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

Phase 4

Completed

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

Interventions: Biological: Induction therapy
Drug: Corticosteroids
Drug: EVR+rCNI
Drug: MPA+sCNI

Registration Number: NCT01950819

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 2037

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EVR+rCNI	Induction therapy	Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus)
EVR+rCNI	Corticosteroids	Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus)
EVR+rCNI	EVR+rCNI	Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus)
MPA+sCNI	Induction therapy	Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).
MPA+sCNI	Corticosteroids	Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).
MPA+sCNI	MPA+sCNI	Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).

Primary Outcome Measures

Name	Time	Method
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	Incidence of failure on the composite of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) \< 50 mL/min/1.73m2.

Secondary Outcome Measures

Name	Time	Method
Incidence of Death, Graft Loss, tBPAR, BPAR, tAR, AR and Humoral Rejection	Month 12 and 24	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)
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 of (treated biopsy proven acute rejection (tBPAR), graft loss or death
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 tBPAR, graft loss, death or eGFR \< 50 mL/min/1.73m2
Incidence of Failure on the Composite Endpoint of Graft Loss or Death.	Month 12 and 24	Incidence of failure on the composite endpoint of graft loss or death.
Incidence of eGFR < 50 mL/Min/1.73m2	Month 12 and 24	Incidence of eGFR \< 50 mL/min/1.73m2
Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR	Baseline (week 4), Month 12 and 24	Renal allograft function : mean estimated glomerular filtration rate, eGFR
Evolution of Renal Function, as eGFR, Over Time by Slope Analysis.	Month 12 and 24	Rate of change of renal function, as eGFR, calculated using MDRD4 formula (Coresh, 2003) and adjusted by covariates.
Renal Function Assessed by Creatinine Lab Values	Month 12 and 24	Mean Renal function as assessed in clinical practice, by ceatinine values. Analysis is done without considering missing values for analysis.
Urinary Protein and Albumin Excretion by Treatment Estimated by Urinary Protein/Creatinine and Urinary Albumin/Creatinine Ratios.	Baseline, Month 12 and 24	Mean urinary protein and albumin excretion by treatment estimated by mean urinary protein/creatinine and urinary albumin/creatinine ratios.
Renal Function by Alternative Formulae (e.g. CKD-EPI). eGFR Values Reported	Month 12 and 24	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.
Incidence of Adverse Events, Serious Adverse Events and Adverse Events Leading to Study Regimen Discontinuation.	Month 24	Incidence of adverse events, serious adverse events and adverse events leading to study regimen discontinuation.
Incidence of Cytomegalovirus and BK Virus, New Onset Diabetes Mellitus, Chronic Kidney Disease With Associated Proteinuria and Calcineurin Inhibitor Associated Adverse Events.	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 Malignancies.	Month 24	Incidence of malignancies.
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 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 Major Cardiovascular Events.	Month 24	Incidence of major cardiovascular events by Preferred Term
Incidence of tBPAR (Treated Biopsy-proven Acute Rejection) Excluding Grade IA Rejections	Month 12 and 24	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)
Incidence of Composite of tBPAR (Treated Biopsy-proven Acute Rejection)or eGRF<50 mL/Min/1.73m2 by Subgroup	Month 12 and 24	Incidence of composite of tBPAR or eGRF\<50 mL/min/1.73m2 by subgroup
Incidence of tBPAR (Excluding Grade IA Rejections) or GFR<50 mL/Min/1.73m2	Month 12 and 24	Incidence of tBPAR (excluding grade IA rejections) or GFR\<50 mL/min/1.73m2
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	Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death or loss to follow-up
Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Participants)	Month 12 and 24	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)
Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events)	Month 12 and 24	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)