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

Hemodialysis Clinical Trial

— TRANSFORM  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01950819
• Other study ID #: CRAD001A2433
• Secondary ID: 2013-000322-66
• Status: Completed
• Phase: Phase 4
• Start date: December 3, 2013
• Est. completion date: January 17, 2018

Study information

• Verified date: January 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Other known NCT identifiers

• NCT02316938

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2037
• Est. completion date: January 17, 2018
• Est. primary completion date: February 1, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Kidney Disease (CKD)
• End Stage Renal Disease (ESRD)
• Hemodialysis
• Kidney Diseases
• Kidney Failure, Chronic
• Renal Insufficiency, Chronic
• Renal Replacement Therapy
• Renal Transplantation

Intervention

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

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

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	San Martin	Buenos Aires
Argentina	Novartis Investigative Site	Santa Fe
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Camperdown	New South Wales
Australia	Novartis Investigative Site	Clayton	Victoria
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Murdoch	Western Australia
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Randwick	New South Wales
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Austria	Novartis Investigative Site	Linz
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Bulgaria	Novartis Investigative Site	Sofia	BGR
Chile	Novartis Investigative Site	Santiago
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Cali	Valle Del Cauca
Croatia	Novartis Investigative Site	Rijeka
Croatia	Novartis Investigative Site	Zagreb
Croatia	Novartis Investigative Site	Zagreb
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Praha 4
Egypt	Novartis Investigative Site	Mansoura
France	Novartis Investigative Site	Montpellier Cedex 5
France	Novartis Investigative Site	Nice	Cedex1
France	Novartis Investigative Site	Paris cedex 15
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Tours Cedex 9	Indre Et Loire
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Hannover Muenden
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Kaiserslautern
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	München
Germany	Novartis Investigative Site	Regensburg	Bavaria
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Patras
Greece	Novartis Investigative Site	Thessaloniki	GR
India	Novartis Investigative Site	Bangalore	Karnataka
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	New Delhi	Delhi
India	Novartis Investigative Site	Vellore	Tamil Nadu
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Bari	BA
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Novara
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Parma	PR
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Siena	SI
Italy	Novartis Investigative Site	Torino	TO
Japan	Novartis Investigative Site	Chiba-city	Chiba
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Toyoake city	Aichi
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Kuwait	Novartis Investigative Site	Kuwait
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Saida
Lebanon	Novartis Investigative Site	Saida
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Selangor Darul Ehsan
Mexico	Novartis Investigative Site	Guadalajara	Jalisco
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Leiden
Netherlands	Novartis Investigative Site	Maastricht	AZ
Netherlands	Novartis Investigative Site	Nijmegen
Netherlands	Novartis Investigative Site	Utrecht	The Netherlands
Norway	Novartis Investigative Site	Oslo
Philippines	Novartis Investigative Site	Quezon City
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Szczecin	Pomorskie
Portugal	Novartis Investigative Site	Carnaxide	Lisboa
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Lisbon
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Ekaterinburg
Russian Federation	Novartis Investigative Site	Krasnodar
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Nizhnii Novgorod
Russian Federation	Novartis Investigative Site	Volzhskiy
Saudi Arabia	Novartis Investigative Site	Dammam
Saudi Arabia	Novartis Investigative Site	Jeddah
Saudi Arabia	Novartis Investigative Site	Riyadh
Serbia	Novartis Investigative Site	Belgrade
Serbia	Novartis Investigative Site	Nis
Serbia	Novartis Investigative Site	Novi Sad
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Banská Bystrica
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Slovakia	Novartis Investigative Site	Martin
Slovenia	Novartis Investigative Site	Ljubljana
South Africa	Novartis Investigative Site	Cape Town	Western Province
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Hospitalet de Llobregat	Barcelona
Spain	Novartis Investigative Site	La Laguna	Santa Cruz De Tenerife
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santander	Cantabria
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Zaragoza
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	Bern
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Tainan	Taiwan ROC
Taiwan	Novartis Investigative Site	Taipei
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Ratchathewi	Bangkok
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Mecidiyekoy/Istanbul
United States	Novartis Investigative Site	Ann Arbor	Michigan
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Buffalo	New York
United States	Novartis Investigative Site	Burlington	Massachusetts
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlottesville	Virginia
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Harrisburg	Pennsylvania
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Livingston	New Jersey
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	Madison	Wisconsin
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Providence	Rhode Island
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Salt Lake City	Utah
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	Seattle	Washington
United States	Novartis Investigative Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Bulgaria,  Chile,  Colombia,  Croatia,  Czechia,  Egypt,  France,  Germany,  Greece,  India,  Israel,  Italy,  Japan,  Korea, Republic of,  Kuwait,  Lebanon,  Malaysia,  Mexico,  Netherlands,  Norway,  Philippines,  Poland,  Portugal,  Russian Federation,  Saudi Arabia,  Serbia,  Singapore,  Slovakia,  Slovenia,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of eGFR < 50 mL/Min/1.73m2	Incidence of eGFR < 50 mL/min/1.73m2	Month 12 and 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Incidence of Major Cardiovascular Events.	Incidence of major cardiovascular events by Preferred Term	Month 24
Secondary	Incidence of Malignancies.	Incidence of malignancies.	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 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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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