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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 194
- 试验地点
- 1
- 主要终点
- Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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 M
- •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.
研究组 & 干预措施
Certican EMT+
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Certican® (Drug)
Certican EMT+
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Myfortic (Drug)
Certican EMT+
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Simulect® (Drug)
Certican EMT+
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Corticosteroids (Drug)
Certican EMT-
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Certican® (Drug)
Certican EMT-
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Myfortic (Drug)
Certican EMT-
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Simulect® (Drug)
Certican EMT-
Patients randomized to the Certican® treatment group started this treatment after randomization (which took place 3 to 4 months post-transplantation), preferably in the evening, otherwise the following morning. Patients in the Neoral® treatment group did not receive Certican®.
干预措施: Corticosteroids (Drug)
Neoral EMT+
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Neoral (Drug)
Neoral EMT+
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Myfortic (Drug)
Neoral EMT+
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Simulect® (Drug)
Neoral EMT+
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Corticosteroids (Drug)
Neoral EMT-
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Neoral (Drug)
Neoral EMT-
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Myfortic (Drug)
Neoral EMT-
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Simulect® (Drug)
Neoral EMT-
Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
干预措施: Corticosteroids (Drug)
结局指标
主要结局
Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population
时间窗: Month 3 (M3) and Month 12 (M12) post transplantation
Progression of Interstitial Fibrosis/Tabular Atrophy (IF/TA) is the percentage (%) of participants with an increase \>= 1 in IF/TA grade according to Banff (2005 - 2007)according to Epithelial-mesenchymal transition (EMT) profile and by treatment groups. Grade I (the better): mild interstitial fibrosis and tubular atrophy (\<25% of cortical area) Grade II : moderate interstitial fibrosis and tubular atrophy (26-50% of cortical area) Grade III (the worse) : severe interstitial fibrosis and tubular atrophy (\>50% of cortical area)
次要结局
- Interstitial Fibrosis/Tabular Atrophy (IF/TA)(M3 and M12 post transplantation)
- Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade(M3 and M12 post transplantation)
- Risk Factors of IF/TA Progression(M12 post transplantation)
- Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification(M3 and M12 post transplantation)
- Incidence (Number) of Subclinical Rejections and Borderline Lesions(M3)
- Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR)(M3 (baseline) to M12 post transplantation)
- Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model(Baseline (M3), M12)
- Change in Urine Protein/Creatinine Ratio (Without Imputation)(Month 3 (baseline), Month 12)
- Treatment Failures(M6 and M12 post transplantation)
- Type of Biopsy Proven Acute Rejection (BPAR)(M6 and M12 post transplantation)
- Severity of BPAR(M6 and M12 post transplantation)
- Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification(M3 to M12 post transplantation)
- Number of Participants With Epithelial-mesenchymal Transition (EMT) Status(M3 and M12 post transplantation)
- Number of Participants With Epithelial-mesenchymal Transition (EMT) Score(M3 and M12 post transplantation)
- Change in EMT Score(M3 and M12 post transplantation)
- Incidence (Number) of BPAR(M6 and M12 post transplantation)
- Incidence (Number) of Participants With Graft Losses(M6 and M12 post transplantation)