24 Months Follow-up, Two Arm Study to Compare the Cardiovascular Profile in a Regimen With Everolimus + Mycophenolic Acid (MPA) Versus (vs.) a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients

Study Overview
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Brief Summary
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The objective of the study is to compare the cardiovascular profile of an everolimus and mycophenolic acid immunosuppressive regimen with a calcineurin inhibitor and mycophenolic acid regimen in maintenance renal transplant patients

Official Title
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Multicenter, Open-label, Randomized, 24 Months Follow-up, Two Arm Study to Compare the Efficacy of Everolimus in Improving the Cardiovascular Profile in a Regimen With Mycophenolic Acid vs. a Regimen of CNI+MPA in Maintenance Renal Transplant Recipients.

Conditions
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Renal Transplant

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Mycophenolic acid (MPA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Received kidney transplant > 6 months and < 3 years prior to study enrollment Receiving immunosuppressive regimen that includes tacrolimus and mycophenolic acid Between 18 and 70 years of age Willing to provide written informed consent Exclusion Criteria: Patients with an actual serum creatinine ≥ 2 mg/dl and/or eGFR≤ 40 ml/min and/or proteinuria≥ 500mg/day Patients who suffered from severe humoral and/or cellular rejection (≥ BANFF IIb, recurrent acute rejection or steroid resistant acute rejection in the previous years Patients who have severe hypercholesterolemia (>350 mg/dL; >9 mmol/L) or hypertriglyceridemia (>500 mg/dL; >8.5 mmol/L). Patients with controlled hyperlipidemia are acceptable. Diabetic patients Woman of child-bearing potential who is planning to become pregnant or is pregnant and/or lactating who is unwilling to use effective means of contraception Presence of psychiatric illness (i.e., schizophrenia, major depression) that, in the opinion of the site investigator, would interfere with study requirements Any other medical condition that, in the opinion of the site investigator based on recall or chart review would interfere with completing the study Receiving any investigational drug or have received any investigational drug within 30 days prior to study enrollment

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

Accepts Healthy Volunteers
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No

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: Tacrolimus<br>Participants continued with the same tacrolimus+Mycophenolic acid (MPA) (Myfortic® or Cell-Cept®) doses that were taken before study initiation (tacrolimus levels 4-7 ng/ml). | Drug: Tacrolimus<br>* Tacrolimus was administrated as Prograf® or Advagraf®, but could not be changed during study.<br>* Other names: Prograf®, Advagraf®;Drug: Mycophenolic acid (MPA)<br>* Myfortic® (MFS) was given as 720-1440 mg/day or 360-1440 mg/day. Cell-Cept® (MMF) was given as 1000-2000 mg/day or 500-2000 mg/day.<br>* Other names: Cell-Cept®;|
| Experimental: Everolimus<br>Participants received an initial dose (day 1) of Everolimus (EVL) 2mg at night and tacrolimus (if taking Prograf®, a full dose of Prograf® in the morning and a 50% dose of Prograf® at night; if taking Advagraf®, a 75% dose in the morning. On days 2 and 3, participants took EVL 2 mg twice daily (bid) without tacrolimus. On days 4 and 5, the EVL dose was adjusted and levels maintained between 5-8 ng/mL. Participants also continued with their MPA doses that were taken prior to study initiation. | Drug: Everolimus<br>* Everolimus was supplied in boxes with 60 tablets. Available tablets: 1.0 mg, 0.5 mg and 0.25 mg.<br>* Other names: Certican®;Drug: Tacrolimus<br>* Tacrolimus was administrated as Prograf® or Advagraf®, but could not be changed during study.<br>* Other names: Prograf®, Advagraf®;Drug: Mycophenolic acid (MPA)<br>* Myfortic® (MFS) was given as 720-1440 mg/day or 360-1440 mg/day. Cell-Cept® (MMF) was given as 1000-2000 mg/day or 500-2000 mg/day.<br>* Other names: Cell-Cept®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Left Ventricular Mass Index (LVMI) | Left ventricular hypertrophy grade was assessed by echocardiogram where the left ventricular mass index was calculated. The presence of LVM was defined as > 49.2 g/m^2.7 in men and >46.7 g/m^2.7 in women. A negative change from baseline indicates improvement. | Baseline, Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24 Hour Systolic and Diastolic Blood Pressure | Blood pressure was measured using ambulatory blood pressure monitoring (ABPM). A negative change from baseline indicates improvement. | Baseline, Month 6, month 12, month 24 | 
| Pulse Wave Velocity (PWV) | Utilizing the SphygmoCor Device, ECG leads placed at the carotid and femoral arteries provided the measure of the pulse wave at that particular arterial location. The distance between the two vascular beds divided by the pulse wave time shift provided a measure of the pulse wave velocity. | Month 6, month 24 | 
| Percentage of Participants With Major Cardiovascular Events (MACE) | The percentage of participants who experienced MACE were reported. MACE included acute myocardial infarction, insertion or replacement of implantable defibrillator, peripheral vascular disorders, congestive heart failure, coronary artery bypass, other events, percutaneous coronary intervention and stroke. | Month 24 | 
| Renal Function Measured by Serum Creatinine | Serum samples were collected to analyze serum creatinine. | Month 6, month 12, month 24 | 
| Renal Function as Measured by Creatinine Clearance | Creatinine clearance was calculated using the Cockroft-Gault formula. | Month 6, month 12, month 24 | 
| Renal Function as Measured by Estimated Glomerular Filtration Rate (eGFR) | Estimated GFR was caluclated using the modification of diet in renal disease (MDRD) formula. | Month 6, month 12, month 24 | 
| Change From Baseline in Cardiovascular Biomarkers: Troponin I and Collagen Type 1 C-telopeptide (ICTP) | Blood samples were collected to analyze Troponin I and collagen type 1 C-telopeptide (ICTP). A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Change From Baseline in the Cardiovascular Biomarker, Glycosylated Hemoglobin (HbA1c) | Blood samples were collected to analyze HbA1c. A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Change From Baseline in the Cardiovascular Biomarker, Myeloperoxidase (MPO) | Blood samples were collected to analyze MPO. A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Change From Baseline in the Cardiovascular Biomarker, N-terminal Pro-brain Natriuretic Peptide Fraction (NT-proBNP) | Blood samples were collected to analyze NT-proBNP. A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Change From Baseline in the Cardiovascular Biomarker, Type 1 Procollagen Amino-terminal-propeptide (PINP) | Blood samples were collected to analyze PCR. A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Change From Baseline in Cardiovascular Biomarkers, C-reactive Protein (CRP) | Blood samples were collected to analyze CRP. A negative change from baseline indicates improvement. | Baseline, month 6, month 24 | 
| Percentage of Participants With Biopsy-proven Acute Rejection (BPAR), Graft Loss, Death and Lost to Follow up | The incidence of BPAR, graft loss, death and lost to follow-up events was calculated using relative frequency. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplant, everolimus, cardiovascular profile, CNI-free immunosuppression, left ventricular hypertrophy, biopsy proved acute rejection (BPAR)