Clinical trial NCT01950819: Advancing Renal TRANSplant eFficacy and Safety Outcomes With an eveRolimus-based regiMen (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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: End Stage Renal Disease (ESRD)
Chronic Kidney Disease (CKD)
Hemodialysis
Renal Replacement Therapy
Renal Transplantation
Keywords: kidney failure
dialysis
renal failure
transplantation
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-09-26
Enrollment: 2037
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label study
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
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.
timeFrame: Month 12 is Primary, Month 24 secondary
Secondary outcomes:
measure: Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death
timeFrame: Month 12 and 24
measure: Incidence of Failure on the Composite Endpoint of tBPAR, Graft Loss, Death or eGFR < 50 mL/Min/1.73m2
timeFrame: Month 12 and 24
measure: Incidence of Failure on the Composite Endpoint of Graft Loss or Death.
timeFrame: Month 12 and 24
measure: Incidence of Death, Graft Loss, tBPAR, BPAR, tAR, AR and Humoral Rejection
timeFrame: Month 12 and 24
measure: Incidence of eGFR < 50 mL/Min/1.73m2
timeFrame: Month 12 and 24
measure: Renal Allograft Function : Mean Estimated Glomerular Filtration Rate, eGFR
timeFrame: Baseline (week 4), Month 12 and 24
measure: Evolution of Renal Function, as eGFR, Over Time by Slope Analysis.
timeFrame: Month 12 and 24
measure: Renal Function Assessed by Creatinine Lab Values
timeFrame: Month 12 and 24
measure: Renal Function by Alternative Formulae (e.g. CKD-EPI). eGFR Values Reported
timeFrame: Month 12 and 24
measure: Incidence of Adverse Events, Serious Adverse Events and Adverse Events Leading to Study Regimen Discontinuation.
timeFrame: Month 24
measure: Incidence of Cytomegalovirus and BK Virus, New Onset Diabetes Mellitus, Chronic Kidney Disease With Associated Proteinuria and Calcineurin Inhibitor Associated Adverse Events.
timeFrame: Month 24
measure: Urinary Protein and Albumin Excretion by Treatment Estimated by Urinary Protein/Creatinine and Urinary Albumin/Creatinine Ratios.
timeFrame: Baseline, Month 12 and 24
measure: Incidence of Major Cardiovascular Events.
timeFrame: Month 24
measure: Incidence of Malignancies.
timeFrame: Month 24
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.
timeFrame: Month 12 and 24
measure: Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Participants)
timeFrame: Month 12 and 24
measure: Incidence tBPAR (Treated Biopsy-proven Acute Rejection) by Severity and Time to Event (Events)
timeFrame: Month 12 and 24
measure: Incidence of tBPAR (Treated Biopsy-proven Acute Rejection) Excluding Grade IA Rejections
timeFrame: Month 12 and 24
measure: Incidence of Composite of tBPAR (Treated Biopsy-proven Acute Rejection)or eGRF<50 mL/Min/1.73m2 by Subgroup
timeFrame: Month 12 and 24
measure: Incidence of tBPAR (Excluding Grade IA Rejections) or GFR<50 mL/Min/1.73m2
timeFrame: Month 12 and 24
measure: Incidence of Failure on the Composite of (Treated Biopsy Proven Acute Rejection (tBPAR), Graft Loss or Death or Loss to Follow-up
timeFrame: Month 12 and 24
Other outcomes:
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city: Parkville
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city: Nedlands
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state: Tyrol
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city: Sofia
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state: BGR
city: Santiago
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city: Zagreb
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city: Krasnodar
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city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhnii Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Volzhskiy
country: Russian Federation
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city: Singapore
country: Singapore
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city: Banská Bystrica
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Martin
country: Slovakia
facility: Novartis Investigative Site
city: Ljubljana
country: Slovenia
facility: Novartis Investigative Site
city: Cape Town
country: South Africa
facility: Novartis Investigative Site
state: Western Province
city: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Santander
country: Spain
facility: Novartis Investigative Site
state: Cantabria
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: La Laguna
country: Spain
facility: Novartis Investigative Site
state: Santa Cruz De Tenerife
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
city: Göteborg
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Ratchathewi
country: Thailand
facility: Novartis Investigative Site
state: Bangkok
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Mecidiyekoy/Istanbul
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Aubert O, Divard G, Pascual J, Oppenheimer F, Sommerer C, Citterio F, Tedesco H, Chadban S, Henry M, Vincenti F, Srinivas T, Watarai Y, Legendre C, Bernhardt P, Loupy A. Application of the iBox prognostication system as a surrogate endpoint in the TRANSFORM randomised controlled trial: proof-of-concept study. BMJ Open. 2021 Oct 7;11(10):e052138. doi: 10.1136/bmjopen-2021-052138.
citation: Watarai Y, Danguilan R, Casasola C, Chang SS, Ruangkanchanasetr P, Kee T, Wong HS, Kenmochi T, Amante AJ, Shu KH, Ingsathit A, Bernhardt P, Hernandez-Gutierrez MP, Han DJ, Kim MS. Everolimus-facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2-year results from the subgroup analysis of the TRANSFORM study. Clin Transplant. 2021 Oct;35(10):e14415. doi: 10.1111/ctr.14415. Epub 2021 Sep 23.
citation: Citterio F, Henry M, Kim DY, Kim MS, Han DJ, Kenmochi T, Mor E, Tisone G, Bernhardt P, Hernandez Gutierrez MP, Watarai Y. Wound healing adverse events in kidney transplant recipients receiving everolimus with reduced calcineurin inhibitor exposure or current standard-of-care: insights from the 24-month TRANSFORM study. Expert Opin Drug Saf. 2020 Oct;19(10):1339-1348. doi: 10.1080/14740338.2020.1792441. Epub 2020 Jul 20.
citation: Berger SP, Sommerer C, Witzke O, Tedesco H, Chadban S, Mulgaonkar S, Qazi Y, de Fijter JW, Oppenheimer F, Cruzado JM, Watarai Y, Massari P, Legendre C, Citterio F, Henry M, Srinivas TR, Vincenti F, Gutierrez MPH, Marti AM, Bernhardt P, Pascual J; TRANSFORM investigators. Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study. Am J Transplant. 2019 Nov;19(11):3018-3034. doi: 10.1111/ajt.15480. Epub 2019 Jul 1.
citation: Pascual J, Berger SP, Witzke O, Tedesco H, Mulgaonkar S, Qazi Y, Chadban S, Oppenheimer F, Sommerer C, Oberbauer R, Watarai Y, Legendre C, Citterio F, Henry M, Srinivas TR, Luo WL, Marti A, Bernhardt P, Vincenti F; TRANSFORM Investigators. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J Am Soc Nephrol. 2018 Jul;29(7):1979-1991. doi: 10.1681/ASN.2018010009. Epub 2018 May 11.