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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)

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ClinicalTrials.gov Identifier: NCT02909335
Recruitment Status : Not yet recruiting
First Posted : September 21, 2016
Last Update Posted : September 21, 2016
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

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.


Condition or disease Intervention/treatment Phase
Liver Transplantation Drug: Tacrolimus Drug: Everolimus Drug: Mycophenolate mofetil Drug: Prednisolone, Prednisone or Methylprednisolone Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Study Start Date : November 2016
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021


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 Name: 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 Name: 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: 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 Name: Prograf

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 Name: 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®




Primary Outcome Measures :
  1. 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.


  2. 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).


Secondary Outcome Measures :
  1. Plasma creatinine [ Time Frame: At the end of the treatment (week 48) ]
  2. Glomerular filtration rate [ Time Frame: At the end of the treatment (week 48) ]
    Glomerular filtration rate calculated following Modification of Diet in Renal Disease (MDRD) formula

  3. Occurrence of mental trouble [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Occurrence of an episode of confusion, agitation or delirium assessed by neurological examination

  4. Occurence of convulsions [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Occurrence of convulsion episodes from baseline to the end of W48 (censored criterion)

  5. Hypertension control [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Occurrence of hypertension requiring the introduction of antihypertensive therapy (censored criterion)

  6. Number of patients with incident diabetes [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Patients presenting development of diabetes requiring the introduction of a hypoglycaemic therapy (censored criterion)

  7. Hypercholesterolemia [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Occurrence of hypercholesterolemia requiring the introduction of lipid-lowering therapy (censored criterion)

  8. Hypertriglyceridemia [ Time Frame: Between the baseline and the end of the treatment (week 48) (censored criterion) ]
    Occurrence of hypertriglyceridemia requiring the introduction of lipid-lowering therapy (censored criterion)

  9. Number of patients with infection [ Time Frame: At the end of the treatment (week 48) ]
    Rate of patients who had at least one infection between baseline and the end of S48 requiring the use of an etiological treatment

  10. Number of everolimus linked adverse events [ Time Frame: At the end of the treatment (week 48) ]
    Rate of patients who had at least one adverse effect of everolimus: ulcer, scar dehiscence, lower limb edema, hyperlipidemia, anemia, leukopenia, thrombocytopenia.

  11. Number of mycophenolate mofetil linked adverse events [ Time Frame: At the end of the treatment (week 48) ]
    Rate of patients who had at least one adverse effect of mycophenolate mofetil: persistent diarrhea, nausea, vomiting, abdominal pain , leukopenia, anemia, thrombocytopenia



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02909335


Contacts
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Contact: Karim BOUDJEMA, MD, PhD karim.boudjema@chu-rennes.fr
Contact: Anne HESPEL, PhD anne.hespel@chu-rennes.fr

Locations
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France
CHU Rennes
Rennes, France, 35000
Contact: Anne HESPEL, PhD       anne.hespel@chu-rennes.fr   
Principal Investigator: Karim BOUDJEMA, MD, PhD         
Sponsors and Collaborators
Rennes University Hospital
Investigators
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Study Director: Karim BOUDJEMA, MD, PhD CHU Rennes
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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT02909335    
Other Study ID Numbers: 35RC12_8985
2013-003802-19 ( EudraCT Number )
First Posted: September 21, 2016    Key Record Dates
Last Update Posted: September 21, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Mycophenolic Acid
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Everolimus
Prednisolone hemisuccinate
Prednisolone phosphate
Tacrolimus
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antiemetics
Autonomic Agents