Clinical trial NCT01114529: Efficacy, Safety and Evolution of Cardiovascular Parameters in Renal Transplant Recipients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Kidney Transplantation
Keywords: de novo renal allograft recipients
renal allograft function
CNI-free regimen
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-05-03
Enrollment: 828
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Month 12
Secondary outcomes:
measure: Incidence of Composite Efficacy Endpoint for Each Arm at Month 12 and Month 24
timeFrame: at 12 months and month 24 post-transplantation
measure: Change in Left Ventricular Mass Index (LVMi) From Randomization to Month 12 and Month 24
timeFrame: Randomization, Month 12 and Month 24
measure: Comparison of Incidence Rates of Efficacy Endpoints Between Treatment Arms (Full Analysis Set - 24 Month Analysis)
timeFrame: at 24 months post-transplantation
Other outcomes:
Locations:
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: San Martin
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Resistencia
country: Argentina
facility: Novartis Investigative Site
state: Chaco
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Camperdown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Linz
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Tartu
country: Estonia
facility: Novartis Investigative Site
city: Brest
country: France
facility: Novartis Investigative Site
city: Nice Cedex 1
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 4
country: France
facility: Novartis Investigative Site
city: Tours Cedex
country: France
facility: Novartis Investigative Site
city: Vandoeuvre Les Nancy
country: France
facility: Novartis Investigative Site
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover Muenden
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Vishakhapatnam
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Bangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Lucknow
country: India
facility: Novartis Investigative Site
state: Uttar Pradesh
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Siena
country: Italy
facility: Novartis Investigative Site
state: SI
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Riga
country: Latvia
facility: Novartis Investigative Site
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Torreón
country: Mexico
facility: Novartis Investigative Site
state: Coahuila
city: Mexico
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Aguascalientes
country: Mexico
facility: Novartis Investigative Site
city: Veracruz
country: Mexico
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Carnaxide - Linda-A-Velha
country: Portugal
facility: Novartis Investigative Site
state: Lisboa
city: Lisbon
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Cluj-Napoca
country: Romania
facility: Novartis Investigative Site
state: Jud Cluj
city: Krasnodar
country: Russian Federation
facility: Novartis Investigative Site
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: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: S.-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Samara
country: Russian Federation
facility: Novartis Investigative Site
city: Volzhskiy
country: Russian Federation
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
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: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Cataluña
city: A Coruña
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Antalya
country: Turkey
facility: Novartis Investigative Site
city: Büyükçekmece / Ýstanbul
country: Turkey
facility: Novartis Investigative Site
city: Fatih / Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: