglycerides. It often develops gradually due to diet, genetics, or lifestyle. Elevated blood fats can deposit in blood vessel walls. The buildup may narrow the vessels. The condition can worsen if not managed.

  • Diabetes mellitus

    Diabetes is a chronic condition where the body cannot properly control blood sugar levels. It may develop gradually and often has few early signs. High blood sugar can affect nerves, blood vessels, and organs. The disease can become more difficult to control over time. Ongoing high sugar levels can lead to further complications.

  • Malignancy

    Malignancy means the presence of cancerous cells that grow uncontrollably. It can start as a small cluster of abnormal cells. Over months to years, the cells may multiply and spread. The growth can invade surrounding tissues. The disease may become more extensive if it continues.

Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-524312-11-00Protocol codeALTERNATIONEstimated enrolment150 patientsSponsorMedizinische Hochschule Hannover

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