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 (FOREVER)

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.

Study Overview

• Status: Withdrawn
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Mycophenolate mofetil; Drug: Prednisolone, Prednisone or Methylprednisolone; Drug: Tacrolimus

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 Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Pre-transplantation Inclusion Criteria:

• Adults (≥18 years), male or female,
• Patients due to receive a first liver transplant with a full or reduced graft taken from a donor brain-dead beating heart or a related living donor,
• Patients having given a free and informed written consent .

Post-transplantation Inclusion criteria: Patients meeting the following criteria will be included:

• Receiving basiliximab (Simulect)
• Whose immunosuppression regimen from day 5 could immediately consist of either tacrolimus or everolimus, in combination with mycophenolate mofetil and low dose corticosteroids
• With hepatic artery permeable to echo Doppler 4 days after transplant.

Exclusion Criteria:

• 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,
• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus group; Tacrolimus + mycophenolate mofetil + corticosteroids	Drug: Everolimus; 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.; Other Names: Certican; Drug: Mycophenolate mofetil; 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.; Other Names: Cellcept; Drug: Prednisolone, Prednisone or Methylprednisolone; Corticosteroid is similarly administered in both groups between baseline and the end of M6 and adjusted in case of acute rejection; Other Names: Methylprednisolone: Solumedrol®; Prednisolone: Solupred®; Prednisone: Cortancyl®
Experimental: Everolimus group; Everolimus + mycophenolate mofetil + corticosteroids	Drug: Mycophenolate mofetil; 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.; Other Names: Cellcept; Drug: Prednisolone, Prednisone or Methylprednisolone; Corticosteroid is similarly administered in both groups between baseline and the end of M6 and adjusted in case of acute rejection; Other Names: Methylprednisolone: Solumedrol®; Prednisolone: Solupred®; Prednisone: Cortancyl®; Drug: Tacrolimus; 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.; Other Names: Prograf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	Between the baseline and the end of the treatment (week 48) (censored criterion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma creatinine		At the end of the treatment (week 48)
Glomerular filtration rate	Glomerular filtration rate calculated following Modification of Diet in Renal Disease (MDRD) formula	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	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)	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)	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)	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)	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)	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	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.	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	At the end of the treatment (week 48)

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Study Director: Karim Boudjema, MD, PhD, CHU Rennes

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Anticipated): November 1, 2021
• Study Completion (Anticipated): November 1, 2021

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: September 16, 2016
• First Posted (Estimate): September 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 14, 2022
• Last Update Submitted That Met QC Criteria: December 13, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Prednisone; Tacrolimus; Mycophenolic Acid; Everolimus
• Other Study ID Numbers: 35RC12_8985; 2013-003802-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No