Efficacy, Safety and Evolution of Cardiovascular Parameters in Renal Transplant Recipients (ELEVATE)

A 24-month, Multi-center, Open-label, Randomized, Controlled Trial to Investigate Efficacy, Safety and Evolution of Cardiovascular Parameters in de Novo Renal Transplant Recipients After Early Calcineurin Inhibitor to Everolimus Conversion

The purpose of this study was to determine whether an early Calcineurin Inhibitor (CNI) to everolimus conversion at 10-14 weeks post transplantation improves renal allograft function without compromising efficacy compared to standard CNI treatment in de novo renal allograft recipients. In addition, the study was designed to evaluate the impact of a CNI-free regimen on evolution of cardiovascular parameters in de novo renal allograft recipients

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Prograf or Neoral

Detailed Description

This was a 24-month, multi-center, randomized, open-label trial with two parallel arms in adult de novo renal allograft recipients. The study consisted of a run-in period from transplantation to Randomization and a treatment period from Randomization until Month 24. At baseline visit, patients were transplanted and entered the run-in period from transplantation (Baseline) to Randomization (week 10-14 post-transplantation). At Week 10-14, eligible patients were randomized into one of the 2 treatment arms: standard CNIs and Myfortic versus everolimus and Myfortic and entered the treatment period of the study from Randomization to Month 24. Patients in both arms received steroids as per center practice and in any caseat least 5 mg/Day. At Randomization, patients were stratified according to their renal allograft function and previous cardiovascular events. The main analysis was performed at Month 12 and the follow-up analysis was performed at Month 24.

• Study Type: Interventional
• Enrollment (Actual): 828
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Cordoba, Argentina, X5022CPU
    • Novartis Investigative Site
  • Cordoba, Argentina, X5016JDA
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000EPV
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1118AAT
      • Novartis Investigative Site
    • San Martin, Buenos Aires, Argentina, C1107BEA
      • Novartis Investigative Site
  • Chaco
    • Resistencia, Chaco, Argentina, H3508AZP
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3050
      • Novartis Investigative Site
• Austria
  • Linz, Austria, A-4010
    • Novartis Investigative Site
  • Linz, Austria, A-4020
    • Novartis Investigative Site
  • Wien, Austria, 1090
    • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Estonia
  • Tartu, Estonia, 51014
    • Novartis Investigative Site
• France
  • Brest, France, 29200
    • Novartis Investigative Site
  • Nice Cedex 1, France, 06602
    • Novartis Investigative Site
  • Toulouse Cedex 4, France, 31054
    • Novartis Investigative Site
  • Tours Cedex, France, 37044
    • Novartis Investigative Site
  • Vandoeuvre Les Nancy, France, 54511
    • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Berlin, Germany, 12203
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Frankfurt am Main, Germany, 60596
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover Muenden, Germany, 34346
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Muenster, Germany, 48149
    • Novartis Investigative Site
• Greece
  • Athens, Greece, GR 11527
    • Novartis Investigative Site
  • Athens, Greece, GR-106 76
    • Novartis Investigative Site
  • Patras, Greece, 265 00
    • Novartis Investigative Site
• India
  • New Delhi, India, 110044
    • Novartis Investigative Site
  • Andhra Pradesh
    • Vishakhapatnam, Andhra Pradesh, India
      • Novartis Investigative Site
  • Delhi
    • New Delhi, Delhi, India, 110017
      • Novartis Investigative Site
  • Karnataka
    • Bangalore, Karnataka, India, 560 055
      • Novartis Investigative Site
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226014
      • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00144
      • Novartis Investigative Site
  • SI
    • Siena, SI, Italy, 53100
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Latvia
  • Riga, Latvia, 1002
    • Novartis Investigative Site
• Lithuania
  • Vilnius, Lithuania, LT-08661
    • Novartis Investigative Site
• Mexico
  • Aguascalientes, Mexico, 20230
    • Novartis Investigative Site
  • Veracruz, Mexico, 91700
    • Novartis Investigative Site
  • Coahuila
    • Torreón, Coahuila, Mexico, 27250
      • Novartis Investigative Site
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 14080
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Leiden, Netherlands, 2300 RC
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Portugal
  • Lisbon, Portugal, 1069-166
    • Novartis Investigative Site
  • Porto, Portugal, 4200-319
    • Novartis Investigative Site
  • Lisboa
    • Carnaxide - Linda-A-Velha, Lisboa, Portugal, 2790-134
      • Novartis Investigative Site
• Romania
  • Jud Cluj
    • Cluj-Napoca, Jud Cluj, Romania, 400006
      • Novartis Investigative Site
• Russian Federation
  • Krasnodar, Russian Federation, 350086
    • Novartis Investigative Site
  • Moscow, Russian Federation, 123182
    • Novartis Investigative Site
  • Moscow, Russian Federation, 115446
    • Novartis Investigative Site
  • Nizhnii Novgorod, Russian Federation, 603000
    • Novartis Investigative Site
  • Novosibirsk, Russian Federation, 630087
    • Novartis Investigative Site
  • S.-Petersburg, Russian Federation, 192242
    • Novartis Investigative Site
  • Samara, Russian Federation, 443079
    • Novartis Investigative Site
  • Volzhskiy, Russian Federation, 404120
    • Novartis Investigative Site
• Spain
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Andalucia
    • Malaga, Andalucia, Spain, 29010
      • Novartis Investigative Site
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
  • Cataluña
    • Hospitalet de Llobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
  • Galicia
    • A Coruña, Galicia, Spain, 15006
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • THA
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site
• Turkey
  • Antalya, Turkey, 07000
    • Novartis Investigative Site
  • Büyükçekmece / Ýstanbul, Turkey, 34520
    • Novartis Investigative Site
  • Fatih / Istanbul, Turkey, 34098
    • Novartis Investigative Site
  • Istanbul, Turkey, 34093
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria at Baseline:

• Male or female renal allograft recipients at least 18 years old.
• Written informed consent.
• Patient receiving a primary or secondary kidney transplant from a cadaveric or living unrelated-/related donor.
• Cold ischemia time (CIT) < 24 hours.
• Negative pregnancy test for female patients.

Inclusion Criteria at Randomization:

• Patients on CNI (TAC or CsA) + Myfortic + steroids.
• Serum creatinine < 2.8 mg/dL (250 µmol/L) and an actual eGFR (MDRD4) ≥ 25 mL/min/1.73m exp2 (without renal replacement therapy).

Exclusion Criteria at Baseline:

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

• Recipient of multiple organ transplants.
• Recipient of ABO incompatible allograft or a positive cross-match.
• Panel Reactive Antibodies (PRA) level ≥ 30 %.
• Positive test for human immunodeficiency virus (HIV).
• Patient receiving an allograft from a Hepatitis B surface Antigen (HBsAg) or a Hepatitis C Virus (HCV) positive donor.
• HBsAg and/or a HCV positive patient with evidence of elevated LFTs (ALT/AST levels ≥ 2.5 times ULN).
• Severe restrictive or obstructive pulmonary disorders.
• Patient with severe allergy requiring acute or chronic treatment or hypersensitivity to any of the study drugs or similar drugs.
• Severe hypercholesterolemia or hypertriglyceridemia.
• Low platelet count.
• Low white blood cell count.
• History of malignancy of any organ system

Exclusion Criteria at Randomization:

• Graft loss.
• Patient on renal replacement therapy.
• Patient who experienced severe humoral and/or cellular rejection (BANFF ≥ IIb).
• Patient with ≥ 2 episodes of AR or an AR episode that needed antibody treatment.
• Patient with ongoing or currently treated AR (2 weeks prior to randomization).
• Proteinuria > 1 g/day.
• Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS).
• Low platelet count; Low white blood cell count; Low absolute neutrophil count; Low hemoglobin.
• Severe liver disease.
• Systemic infection requiring continued therapy that would interfere with the objectives of the study.
• Severe hypercholesterolemia or hypertriglyceridemia.
• Patients with ongoing wound healing problems, clinically significant infection requiring continued therapy.
• Presence of intractable immunosuppressant complications or side effects.
• Patients on anticoagulants that prevents renal allograft biopsy.
• Use of prohibited medication.
• Use of immunosuppressive agents not utilized in the protocol.
• Pregnant or nursing (lactating) women.
• Women of child-bearing potential not using a highly effective method of birth control.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Everolimus; Conversion from CNI to everolimus in combination with Myfortic and steroids	Drug: Everolimus; Early CNI to everolimus conversion; Other Names: Certican, Zortress, RAD001
Active Comparator: Calcineurin inhibitor, Prograf or Neoral; Control arm: CNI continuation, either Prograf or Neoral in combination with Myfortic and steroids	Drug: Prograf or Neoral; Active CNI-based control (Prograf or Neoral); Other Names: Tacrolimus or Cyclosporine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimated Glomerular Filtration Rate (eGFR)	Assessment of renal function by comparing change from randomization to Month 12 in eGFR (MDRD4) between treatment arms (Full analysis set). Renal function was assessed by estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula. MDRD formula: GFR [mL/min/1.73m˄2] = 186.3*(C˄-1.154)*(A˄-0.203)*G*R. DEFINITIONS: C = serum concentration of creatinine [mg/dL]; A = age [years]; G = 0.742 when gender is female, otherwise G = 1; R = 1.21 when race is black, otherwise R = 1	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Composite Efficacy Endpoint for Each Arm at Month 12 and Month 24	Efficacy failure rate used the composite endpoint of: (1) treated biopsy-proven acute rejection (BPAR)*, (2) graft loss**, or (3) death . *A treated BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III and which was treated with anti-rejection therapy. **Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis or re-transplanted.	at 12 months and month 24 post-transplantation
Change in Left Ventricular Mass Index (LVMi) From Randomization to Month 12 and Month 24	Evolution of left ventricular mass and hypertrophy were evaluated by left ventricular mass index (LVMi) assessed by echocardiography. LVMi is derived using a standard formula from dimensional measurements on the echocardiogram. Analysis of covariance was applied with treatment, center (as a random effect), and donor type as factors and LVMi at Randomization as covariate.	Randomization, Month 12 and Month 24
Comparison of Incidence Rates of Efficacy Endpoints Between Treatment Arms (Full Analysis Set - 24 Month Analysis)	(treated BPAR ≥ IB, graft loss or death)A comparison of the incidence rates for the individual components of the composite efficacy endpoint between treatment arms	at 24 months post-transplantation

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• <p>The American Journal of Transplantation, Poster Abstracts, 2016</p><p>Provider: John Wiley & Sons, Ltd</p>

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2010
• Primary Completion (Actual): October 30, 2014
• Study Completion (Actual): October 30, 2014

Study Registration Dates

• First Submitted: April 27, 2010
• First Submitted That Met QC Criteria: April 29, 2010
• First Posted (Estimate): May 3, 2010

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 24, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: renal allograft function; de novo renal allograft recipients; CNI-free regimen
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001A2429; 2009-015918-22 (EudraCT Number)