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

NCT02909335 | Withdrawn Phase 3

• 2 other identifiers: 35RC12_89852013-003802-19
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief 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). 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.

Conditions

Liver Transplantation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (11)

• Plasma creatinine

  At the end of the treatment (week 48)

• Glomerular filtration rate

  At the end of the treatment (week 48)

• Occurrence of mental trouble

  Between the baseline and the end of the treatment (week 48) (censored criterion)

• Occurence of convulsions

  Between the baseline and the end of the treatment (week 48) (censored criterion)

• Hypertension control

  Between the baseline and the end of the treatment (week 48) (censored criterion)

Study Arms (2)

Tacrolimus group

ACTIVE COMPARATOR

Tacrolimus + mycophenolate mofetil + corticosteroids

Drug: Everolimus; Drug: Mycophenolate mofetil; Drug: Prednisolone, Prednisone or Methylprednisolone

Everolimus group

EXPERIMENTAL

Everolimus + mycophenolate mofetil + corticosteroids

Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Prednisolone, Prednisone or Methylprednisolone

Interventions

Tacrolimus DRUG

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.

Also known as: Prograf

Everolimus group

Everolimus DRUG

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 known as: Certican

Tacrolimus group

Mycophenolate mofetil DRUG

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.

Also known as: Cellcept

Everolimus group; Tacrolimus group

Prednisolone, Prednisone or Methylprednisolone DRUG

Corticosteroid is similarly administered in both groups between baseline and the end of M6 and adjusted in case of acute rejection

Also known as: Methylprednisolone: Solumedrol®, Prednisolone: Solupred®, Prednisone: Cortancyl®

Everolimus group; Tacrolimus group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 .
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rennes University Hospital: lead

MeSH Terms

Interventions

Tacrolimus; Everolimus; Mycophenolic Acid; Prednisolone; Prednisone; Methylprednisolone; Methylprednisolone Hemisuccinate

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Sirolimus; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols

Study Officials

• Karim BOUDJEMA, MD, PhD

  CHU Rennes

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2016
• First Posted: September 21, 2016
• Study Start: November 1, 2016
• Primary Completion: November 1, 2021
• Study Completion: November 1, 2021
• Last Updated: December 14, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share