Advancing Renal TRANSplant eFficacy and Safety Outcomes With an eveRolimus-based regiMen (TRANSFORM)

Study Overview
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Brief Summary
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This is a 2-year, randomized, multicenter, open-label, 2-arm study evaluating the graft function of everolimus and reduced CNI versus MPA and standard CNI in adult de novo renal transplant recipients.

Official Title
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A 24 Month, Multicenter, Randomized, Open-label Safety and Efficacy Study of Concentration-controlled Everolimus With Reduced Calcineurin Inhibitor vs Mycophenolate With Standard Calcineurin Inhibitor in de Novo Renal Transplantation

Conditions
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Hemodialysis, End Stage Renal Disease (ESRD), Chronic Kidney Disease (CKD), Renal Replacement Therapy, Renal Transplantation

Intervention / Treatment
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* Biological: Induction therapy
* Drug: Corticosteroids
* Drug: EVR+rCNI
* Drug: MPA+sCNI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained. Subject randomized within 24 hr of completion of transplant surgery. Recipient of a kidney with a cold ischemia time < 30 hours. Recipient of a primary (or secondary, if first graft is not lost due to immunological reasons) renal transplant from a deceased heart beating, living unrelated, living related non-human leukocyte antigen identical or an expanded criteria donor. Exclusion Criteria: Subject unable to tolerate oral medication at time of randomization. Use of other investigational drugs at the time of enrollment. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. Multi-organ transplant recipient. Recipient of ABO incompatible allograft or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant. Subject at high immunological risk for rejection as determined by local practice for assessment of anti-donor reactivity e.g. high PRA, presence of pre-existing DSA. Subject who is HIV-positive. HBsAg and/or a HCV positive subject with evidence of elevated LFTs (ALT/AST levels ≥ 2.5 times ULN). Viral serology results obtained within 6 months prior to randomization are acceptable. Recipient of a kidney from a donor who tests positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV). Subject with a BMI greater than 35. Subject with severe systemic infections, current or within the two weeks prior to randomization. Subject requiring systemic anticoagulation. History of malignancy of any organ system. Subject with severe restrictive or obstructive pulmonary disorders. Subject with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled. Subject with white blood cell (WBC) count ≤ 2,000 /mm3 or with platelet count ≤ 50,000 /mm3. Pregnant or nursing (lactating) women. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Open-label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EVR+rCNI<br>Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus) | Biological: Induction therapy<br>* All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period.<br>* Other names: Simulect, basiliximab, rATG, Thymoglobulin;Drug: Corticosteroids<br>* All subjects received maintenance therapy with corticosteroids throughout the 24 month study period. A minimum dose of 5 mg prednisone, or equivalent, per day was maintained.<br>* Other names: prednisone, methylprednisone, methylprednisolone, etc.;Drug: EVR+rCNI<br>* Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus)<br>* Other names: Zortress, Certican, Neoral, Prograf;|
| Active Comparator: MPA+sCNI<br>Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus). | Biological: Induction therapy<br>* All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period.<br>* Other names: Simulect, basiliximab, rATG, Thymoglobulin;Drug: Corticosteroids<br>* All subjects received maintenance therapy with corticosteroids throughout the 24 month study period. A minimum dose of 5 mg prednisone, or equivalent, per day was maintained.<br>* Other names: prednisone, methylprednisone, methylprednisolone, etc.;Drug: MPA+sCNI<br>* Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).<br>* Other names: Myfortic, Cellcept, Neoral, Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Failure on the Composite of Treated Biopsy-proven Acute Rejection (tBPAR) or Estimated Glomerular Filtration Rate (eGFR) < 50 mL/Min/1.73m2. | Incidence of failure on the composite of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2. | Month 12 is Primary, Month 24 secondary | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death | Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death | Month 12 and 24 | 
| Incidence of Failure on the Composite Endpoint of tBPAR, Graft Loss, Death or eGFR < 50 mL/Min/1.73m2 | Incidence of failure on the composite endpoint of tBPAR, graft loss, death or eGFR < 50 mL/min/1.73m2 | Month 12 and 24 | 
| Incidence of Failure on the Composite Endpoint of Graft Loss or Death. | Incidence of failure on the composite endpoint of graft loss or death. | Month 12 and 24 | 
| Incidence of Death, Graft Loss, tBPAR, BPAR, tAR, AR and Humoral Rejection | Incidence of death, graft loss, tBPAR (treated biopsy proven acute rejection), BPAR (biopsy proven acute rejection), tAR (treated acute rejection), AR (acute rejection) and humoral rejection (aAMR : active antibody mediated rejection and cAMR: chronic antibody mediated rejection) | Month 12 and 24 | 
| Incidence of eGFR < 50 mL/Min/1.73m2 | Incidence of eGFR < 50 mL/min/1.73m2 | Month 12 and 24 | 
| Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR | Renal allograft function : mean estimated glomerular filtration rate, eGFR | Baseline (week 4), Month 12 and 24 | 
| Evolution of Renal Function, as eGFR, Over Time by Slope Analysis. | Rate of change of renal function, as eGFR, calculated using MDRD4 formula (Coresh, 2003) and adjusted by covariates. | Month 12 and 24 | 
| Renal Function Assessed by Creatinine Lab Values | Mean Renal function as assessed in clinical practice, by ceatinine values. Analysis is done without considering missing values for analysis. | Month 12 and 24 | 
| Renal Function by Alternative Formulae (e.g. CKD-EPI). eGFR Values Reported | Mean Renal function as used in clinical practice, using different formula for calculation of renal function than MDRD4 (our primary efficacy parameter), and other alternate formulae (e.g. CKD-EPI). Analysis is done without considering missing values for analysis. | Month 12 and 24 | 
| Incidence of Adverse Events, Serious Adverse Events and Adverse Events Leading to Study Regimen Discontinuation. | Incidence of adverse events, serious adverse events and adverse events leading to study regimen discontinuation. | Month 24 | 
| Incidence of Cytomegalovirus and BK Virus, New Onset Diabetes Mellitus, Chronic Kidney Disease With Associated Proteinuria and Calcineurin Inhibitor Associated Adverse Events. | Incidence of cytomegalovirus and BK virus, new onset diabetes mellitus, chronic kidney disease with associated proteinuria and calcineurin inhibitor associated adverse events. | Month 24 | 
| Urinary Protein and Albumin Excretion by Treatment Estimated by Urinary Protein/Creatinine and Urinary Albumin/Creatinine Ratios. | Mean urinary protein and albumin excretion by treatment estimated by mean urinary protein/creatinine and urinary albumin/creatinine ratios. | Baseline, Month 12 and 24 | 
| Incidence of Major Cardiovascular Events. | Incidence of major cardiovascular events by Preferred Term | Month 24 | 
| Incidence of Malignancies. | Incidence of malignancies. | Month 24 | 
| Incidence of Failure on the Composite of Treated Biopsy-proven Acute Rejection (tBPAR) or Estimated Glomerular Filtration Rate (eGFR) < 50 mL/Min/1.73m2 Among Compliant Subjects. | Incidence of failure on the composite of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2 among compliant subjects. | Month 12 and 24 | 
| Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Participants) | Incidence tBPAR, defined as any condition where the subject received anti-rejection treatment and was histologically diagnosed as acute rejection (according to the Banff 2009 criteria), by severity (grade IA, IB, IIA, IIB, III) and time to event. Grades for T-cell mediated rejection, with increasing severity: Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation) | Month 12 and 24 | 
| Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events) | Incidence tBPAR, defined as any condition where the subject received anti-rejection treatment and was histologically diagnosed as acute rejection (according to the Banff 2009 criteria), by severity (grade IA, IB, IIA, IIB, III) and time to event. Grades for T-cell mediated rejection, with increasing severity: Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation) | Month 12 and 24 | 
| Incidence of tBPAR (Treated Biopsy-proven Acute Rejection) Excluding Grade IA Rejections | Incidence of tBPAR, defined as any condition where the subject received anti-rejection treatment and was histologically diagnosed as acute rejection (according to the Banff 2009 criteria), excluding grade IA rejections. Grades for T-cell mediated rejection, with increasing severity: Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation) | Month 12 and 24 | 
| Incidence of Composite of tBPAR (Treated Biopsy-proven Acute Rejection)or eGRF<50 mL/Min/1.73m2 by Subgroup | Incidence of composite of tBPAR or eGRF<50 mL/min/1.73m2 by subgroup | Month 12 and 24 | 
| Incidence of tBPAR (Excluding Grade IA Rejections) or GFR<50 mL/Min/1.73m2 | Incidence of tBPAR (excluding grade IA rejections) or GFR<50 mL/min/1.73m2 | Month 12 and 24 | 
| Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death or Loss to Follow-up | Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death or loss to follow-up | Month 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal failure, kidney failure, dialysis, transplantation