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

Phase 4CompletedNCT01950819

Novartis Pharmaceuticals2,037 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

2,037

Conditions

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

Interventions

Induction therapyBIOLOGICAL

All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period.

CorticosteroidsDRUG

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.

EVR+rCNIDRUG

Everolimus with reduced calcineurin inhibitor- everolimus (target trough level of 3-8 ng/mL) in combination with reduced exposure to CNI (cyclosporine or tacrolimus)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Written informed consent obtained. 2. Subject randomized within 24 hr of completion of transplant surgery. 3. Recipient of a kidney with a cold ischemia time \< 30 hours. 4. 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: 1. Subject unable to tolerate oral medication at time of randomization. 2. Use of other investigational drugs at the time of enrollment. 3. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. 4. Multi-organ transplant recipient. 5. Recipient of ABO incompatible allograft or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant. 6. 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. 7. Subject who is HIV-positive. 8. 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. 9. 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). 10. Subject with a BMI greater than 35. 11. Subject with severe systemic infections, current or within the two weeks prior to randomization. 12. Subject requiring systemic anticoagulation. 13. History of malignancy of any organ system. 14. Subject with severe restrictive or obstructive pulmonary disorders. 15. Subject with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled. 16. Subject with white blood cell (WBC) count ≤ 2,000 /mm3 or with platelet count ≤ 50,000 /mm3. 17. Pregnant or nursing (lactating) women. 18. 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.

Locations (184)

Outcomes

Primary Outcomes

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.

Time frame: Month 12 is Primary, Month 24 secondary

Secondary Outcomes

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

Time frame: 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

Time frame: 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.

Time frame: 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)

Time frame: Month 12 and 24

Incidence of eGFR < 50 mL/Min/1.73m2

Incidence of eGFR \< 50 mL/min/1.73m2

Time frame: Month 12 and 24

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).

Novartis Investigative Site

Birmingham, Alabama, United States

Novartis Investigative Site

Loma Linda, California, United States

Novartis Investigative Site

Los Angeles, California, United States

Novartis Investigative Site

Los Angeles, California, United States

Novartis Investigative Site

Sacramento, California, United States

Novartis Investigative Site

San Diego, California, United States

Novartis Investigative Site

San Francisco, California, United States

Novartis Investigative Site

San Francisco, California, United States

Novartis Investigative Site

Aurora, Colorado, United States

Novartis Investigative Site

Denver, Colorado, United States

...and 174 more locations

Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR

Renal allograft function : mean estimated glomerular filtration rate, eGFR

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Month 12 and 24

Incidence of Major Cardiovascular Events.

Incidence of major cardiovascular events by Preferred Term

Time frame: Month 24

Incidence of Malignancies.

Incidence of malignancies.

Time frame: 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.

Time frame: 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)

Time frame: Month 12 and 24

Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events)

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Month 12 and 24