RESCUE Study - Everolimus in Liver Transplantation Recipients With Renal Insufficiency

Study Overview
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Brief Summary
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The purpose of the study is to assess the effect of everolimus initiation together with reduction or discontinuation of calcineurin inhibitor (CNI) on renal function in maintenance liver transplant recipients with CNI-related renal impairment, while maintaining efficacy.

Official Title
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A 6-month, Multicenter, Randomized, Open-label Study of Safety and Efficacy of Everolimus-based Regimen Versus Calcineurin Inhibitor (CNI)-Based Regimen in Maintenance Liver Transplant Recipients

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Calcineurin inhibitors (CNI)
* Drug: Mycophenolate acid (MPA)/ Azathioprine (AZA)
* Drug: Steroids


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female 18 - 70 years old Patient who has undergone a primary liver transplantation 12 to 60 months ago from a cadaveric or a living donor Patient with a calculated GFR ≤ 60 and ≥ 20mL/min Patient receiving tacrolimus with C0-h level ≥ 3 and ≤ 8 ng/mL or Neoral® with C0-h level ≥ 50 and ≤ 150 ng/mL or with C2-h level ≥ 250 ng/mL and ≤ 650 ng/mL with or without any of the following (MPA or AZA or steroids) Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 6 months Patient in whom an allograft biopsy will not be contraindicated Female capable of becoming pregnant must have a negative pregnancy test prior to randomization and are required to practice a medically approved method of birth control for the duration of the study Exclusion criteria Recipient of multiple solid organ transplants Patient on dialysis Patient with an identifiable cause of renal dysfunction other than CNI toxicity Patient with proteinuria ≥ 1.0 g/24h Patient with any acute rejection within 6 months prior to randomization Patient with platelet count of ≤ 50,000/mm³ or white blood cell count of ≤ 2,000/mm³ or hemoglobin value ≤ 8 g/dL Undergone a liver transplantation for a hepatocellular carcinoma with sign of recurrence; Severe graft dysfunction; HCV positive patient who needs an active anti-viral treatment HIV positive patient Patient who is breast feeding Patient with a current severe systemic infection Patient who has received an unlicensed drug or therapy within one month prior to study entry Presence of any hypersensitivity to drugs similar to everolimus (e.g. macrolides) Use of any other immunosuppressive drugs than tacrolimus/cyclosporine microemulsion, steroids, azathioprine and mycophenolic acid Additional protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reduced CNI dose + everolimus ± steroids<br>Reduced CNI dose + everolimus (1.5 mg twice daily (b.i.d)) ± steroids | Drug: Everolimus<br>* 1.5 mg bid adjusted in order to achieve a trough level between 3 and 8 ng/mL while in combination with CNI and between 6 and 12 ng/mL after CNI discontinuation<br>* Other names: Neoral®/Prograf®;Drug: Calcineurin inhibitors (CNI)<br> <br> * Other names: Neoral/Prograf;Drug: Steroids<br> <br> |
| Experimental: CNI continuation ± MPA/AZA ± Steroids<br>Standard CNI dose ± MPA/AZA ± steroids | Drug: Calcineurin inhibitors (CNI)<br> <br> * Other names: Neoral/Prograf;Drug: Mycophenolate acid (MPA)/ Azathioprine (AZA)<br> <br> * Other names: Myfortic/Cellecept;Drug: Steroids<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Cockcroft-Gault Calculated Creatinine Clearance (CrCl) | The primary variable was renal function assessed by calculated creatinine clearance using the Cockcroft-Gault formula, and was assessed at all visits. CrCl[mL/min] = (140 - A) * W / (72 * C) * R. Where A is age at sample date [years], W is body weight at specific visit [kg], C is the serum concentration of creatinine [mg/dL], R = 1 if the patient is male and = 0.85 if female. | From baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Efficacy Failure (Biopsy Proven Acute Rejection [BPAR], Graft Loss or Death) | The composite efficacy failure endpoint encompasses at least one of: biopsy proven acute rejection, graft loss, or death for the patient. BPAR was defined as a clinically suspected acute rejection confirmed by biopsy. Acute rejection episodes were recorded as Liver Allograft Rejection. The allograft was presumed to be lost if a patient had a liver retransplant or died. | 6 months | 
| Number of Patients With Discontinuation of Study Medication |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, everolimus, calcineurin inhibitor, renal function