Clinical trial NCT01079143: Progression of Renal Interstitial Fibrosis / Tubular Atrophy (IF/TA) According to Epithelial-mesenchymal Transition (EMT) and Immunosuppressive Regimen (Everolimus Based Versus CNI Based) in de Novo Renal Transplant Recipients
Official title: Prospective, Multicenter, Randomized Open Study to Evaluate the Progression of Renal Graft Fibrosis According to the Epithelial-mesenchymal Transition (EMT) in de Novo Renal Transplant Recipients Treated Either by a CNI Free Immunosuppressive Regimen With Everolimus and Enteric-coated Mycophenolate Sodium or a CNI Based Regimen With Cyclosporine and Enteric-coated Mycophenolate Sodium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Renal Interstitial Fibrosis
Keywords: De Novo renal transplantation
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-03-02
Enrollment: 194
Sex: ALL
Minimum age (years): 19
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Recently, early biomarkers of renal interstitial fibrosis have been identified, amongst them de novo expression of vimentin by tubular epithelial cells, which is an intermediate filament, and the translocation of beta-catenin into their cytoplasm. These markers, when present, suggest that the epithelial cell undergoes a phenomenon well known as "epithelial to mesenchymal transition" (EMT) and could behaves like a myo-fibroblast. EMT is highly instrumental in several models of tissue fibrosis, including in the kidney. Actually, it has not only been demonstrated that these markers are detectable in the renal graft at an early time point post-transplant (i.e. as soon as three months), but also that the intensity of their expression correlates with the progression of interstitial fibrosis of the graft between 3 and 12 months


Eligibility criteria: Inclusion Criteria:

* Recipient of a primary or secondary deceased or living (related or not) donor kidney transplant and who requires basiliximab induction therapy.
* Cold ischemia time \< 30 hours.
* Women of child-bearing age, even those with a history of infertility, must have had a negative pregnancy test during the 7 days before screening or at the time of screening, and must use a recognized and reliable method of contraception throughout the study and for 2 months after discontinuing the study treatment.
* Patients who want and are able to take part in the entire study, and have given their written consent.
* Patients who are registered with a French national health insurance scheme or are covered by such a scheme.

Exclusion Criteria:

* Recipient of multi-organ transplantation, including dual kidneys, or who have previously received non renal transplant organ.
* Patients receiving a graft from a non-heart-beating donor.
* Anti-HLA antibody levels ≥ 20% in the last 3 months before the inclusion.
* ABO incompatible graft or with positive cross match T.
* Severe hyperlipidemia: total cholesterol ≥ 9.1 mmol/L (≥ 350 mg/dL) and/or triglycerides ≥ 8.5 mmol/L (≥ 750 mg/dL) despite appropriate lipid-lowering therapy.
* Known hypersensitivity or contraindications to mycophenolic acid, cyclosporine or lactose.
* Known hypersensitivity or contraindications to macrolides or drugs of the mTOR inhibitor class.
* HIV seropositive, or active chronic hepatitis B (HBs Ab) or C. Results obtained during the 6 months before the inclusion are accepted. Recipients from donors with hepatitis B or C will be excluded.
* Patients with thrombocytopenia (≤ 75000/mm3), absolute neutrophil count (≤ 1500/mm3), leukocytopenia (≤ 2500/mm3) and/or hemoglobin \< 8g/dL at the inclusion visit.
* ASAT, ALAT or total bilirubin ≥ 3 UNL.
* Uncontrolled severe infection, severe allergy requiring an acute or chronic treatment.
* Patients with a malignant disease or previous malignancy in the past 5 years, with the exception of excised basal cell or squamous cell carcinoma and in situ cervical cancer treated.
* Medical or surgical condition, with the exception of the transplantation, which in the investigator's opinion could exclude the patient.
* Women who are pregnant, breastfeeding or of reproductive age and refuse or are unable to use a recognized and reliable method of contraception.
* Patients with symptoms of significant mental or somatic disease. Inability to cooperate or communicate with the investigator.
* Patients under supervision or guardianship or any patient subject to legal protection

Randomization criteria:

Eligibility criteria (no later than 4 months post-transplantation:

* Renal graft biopsy performed at M3 and adequate histological material sent within the deadline for the determination of EMT.
* Woman of child-bearing potential, even in case of a history of infertility, must use a recognized and reliable method of contraception throughout the study and for 2 months after discontinuing the study treatment.

Non-eligibility criteria (no later than 4 months post-transplantation):

* Acute rejection histologically proven between transplantation and randomization (local reading).
* Acute subclinical rejection diagnosed on the M3 biopsy (except borderline lesions) (local reading).
* Positive anti-donor antibodies at M3.
* Estimated glomerular filtration rate (eGFR) \< 30 ml/min/1.73 m2 (MDRDa).
* Proteinuria ≥ 1 g/24h.
* Severe hyperlipidemia: total cholesterol ≥ 9.1 mmol/L (≥ 350 mg/dL) and/or triglycerides ≥ 8.5 mmol/L (≥ 750 mg/dL) despite appropriate lipid-lowering therapy.
* Thrombocytopenia (≤ 75000/mm3), absolute neutrophil count (≤ 1500/mm3), leukocytopenia (≤ 2500/mm3) and/or hemoglobin \< 8 g/dL.
* ASAT, ALAT or total bilirubin ≥ 3 UNL.
* Medical or surgical condition which in the investigator's opinion might exclude the patient.

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population
timeFrame: Month 3 (M3) and Month 12 (M12) post transplantation
Secondary outcomes:
measure: Interstitial Fibrosis/Tabular Atrophy (IF/TA)
timeFrame: M3 and M12 post transplantation
measure: Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade
timeFrame: M3 and M12 post transplantation
measure: Risk Factors of IF/TA Progression
timeFrame: M12 post transplantation
measure: Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification
timeFrame: M3 and M12 post transplantation
measure: Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification
timeFrame: M3 to M12 post transplantation
measure: Number of Participants With Epithelial-mesenchymal Transition (EMT) Status
timeFrame: M3 and M12 post transplantation
measure: Number of Participants With Epithelial-mesenchymal Transition (EMT) Score
timeFrame: M3 and M12 post transplantation
measure: Change in EMT Score
timeFrame: M3 and M12 post transplantation
measure: Incidence (Number) of Subclinical Rejections and Borderline Lesions
timeFrame: M3
measure: Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: M3 (baseline) to M12 post transplantation
measure: Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model
timeFrame: Baseline (M3), M12
measure: Change in Urine Protein/Creatinine Ratio (Without Imputation)
timeFrame: Month 3 (baseline), Month 12
measure: Treatment Failures
timeFrame: M6 and M12 post transplantation
measure: Type of Biopsy Proven Acute Rejection (BPAR)
timeFrame: M6 and M12 post transplantation
measure: Severity of BPAR
timeFrame: M6 and M12 post transplantation
measure: Incidence (Number) of BPAR
timeFrame: M6 and M12 post transplantation
measure: Incidence (Number) of Participants With Graft Losses
timeFrame: M6 and M12 post transplantation
Other outcomes:
Locations:
city: Caen
country: France
facility: Novartis Investigative Site
state: Cedex
city: Amiens cedex1
country: France
facility: Novartis Investigative Site
city: Angers
country: France
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Brest
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Le Kremlin Bicetre
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Nice Cedex 1
country: France
facility: Novartis Investigative Site
city: Paris cedex 15
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pierre Benite Cedex
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Reims
country: France
facility: Novartis Investigative Site
city: St Priest en Jarez Cedex
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Suresnes
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 Nancys
country: France
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Loupy A, Aubert O, Orandi BJ, Naesens M, Bouatou Y, Raynaud M, Divard G, Jackson AM, Viglietti D, Giral M, Kamar N, Thaunat O, Morelon E, Delahousse M, Kuypers D, Hertig A, Rondeau E, Bailly E, Eskandary F, Bohmig G, Gupta G, Glotz D, Legendre C, Montgomery RA, Stegall MD, Empana JP, Jouven X, Segev DL, Lefaucheur C. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019 Sep 17;366:l4923. doi: 10.1136/bmj.l4923.