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.
Brief Title
Advancing Renal TRANSplant eFficacy and Safety Outcomes With an eveRolimus-based regiMen (TRANSFORM)
Completion Date
Completion Date Type
Actual
Conditions
End Stage Renal Disease (ESRD)
Chronic Kidney Disease (CKD)
Hemodialysis
Renal Replacement Therapy
Renal Transplantation
Eligibility Criteria
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.
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.
Inclusion Criteria
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.
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.
Gender
All
Gender Based
false
Keywords
kidney failure
dialysis
renal failure
transplantation
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01950819
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CRAD001A2433
Overall Status
Completed
Phases
Phase 4
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
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
Primary Outcomes
Outcome Description
Incidence of failure on the composite of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) \< 50 mL/min/1.73m2.
Outcome Measure
Incidence of Failure on the Composite of Treated Biopsy-proven Acute Rejection (tBPAR) or Estimated Glomerular Filtration Rate (eGFR) < 50 mL/Min/1.73m2.
Outcome Time Frame
Month 12 is Primary, Month 24 secondary
Secondary Ids
Secondary Id
2013-000322-66
Secondary Outcomes
Outcome Description
Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death
Outcome Description
Incidence of failure on the composite endpoint of tBPAR, graft loss, death or eGFR \< 50 mL/min/1.73m2
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Failure on the Composite Endpoint of tBPAR, Graft Loss, Death or eGFR < 50 mL/Min/1.73m2
Outcome Description
Incidence of failure on the composite endpoint of graft loss or death.
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Failure on the Composite Endpoint of Graft Loss or Death.
Outcome Description
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)
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Death, Graft Loss, tBPAR, BPAR, tAR, AR and Humoral Rejection
Outcome Description
Incidence of eGFR \< 50 mL/min/1.73m2
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of eGFR < 50 mL/Min/1.73m2
Outcome Description
Renal allograft function : mean estimated glomerular filtration rate, eGFR
Outcome Time Frame
Baseline (week 4), Month 12 and 24
Outcome Measure
Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR
Outcome Description
Rate of change of renal function, as eGFR, calculated using MDRD4 formula (Coresh, 2003) and adjusted by covariates.
Outcome Time Frame
Month 12 and 24
Outcome Measure
Evolution of Renal Function, as eGFR, Over Time by Slope Analysis.
Outcome Description
Mean Renal function as assessed in clinical practice, by ceatinine values. Analysis is done without considering missing values for analysis.
Outcome Time Frame
Month 12 and 24
Outcome Measure
Renal Function Assessed by Creatinine Lab Values
Outcome Description
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.
Outcome Time Frame
Month 12 and 24
Outcome Measure
Renal Function by Alternative Formulae (e.g. CKD-EPI). eGFR Values Reported
Outcome Description
Incidence of adverse events, serious adverse events and adverse events leading to study regimen discontinuation.
Outcome Time Frame
Month 24
Outcome Measure
Incidence of Adverse Events, Serious Adverse Events and Adverse Events Leading to Study Regimen Discontinuation.
Outcome Description
Incidence of cytomegalovirus and BK virus, new onset diabetes mellitus, chronic kidney disease with associated proteinuria and calcineurin inhibitor associated adverse events.
Outcome Time Frame
Month 24
Outcome Measure
Incidence of Cytomegalovirus and BK Virus, New Onset Diabetes Mellitus, Chronic Kidney Disease With Associated Proteinuria and Calcineurin Inhibitor Associated Adverse Events.
Outcome Description
Mean urinary protein and albumin excretion by treatment estimated by mean urinary protein/creatinine and urinary albumin/creatinine ratios.
Outcome Time Frame
Baseline, Month 12 and 24
Outcome Measure
Urinary Protein and Albumin Excretion by Treatment Estimated by Urinary Protein/Creatinine and Urinary Albumin/Creatinine Ratios.
Outcome Description
Incidence of major cardiovascular events by Preferred Term
Outcome Time Frame
Month 24
Outcome Measure
Incidence of Major Cardiovascular Events.
Outcome Description
Incidence of malignancies.
Outcome Time Frame
Month 24
Outcome Measure
Incidence of Malignancies.
Outcome Description
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.
Outcome Time Frame
Month 12 and 24
Outcome Measure
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.
Outcome Description
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)
* 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)
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Participants)
Outcome Description
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)
* 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)
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events)
Outcome Description
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)
* 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)
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of tBPAR (Treated Biopsy-proven Acute Rejection) Excluding Grade IA Rejections
Outcome Description
Incidence of composite of tBPAR or eGRF\<50 mL/min/1.73m2 by subgroup
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Composite of tBPAR (Treated Biopsy-proven Acute Rejection)or eGRF<50 mL/Min/1.73m2 by Subgroup
Outcome Description
Incidence of tBPAR (excluding grade IA rejections) or GFR\<50 mL/min/1.73m2
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of tBPAR (Excluding Grade IA Rejections) or GFR<50 mL/Min/1.73m2
Outcome Description
Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death or loss to follow-up
Outcome Time Frame
Month 12 and 24
Outcome Measure
Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death or Loss to Follow-up
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Enver Akalin
Investigator Email
eakalin@montefiore.org
Investigator Phone
718-920-4815