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

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ClinicalTrials.gov Identifier: NCT01950819
Recruitment Status : Completed
First Posted : September 26, 2013
Results First Posted : January 30, 2019
Last Update Posted : January 30, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( 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.

Condition or disease Intervention/treatment Phase
End Stage Renal Disease (ESRD) Chronic Kidney Disease (CKD) Hemodialysis Renal Replacement Therapy Renal Transplantation Biological: Induction therapy Drug: Corticosteroids Drug: EVR+rCNI Drug: MPA+sCNI Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2037 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-label study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 3, 2013
Actual Primary Completion Date : February 1, 2017
Actual Study Completion Date : January 17, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Arm Intervention/treatment
Experimental: 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)
Biological: Induction therapy
All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period.
Other Name: Simulect, basiliximab, rATG, Thymoglobulin

Drug: Corticosteroids
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.
Other Name: prednisone, methylprednisone, methylprednisolone, etc.

Drug: 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)
Other Name: Zortress, Certican, Neoral, Prograf

Active Comparator: MPA+sCNI
Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).
Biological: Induction therapy
All subjects received induction therapy with basiliximab or rabbit anti-thymocyte globulin, in the peritransplant period.
Other Name: Simulect, basiliximab, rATG, Thymoglobulin

Drug: Corticosteroids
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.
Other Name: prednisone, methylprednisone, methylprednisolone, etc.

Drug: MPA+sCNI
Mycophenolate (mycophenolic acid sodium or mycophenolate mofetil) in combination with standard exposure to calcineurin inhibitor (cyclosporine or tacrolimus).
Other Name: Myfortic, Cellcept, Neoral, Prograf




Primary Outcome Measures :
  1. 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 ]
    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 :
  1. 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 of (treated biopsy proven acute rejection (tBPAR), graft loss or death

  2. 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 tBPAR, graft loss, death or eGFR < 50 mL/min/1.73m2

  3. Incidence of Failure on the Composite Endpoint of Graft Loss or Death. [ Time Frame: Month 12 and 24 ]
    Incidence of failure on the composite endpoint of graft loss or death.

  4. Incidence of Death, Graft Loss, tBPAR, BPAR, tAR, AR and Humoral Rejection [ Time Frame: 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)

  5. Incidence of eGFR < 50 mL/Min/1.73m2 [ Time Frame: Month 12 and 24 ]
    Incidence of eGFR < 50 mL/min/1.73m2

  6. Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR [ Time Frame: Baseline (week 4), Month 12 and 24 ]
    Renal allograft function : mean estimated glomerular filtration rate, eGFR

  7. Evolution of Renal Function, as eGFR, Over Time by Slope Analysis. [ Time Frame: Month 12 and 24 ]
    Rate of change of renal function, as eGFR, calculated using MDRD4 formula (Coresh, 2003) and adjusted by covariates.

  8. Renal Function Assessed by Creatinine Lab Values [ Time Frame: Month 12 and 24 ]
    Mean Renal function as assessed in clinical practice, by ceatinine values. Analysis is done without considering missing values for analysis.

  9. Renal Function by Alternative Formulae (e.g. CKD-EPI). eGFR Values Reported [ Time Frame: 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.

  10. Incidence of Adverse Events, Serious Adverse Events and Adverse Events Leading to Study Regimen Discontinuation. [ Time Frame: Month 24 ]
    Incidence of adverse events, serious adverse events and adverse events leading to study regimen discontinuation.

  11. 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 ]
    Incidence of cytomegalovirus and BK virus, new onset diabetes mellitus, chronic kidney disease with associated proteinuria and calcineurin inhibitor associated adverse events.

  12. Urinary Protein and Albumin Excretion by Treatment Estimated by Urinary Protein/Creatinine and Urinary Albumin/Creatinine Ratios. [ Time Frame: Baseline, Month 12 and 24 ]
    Mean urinary protein and albumin excretion by treatment estimated by mean urinary protein/creatinine and urinary albumin/creatinine ratios.

  13. Incidence of Major Cardiovascular Events. [ Time Frame: Month 24 ]
    Incidence of major cardiovascular events by Preferred Term

  14. Incidence of Malignancies. [ Time Frame: Month 24 ]
    Incidence of malignancies.

  15. 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 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.

  16. Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Participants) [ Time Frame: 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)

  17. Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events) [ Time Frame: 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)

  18. Incidence of tBPAR (Treated Biopsy-proven Acute Rejection) Excluding Grade IA Rejections [ Time Frame: 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)

  19. Incidence of Composite of tBPAR (Treated Biopsy-proven Acute Rejection)or eGRF<50 mL/Min/1.73m2 by Subgroup [ Time Frame: Month 12 and 24 ]
    Incidence of composite of tBPAR or eGRF<50 mL/min/1.73m2 by subgroup

  20. Incidence of tBPAR (Excluding Grade IA Rejections) or GFR<50 mL/Min/1.73m2 [ Time Frame: Month 12 and 24 ]
    Incidence of tBPAR (excluding grade IA rejections) or GFR<50 mL/min/1.73m2

  21. 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 ]
    Incidence of failure on the composite of (treated biopsy proven acute rejection (tBPAR), graft loss or death or loss to follow-up



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01950819


  Show 184 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] July 14, 2016
Statistical Analysis Plan  [PDF] February 27, 2018


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01950819     History of Changes
Obsolete Identifiers: NCT02316938
Other Study ID Numbers: CRAD001A2433
2013-000322-66 ( EudraCT Number )
First Posted: September 26, 2013    Key Record Dates
Results First Posted: January 30, 2019
Last Update Posted: January 30, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydata request.com
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
kidney failure
dialysis
renal failure
transplantation
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency
Sirolimus
Mycophenolic Acid
Cyclosporine
Prednisone
Methylprednisolone
Everolimus
Tacrolimus
Cyclosporins
Basiliximab
Calcineurin Inhibitors
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents