Liver TransplantationPhase 3FOREVERNCT02909335
De Novo Everolimus Versus Tacrolimus in Combination With Mofetil Mycophenolate and Low Dose Corticosteroids to Reduce Tacrolimus Induced Nephrotoxicity in Liver Transplantation: a Prospective, Multicentric, Randomised Study
A Phase 3 study testing Tacrolimus, Everolimus and Mycophenolate mofetil in people with Liver Transplantation, run by Rennes University Hospital.
Trial summary
Tacrolimus is a calcineurin inhibitor. This is the immunosuppression of reference for patients undergoing a first liver transplant. This treatment can prevent graft rejection, but can cause side effects including kidney failure (in 25% after the first year). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Transplantation
- What is being tested?
- Tacrolimus, Everolimus and Mycophenolate mofetil
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Nov 2016to Nov 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- History of immunosuppressive therapy,
- Known hypersensitivity to the treatments or macrolides,
- HIV infection
- Autoimmune hepatitis,
- Primary sclerosing cholangitis,
- Programming or realization of a combined transplant,
Show all 11Show fewer
- Pregnancy or lack of effective contraception,
- Breastfeeding.
- Incompatibility with the donor,
- Thrombosis of the hepatic artery between D0 and D4,
- Non-primary graft function leading to a re-registration on the waiting list.
About this study
Tacrolimus is a calcineurin inhibitor. This is the immunosuppression of reference for patients undergoing a first liver transplant. This treatment can prevent graft rejection, but can cause side effects including kidney failure (in 25% after the first year).
Everolimus is an immunosuppressive that effectively prevents acute rejection in heart and kidney transplant recipients. It preserves renal function when it is started soon after the transplant, i.e. before a severe dysfunction is installed.
Read the detailed description
In the liver transplant, early interruption of calcineurin inhibitors with a quick relay everolimus monotherapy preserves renal function and is associated with a lower acute rejection rate.
We wish to assess whether the introduction of a de novo immunosuppression everolimus under protection of basiliximab induction, mycophenolate mofetil and then low doses of corticosteroids, reduces the nephrotoxicity of immunosuppressive therapy in liver transplant patients, compared to a standard protocol with tacrolimus associated with mycophenolate mofetil and low dose corticosteroids.
- Conditions
- Liver Transplantation
- Being tested
- Tacrolimus, Everolimus, Mycophenolate mofetil, Prednisolone, Prednisone or Methylprednisolone
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Prograf
Tacrolimus is administered at an initial dose of 0.040 mg / kg twice a day on Day 5.
The doses are then adjusted to maintain trough levels :
- between 6 and 10 ng / ml during the first 2 months,
- between 5 and 8 ng / ml from the start of the end M3 and M6,
- and between 4 and 6 ng / ml between the beginning and the end of M7 M12.
EverolimusDrug
Also called Certican
Everolimus is administered at an initial dose of 1.5 mg twice a day on Day 5.
The doses are then adjusted to maintain trough levels:
- between 6 and 10 ng / ml during the first 2 months,
- between 5-8 ng / ml from the start of the end M3 and M6,
- and between 4 and 6 ng / ml between the beginning and the end of M7 M12.
Also called Cellcept
mycophenolate mofetil is administered similarly in the two groups at the dose of 1.5 g for the first two months and then 1 g twice a day. The doses may be adjusted according to the tolerance of the product.
Prednisolone, Prednisone or MethylprednisoloneDrug
Also called Methylprednisolone: Solumedrol®, Prednisolone: Solupred®, Prednisone: Cortancyl®
Corticosteroid is similarly administered in both groups between baseline and the end of M6 and adjusted in case of acute rejection
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus group | Active comparator | Tacrolimus + mycophenolate mofetil + corticosteroids Receives: Drug: Everolimus; Drug: Mycophenolate mofetil; Drug: Prednisolone, Prednisone or Methylprednisolone |
| Everolimus group | Experimental | Everolimus + mycophenolate mofetil + corticosteroids Receives: Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Prednisolone, Prednisone or Methylprednisolone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Worsening of renal function
The main objective of the study is to evaluate, in liver transplanted patients, the benefit in terms of prevention of renal failure, a regimen that includes a de novo introduction of everolimus instead of tacrolimus, in combination with mycophenolate mofetil and low doses of corticosteroids, to the extent that this benefit is not accompanied by an increased risk of graft loss or hepatic artery thrombosis.
Insofar as the objective of the study is to assess a risk / benefit ratio, the study has two main criteria.
Worsening renal function is validated before the prolonged decline (found on at least 3 assays carried out at least 3 months apart) over 30% of the creatinine clearance compared to the value at baseline . The date of the first evidence of this worsening of renal function is the date used to calculate the distribution of censored criterion.
Measured: Between the initiation of treatment (Day 5) and the end (week 48) (censored criterion)
Occurrence of graft loss
Graft loss , whatever the cause, or thrombosis of the hepatic artery are recorded between baseline and the end of S48 (censored criterion).
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion
Secondary outcomes (11)
Plasma creatinine
Measured: At the end of the treatment (week 48)
Glomerular filtration rate
Glomerular filtration rate calculated following Modification of Diet in Renal Disease (MDRD) formula
Measured: At the end of the treatment (week 48)
Occurrence of mental trouble
Occurrence of an episode of confusion, agitation or delirium assessed by neurological examination
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Occurence of convulsions
Occurrence of convulsion episodes from baseline to the end of W48 (censored criterion)
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypertension control
Occurrence of hypertension requiring the introduction of antihypertensive therapy (censored criterion)
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Number of patients with incident diabetes
Patients presenting development of diabetes requiring the introduction of a hypoglycaemic therapy (censored criterion)
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypercholesterolemia
Occurrence of hypercholesterolemia requiring the introduction of lipid-lowering therapy (censored criterion)
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypertriglyceridemia
Occurrence of hypertriglyceridemia requiring the introduction of lipid-lowering therapy (censored criterion)
Measured: Between the baseline and the end of the treatment (week 48) (censored criterion)
Number of patients with infection
Rate of patients who had at least one infection between baseline and the end of S48 requiring the use of an etiological treatment
Measured: At the end of the treatment (week 48)
Number of everolimus linked adverse events
Rate of patients who had at least one adverse effect of everolimus: ulcer, scar dehiscence, lower limb edema, hyperlipidemia, anemia, leukopenia, thrombocytopenia.
Measured: At the end of the treatment (week 48)
Number of mycophenolate mofetil linked adverse events
Rate of patients who had at least one adverse effect of mycophenolate mofetil: persistent diarrhea, nausea, vomiting, abdominal pain , leukopenia, anemia, thrombocytopenia
Measured: At the end of the treatment (week 48)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2016 (estimated)
- Study startNov 2016
- Primary completionNov 2021 (estimated)
- Study completionNov 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver TransplantationStudies of the same condition, open and under way.
- More trials run by Rennes University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Karim BOUDJEMA, MD, PhD, Study director, Rennes University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02909335
- Sponsor's protocol ID
- 35RC12_8985
- Other IDs
- 2013-003802-19
- Acronym
- FOREVER
- Status last verified
- Dec 2022
- First submitted
- 9 Sep 2016
- Last updated
- 14 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- De Novo Everolimus Versus Tacrolimus in Combination With Mofetil Mycophenolate and Low Dose Corticosteroids to Reduce Tacrolimus Induced Nephrotoxicity in Liver Transplantation: a Prospective, Multicentric, Randomised Study
- ClinicalTrials.gov ID
- NCT02909335
- Acronym / sponsor ID
- FOREVER / 35RC12_8985
- Conditions
- Liver Transplantation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- Nov 2016
- Primary completion
- Nov 2021 (estimated)
- Study completion
- Nov 2021 (estimated)
- First posted
- 21 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Tacrolimus is a calcineurin inhibitor. This is the immunosuppression of reference for patients undergoing a first liver transplant. This treatment can prevent graft rejection, but can cause side effects including kidney failure (in 25% after the first year).
Everolimus is an immunosuppressive that effectively prevents acute rejection in heart and kidney transplant recipients. It preserves renal function when it is started soon after the transplant, i.e. before a severe dysfunction is installed.
Detailed description
In the liver transplant, early interruption of calcineurin inhibitors with a quick relay everolimus monotherapy preserves renal function and is associated with a lower acute rejection rate.
We wish to assess whether the introduction of a de novo immunosuppression everolimus under protection of basiliximab induction, mycophenolate mofetil and then low doses of corticosteroids, reduces the nephrotoxicity of immunosuppressive therapy in liver transplant patients, compared to a standard protocol with tacrolimus associated with mycophenolate mofetil and low dose corticosteroids.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus group | Active comparator | Drug: Everolimus, Drug: Mycophenolate mofetil, Drug: Prednisolone, Prednisone or MethylprednisoloneTacrolimus + mycophenolate mofetil + corticosteroids |
| Everolimus group | Experimental | Drug: Tacrolimus, Drug: Mycophenolate mofetil, Drug: Prednisolone, Prednisone or MethylprednisoloneEverolimus + mycophenolate mofetil + corticosteroids |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (11 listed)
- History of immunosuppressive therapy,
- Known hypersensitivity to the treatments or macrolides,
- HIV infection
- Autoimmune hepatitis,
- Primary sclerosing cholangitis,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: PrografTacrolimus is administered at an initial dose of 0.040 mg / kg twice a day on Day 5. The doses are then adjusted to maintain trough levels : * between 6 and 10 ng / ml during the first 2 months, * between 5 and 8 ng / ml from the start of the end M3 and M6, * and between 4 and 6 ng / ml between the beginning and the end of M7 M12. | Drug | Everolimus group |
| EverolimusAlso: CerticanEverolimus is administered at an initial dose of 1.5 mg twice a day on Day 5. The doses are then adjusted to maintain trough levels: * between 6 and 10 ng / ml during the first 2 months, * between 5-8 ng / ml from the start of the end M3 and M6, * and between 4 and 6 ng / ml between the beginning and the end of M7 M12. | Drug | Tacrolimus group |
| Mycophenolate mofetilAlso: Cellceptmycophenolate mofetil is administered similarly in the two groups at the dose of 1.5 g for the first two months and then 1 g twice a day. The doses may be adjusted according to the tolerance of the product. | Drug | Everolimus group, Tacrolimus group |
| Prednisolone, Prednisone or MethylprednisoloneAlso: Methylprednisolone: Solumedrol®, Prednisolone: Solupred®, Prednisone: Cortancyl®Corticosteroid is similarly administered in both groups between baseline and the end of M6 and adjusted in case of acute rejection | Drug | Everolimus group, Tacrolimus group |
Primary outcome
Worsening of renal function
Time frame: Between the initiation of treatment (Day 5) and the end (week 48) (censored criterion)
The main objective of the study is to evaluate, in liver transplanted patients, the benefit in terms of prevention of renal failure, a regimen that includes a de novo introduction of everolimus instead of tacrolimus, in combination with mycophenolate mofetil and low doses of corticosteroids, to the extent that this benefit is not accompanied by an increased risk of graft loss or hepatic artery thrombosis. Insofar as the objective of the study is to assess a risk / benefit ratio, the study has two main criteria. Worsening renal function is validated before the prolonged decline (found on at least 3 assays carried out at least 3 months apart) over 30% of the creatinine clearance compared to the value at baseline . The date of the first evidence of this worsening of renal function is the date used to calculate the distribution of censored criterion.
Occurrence of graft loss
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion
Graft loss , whatever the cause, or thrombosis of the hepatic artery are recorded between baseline and the end of S48 (censored criterion).
11 secondary outcomes
Plasma creatinine
Time frame: At the end of the treatment (week 48)
Glomerular filtration rate
Time frame: At the end of the treatment (week 48)
Occurrence of mental trouble
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Occurence of convulsions
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypertension control
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Number of patients with incident diabetes
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypercholesterolemia
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Hypertriglyceridemia
Time frame: Between the baseline and the end of the treatment (week 48) (censored criterion)
Number of patients with infection
Time frame: At the end of the treatment (week 48)
Number of everolimus linked adverse events
Time frame: At the end of the treatment (week 48)
Number of mycophenolate mofetil linked adverse events
Time frame: At the end of the treatment (week 48)
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2022.
- Individual participant dataSharing planned: No
Related trials for Liver Transplantation
Not yet recruitingObservational study
Prevalence and Development of Liver Dysfunction in Hematopoietic Stem Cell Transplant
Hematopoietic Stem Cell Transplant
Not yet recruiting
Efficacy of Carnitine Complex in Improving Hepatic Steatosis in Potential Liver Donors
Hepatic Steatosis, Fatty Liver
Not yet recruiting
New Biomarkers for Organ Viability Assessment During Hypothermic Machine Perfusion in Liver Transplantation: the Role of Extemporaneous Histological Examination.
Liver Transplantation (LT), Early Allograft Dysfunction
RecruitingPhase 2
Expanding Liver Transplant Immunosuppression Minimization Via Everolimus
Liver Transplant
RecruitingObservational study
Long-term Follow-up (LTFU) Study of Participants in Any iECURE Protocol Using an Investigational Product (IP)
Ornithine Transcarbamylase Deficiency, Ornithine Transcarbamylase Deficiency Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Karim BOUDJEMA, MD, PhD study director
Rennes University Hospital
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tacrolimus, Everolimus and Mycophenolate mofetil in people with Liver Transplantation, run by Rennes University Hospital.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 14 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Worsening of renal function (time frame: Between the initiation of treatment (Day 5) and the end (week 48) (censored criterion)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2022.