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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-003802-19 | EudraCT Number |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tacrolimus group | Active Comparator | Tacrolimus + mycophenolate mofetil + corticosteroids |
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| Everolimus group | Experimental | Everolimus + mycophenolate mofetil + corticosteroids |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 :
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| 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 |
| 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) |
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Pre-transplantation Inclusion Criteria:
Post-transplantation Inclusion criteria: Patients meeting the following criteria will be included:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Karim BOUDJEMA, MD, PhD | Rennes University Hospital | Study Director |
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| 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:
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| 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. |
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| 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 |
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| 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) |
| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| D000068338 | Everolimus |
| D009173 | Mycophenolic Acid |
| D011239 | Prednisolone |
| D011241 | Prednisone |
| D008775 | Methylprednisolone |
| D008776 | Methylprednisolone Hemisuccinate |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D020123 | Sirolimus |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D011244 | Pregnadienediols |
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