Renal Interstitial Fibrosis
Conditions
Keywords
De Novo renal transplantation
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
Interventions
DRUGCertican®
Certican® was supplied to the participating centers by Novartis for the whole duration of the study in the form of tablets containing 0.75, 0.5 and 0.25 mg and packaged in blister packs.
DRUGNeoral
Neoral® was also supplied to participating centers for the entire duration of the study in the form of soft capsules of 10 mg, 25 mg, 50 mg and 100 mg, and packaged in blister packs.
DRUGMyfortic
Myfortic ® was supplied to the participating centers for the duration of the study in the form of 180 and 360 mg gastro-resistant, film-coated tablets. Myfortic® treatment was provided to patients preoperatively or within 24 hours post-transplantation according to the practices of the center. The starting dose was generally 1,440 mg/day, in 2 daily oral fractions, administered at 12 hour intervals up to randomization. Depending on the practices of the center and for the first 6 weeks post-transplantation, a maximum daily dose of 2160 mg of Myfortic® could be administered. In the Neoral® group, the daily dose of 1440 mg was maintained throughout the study. In the Certican® group, the dose was halved (i.e. 720 mg/day) on introducing Certican® and maintained at 720 mg/day until the end of the study. An increase in the daily dose of Myfortic® (in the Certican® group) was not authorized unless this was a temporary increase that did not exceed a period of 14 consecutive days.
DRUGSimulect®
The administration of Simulect® was part of the standard immunosuppressant therapy. This induction therapy was provided to patients in the form of commercial ampoules each containing 20 mg. Simulect® was administered to each patient at the dose of 20 mg on D0 and D4 post-transplantation.
DRUGCorticosteroids
An intravenous steroid treatment could be administered peri or intraoperatively according to local practice at each center. Oral steroid treatment was quickly introduced (in the week following transplantation) at a daily dose of 20 mg and was then reduced and continued throughout the study at a minimum dose of 5 mg/day.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | M3 and M12 post transplantation | Difference (M12 - M3) in IF/TA grade. IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (\<25%), grade II (25-50%) and grade III (\>50% of lesions). |
| Risk Factors of IF/TA Progression | M12 post transplantation | Composite factors regarding fibrosis progression at 12 months using a logistic regression model; the parameters initially considered concerned the demographic characteristics of both recipient and donor, transplantation characteristics, hypertension, diabetes, study treatments, immunosuppression, EMT, IF/TA, function at M3, the onset of acute rejection, the presence of anti-donor antibodies at M12, infections and BK virus viremia. Arteriolar hyaline thickening is thickening of the walls of arterioles by the deposition of homogeneous pink hyaline material. BPAR is biopsy proven acute rejection. TEM progression is the increase ≥ 1 of TEM score between Month 3 and Month 12 |
| Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | M3 and M12 post transplantation | Percentage of IF measured by numerical quantification. The IF percentage was transposed in grade according to the following rule: grade 0 for an IF % ≤5%, grade I for an IF % ranging from \>5% to \< 25%, grade II for an IF % ranging from 25 to 50%, grade III for an IF % \>50%. Interstitial graft fibrosis has been identified as the primary cause of graft loss following death with a functional graft \[3-5\]. |
| Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | M3 to M12 post transplantation | Comparisons according to epithelial-mesenchymal transition (EMT) profile and immunosuppressive treatment |
| Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | M3 and M12 post transplantation | Incidence and severity of EMT status. EMT status was determined centrally using the graft biopsy taken at 3 months. The result was quickly obtained (within 7 to 15 days) and sent to the company in charge of randomization in order to allocate each patient to a treatment group and to provide the investigator with this information without confirming EMT status. |
| Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | M3 and M12 post transplantation | Incidence and severity of EMT score. The intensity of EMT markers expression present and detectable in the renal graft at an early stage following transplantation is known as EMT score. EMT score 0 (the best): \<1 EMT score 1 (the better): 1-10% of tubular atrophy EMT score 2: 10-25% of tubular atrophy EMT score 3: 25-50% of tubular atrophy EMT score 4 (the worst): \>50% of tubular atrophy |
| Change in EMT Score | M3 and M12 post transplantation | Change (M12 - M3) in EMT Score. Progression in EMT score is defined as an increase by \>=1 of EMT score from M3 to M12. EMT score 0 (the best): \<1 EMT score 1 (the better) : 1-10% of tubular atrophy EMT score 2 : 10-25% of tubular atrophy EMT score 3 : 25-50% of tubular atrophy EMT score 4 (the worst): \>50% of tubular atrophy |
| Incidence (Number) of Subclinical Rejections and Borderline Lesions | M3 | Incidence of subclinical rejections and borderline lesions with regards to histological evidence of rejection with clinical findings. Subclinical rejections: rejection without clinical symptoms which is diagnosed by chance when a graft biopsy is performed. Clinically suspected BPAR: rejection suspected because of the presence of clinical symptoms (fever, pain, increase of creatinine) and then confirmed by the graft biopsy. Borderline lesions: suspicious for acute T-cell mediated rejection. This category is used when no intimal arteritis is present, but there are foci of tubulitis with minor interstitial infiltration or interstitial infiltration with mild tubulitis. |
| Interstitial Fibrosis/Tabular Atrophy (IF/TA) | M3 and M12 post transplantation | Incidence and severity of IF/TA according to 2005/2007 Banff classification system grades (grades l to lll). IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (\<25%), grade II (25-50%) and grade III (\>50% of lesions). |
| Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | Baseline (M3), M12 | The average patient renal function was evaluated on the basis of eGFR was calculated according to the abbreviated MDRD formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²). |
| Change in Urine Protein/Creatinine Ratio (Without Imputation) | Month 3 (baseline), Month 12 | One of the factors associated with EMT progression between M3 and M12 according to univariate analysis (ITT biopsies M3 & M12). |
| Treatment Failures | M6 and M12 post transplantation | A treatment failure is defined as biopsy proven acute rejection (BPAR), a graft loss, a death or a loss to follow up. It was assessed between randomization and 6 and 12 months post-transplantation. |
| Type of Biopsy Proven Acute Rejection (BPAR) | M6 and M12 post transplantation | A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system. Biopsy graded IA: Significant interstitial infiltration (\> 25% of parenchyma) and foci of moderate tubulitis (\> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (\> 25% of parenchyma) and foci of severe tubulitis (\> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising \> 25% of the lumenal area. Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation). |
| Severity of BPAR | M6 and M12 post transplantation | A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system. Biopsy graded IA: Significant interstitial infiltration (\> 25% of parenchyma) and foci of moderate tubulitis (\> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (\> 25% of parenchyma) and foci of severe tubulitis (\> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising \> 25% of the lumenal area. Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation). |
| Incidence (Number) of BPAR | M6 and M12 post transplantation | A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system. |
| Incidence (Number) of Participants With Graft Losses | M6 and M12 post transplantation | If a participant underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss. |
| Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR) | M3 (baseline) to M12 post transplantation | eGFR was calculated according to the abbreviated Modification of Diet in Renal Disease (MDRD) Formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²). LOCF = Last observation carried forward |
Countries
France
Participant flow
Pre-assignment details
EMT+: ≥ 10% tubular cells showing de novo expression of vimentin (or translocation of β catenin if inconclusive) into the cytoplasm EMT-: \< 10% tubular cells showing de novo expression of vimentin (or translocation of β catenin if inconclusive) into the cytoplasm
Participants by arm
| Arm | Count |
|---|---|
| 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®. | 36 |
| 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®. | 60 |
| 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®. | 39 |
| 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®. | 59 |
| Total | 194 |
Baseline characteristics
| Characteristic | Certican EMT+ | Certican EMT- | Neoral EMT+ | Neoral EMT- | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51.2 years STANDARD_DEVIATION 10.7 | 46.4 years STANDARD_DEVIATION 12.9 | 50.0 years STANDARD_DEVIATION 10 | 50.7 years STANDARD_DEVIATION 11.7 | 49.3 years STANDARD_DEVIATION 11.7 |
| BMI | 24.3 kg/m^2 STANDARD_DEVIATION 4.6 | 26.0 kg/m^2 STANDARD_DEVIATION 4.6 | 25.6 kg/m^2 STANDARD_DEVIATION 4 | 25.3 kg/m^2 STANDARD_DEVIATION 4.2 | 25.4 kg/m^2 STANDARD_DEVIATION 4.4 |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 16 Participants | 16 Participants | 66 Participants |
| Sex: Female, Male Male | 19 Participants | 43 Participants | 23 Participants | 43 Participants | 128 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 98 | 59 / 96 |
| serious Total, serious adverse events | 39 / 98 | 46 / 96 |
Outcome results
Primary
Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population
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)
Time frame: Month 3 (M3) and Month 12 (M12) post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12. The primary comparison concerned only the Certican and the Neoral EMT+ groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population | Participants with an IF/TA grade <= II at M3 | 26 Participants |
| Certican EMT+ | Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population | Participants with Fibrosis progression, M3 to M12 | 12 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population | Participants with an IF/TA grade <= II at M3 | 31 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population | Participants with Fibrosis progression, M3 to M12 | 16 Participants |
Secondary
Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR)
eGFR was calculated according to the abbreviated Modification of Diet in Renal Disease (MDRD) Formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²). LOCF = Last observation carried forward
Time frame: M3 (baseline) to M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Certican EMT+ | Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR) | without imputation | 6.99 mL/min/1.73m^2 | Standard Error 1.66 |
| Certican EMT+ | Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR) | imputation by LOCF(96, 97) | 5.96 mL/min/1.73m^2 | Standard Error 1.39 |
| Neoral EMT+ | Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR) | without imputation | 2.54 mL/min/1.73m^2 | Standard Error 1.5 |
| Neoral EMT+ | Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR) | imputation by LOCF(96, 97) | 2.15 mL/min/1.73m^2 | Standard Error 1.37 |
Secondary
Change in EMT Score
Change (M12 - M3) in EMT Score. Progression in EMT score is defined as an increase by \>=1 of EMT score from M3 to M12. EMT score 0 (the best): \<1 EMT score 1 (the better) : 1-10% of tubular atrophy EMT score 2 : 10-25% of tubular atrophy EMT score 3 : 25-50% of tubular atrophy EMT score 4 (the worst): \>50% of tubular atrophy
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Certican EMT+ | Change in EMT Score | -0.3 scores on a scale | Standard Deviation 1.22 |
| Neoral EMT+ | Change in EMT Score | 0.9 scores on a scale | Standard Deviation 1.09 |
| Neoral EMT+ | Change in EMT Score | -0.3 scores on a scale | Standard Deviation 1.05 |
| Neoral EMT- | Change in EMT Score | 0.6 scores on a scale | Standard Deviation 0.99 |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model
The average patient renal function was evaluated on the basis of eGFR was calculated according to the abbreviated MDRD formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²).
Time frame: Baseline (M3), M12
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Certican EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | without imputation | 8.6 mL/min/1.73m² | Standard Deviation 15.21 |
| Certican EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | imputation by LOCF (36, 60, 39, 58) | -11.9 mL/min/1.73m² | Standard Deviation 27.78 |
| Neoral EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | imputation by LOCF (36, 60, 39, 58) | 27.3 mL/min/1.73m² | Standard Deviation 138.44 |
| Neoral EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | without imputation | 5.6 mL/min/1.73m² | Standard Deviation 18.73 |
| Neoral EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | without imputation | 1.5 mL/min/1.73m² | Standard Deviation 9.49 |
| Neoral EMT+ | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | imputation by LOCF (36, 60, 39, 58) | 5.1 mL/min/1.73m² | Standard Deviation 40.8 |
| Neoral EMT- | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | without imputation | 3.8 mL/min/1.73m² | Standard Deviation 10.99 |
| Neoral EMT- | Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model | imputation by LOCF (36, 60, 39, 58) | -4.9 mL/min/1.73m² | Standard Deviation 29.09 |
Secondary
Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade
Difference (M12 - M3) in IF/TA grade. IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (\<25%), grade II (25-50%) and grade III (\>50% of lesions).
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 0 | 9 Number of Participants |
| Certican EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade -1 | 5 Number of Participants |
| Certican EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 1 | 7 Number of Participants |
| Certican EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 3 | 2 Number of Participants |
| Certican EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 2 | 3 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 3 | NA Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade -1 | 1 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 0 | 21 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 1 | 18 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 2 | 3 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 0 | 9 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 1 | 11 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 2 | 5 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade -1 | 7 Number of Participants |
| Neoral EMT+ | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 3 | 0 Number of Participants |
| Neoral EMT- | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 0 | 33 Number of Participants |
| Neoral EMT- | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 2 | 5 Number of Participants |
| Neoral EMT- | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 1 | 13 Number of Participants |
| Neoral EMT- | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade -1 | 2 Number of Participants |
| Neoral EMT- | Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade | Difference in IF/TA grade 3 | NA Number of Participants |
Secondary
Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification
Percentage of IF measured by numerical quantification. The IF percentage was transposed in grade according to the following rule: grade 0 for an IF % ≤5%, grade I for an IF % ranging from \>5% to \< 25%, grade II for an IF % ranging from 25 to 50%, grade III for an IF % \>50%. Interstitial graft fibrosis has been identified as the primary cause of graft loss following death with a functional graft \[3-5\].
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Certican EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M3 (n=26,43,32,53) | 22.8 Percentage of IF | Standard Deviation 8.9 |
| Certican EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Change in Percentage of IF (n=24,42,32,53) | 5.1 Percentage of IF | Standard Deviation 12.4 |
| Certican EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M12 (n=24,42,32,53) | 27.6 Percentage of IF | Standard Deviation 12.2 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M3 (n=26,43,32,53) | 15.9 Percentage of IF | Standard Deviation 7.5 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Change in Percentage of IF (n=24,42,32,53) | 4.9 Percentage of IF | Standard Deviation 12.2 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M12 (n=24,42,32,53) | 20.9 Percentage of IF | Standard Deviation 10.1 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M12 (n=24,42,32,53) | 27.4 Percentage of IF | Standard Deviation 11.5 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M3 (n=26,43,32,53) | 23.4 Percentage of IF | Standard Deviation 9.5 |
| Neoral EMT+ | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Change in Percentage of IF (n=24,42,32,53) | 3.9 Percentage of IF | Standard Deviation 12.3 |
| Neoral EMT- | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M3 (n=26,43,32,53) | 17.8 Percentage of IF | Standard Deviation 8.2 |
| Neoral EMT- | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Change in Percentage of IF (n=24,42,32,53) | 2.7 Percentage of IF | Standard Deviation 9.7 |
| Neoral EMT- | Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification | Percentage of IF at M12 (n=24,42,32,53) | 20.4 Percentage of IF | Standard Deviation 9.1 |
Secondary
Change in Urine Protein/Creatinine Ratio (Without Imputation)
One of the factors associated with EMT progression between M3 and M12 according to univariate analysis (ITT biopsies M3 & M12).
Time frame: Month 3 (baseline), Month 12
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Certican EMT+ | Change in Urine Protein/Creatinine Ratio (Without Imputation) | 44.4 mg/mmol | Standard Deviation 188.99 |
| Neoral EMT+ | Change in Urine Protein/Creatinine Ratio (Without Imputation) | 3.5 mg/mmol | Standard Deviation 48.37 |
| Neoral EMT+ | Change in Urine Protein/Creatinine Ratio (Without Imputation) | 16.0 mg/mmol | Standard Deviation 41.53 |
| Neoral EMT- | Change in Urine Protein/Creatinine Ratio (Without Imputation) | 29.8 mg/mmol | Standard Deviation 189.41 |
Secondary
Incidence (Number) of BPAR
A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system.
Time frame: M6 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Incidence (Number) of BPAR | M12 - Yes | 7 Number of participants |
| Certican EMT+ | Incidence (Number) of BPAR | M12 - No | 29 Number of participants |
| Certican EMT+ | Incidence (Number) of BPAR | M6 - No | 33 Number of participants |
| Certican EMT+ | Incidence (Number) of BPAR | M6 - Yes | 3 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M6 - Yes | 8 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M6 - No | 52 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M12 - No | 43 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M12 - Yes | 17 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M12 - No | 37 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M12 - Yes | 2 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M6 - Yes | 0 Number of participants |
| Neoral EMT+ | Incidence (Number) of BPAR | M6 - No | 39 Number of participants |
| Neoral EMT- | Incidence (Number) of BPAR | M12 - Yes | 3 Number of participants |
| Neoral EMT- | Incidence (Number) of BPAR | M6 - No | 59 Number of participants |
| Neoral EMT- | Incidence (Number) of BPAR | M6 - Yes | 0 Number of participants |
| Neoral EMT- | Incidence (Number) of BPAR | M12 - No | 56 Number of participants |
Secondary
Incidence (Number) of Participants With Graft Losses
If a participant underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.
Time frame: M6 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - No | 36 Participants |
| Certican EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - Yes | 0 Participants |
| Certican EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - Yes | 1 Participants |
| Certican EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - No | 35 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - No | 60 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - Yes | 4 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - Yes | 0 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - No | 56 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - No | 39 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - Yes | 1 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M12 - No | 38 Participants |
| Neoral EMT+ | Incidence (Number) of Participants With Graft Losses | M6 - Yes | 0 Participants |
| Neoral EMT- | Incidence (Number) of Participants With Graft Losses | M12 - Yes | 0 Participants |
| Neoral EMT- | Incidence (Number) of Participants With Graft Losses | M6 - No | 59 Participants |
| Neoral EMT- | Incidence (Number) of Participants With Graft Losses | M12 - No | 59 Participants |
| Neoral EMT- | Incidence (Number) of Participants With Graft Losses | M6 - Yes | 0 Participants |
Secondary
Incidence (Number) of Subclinical Rejections and Borderline Lesions
Incidence of subclinical rejections and borderline lesions with regards to histological evidence of rejection with clinical findings. Subclinical rejections: rejection without clinical symptoms which is diagnosed by chance when a graft biopsy is performed. Clinically suspected BPAR: rejection suspected because of the presence of clinical symptoms (fever, pain, increase of creatinine) and then confirmed by the graft biopsy. Borderline lesions: suspicious for acute T-cell mediated rejection. This category is used when no intimal arteritis is present, but there are foci of tubulitis with minor interstitial infiltration or interstitial infiltration with mild tubulitis.
Time frame: M3
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections- Yes (n=68, 84) | 1 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - Missing (N=68, 84) | 1 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - No (N=68, 84) | 68 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - No (n=68,84) | 62 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections- missing (n=68, 84) | 1 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - Yes (n=68,84) | 6 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - Yes (N=68, 84) | 0 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - Missing (n=68,84) | 1 Participants |
| Certican EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections-No (n=68, 84) | 67 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - Missing (n=68,84) | 1 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections-No (n=68, 84) | 84 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections- Yes (n=68, 84) | 0 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Subclinical rejections- missing (n=68, 84) | 1 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - No (N=68, 84) | 84 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - Yes (N=68, 84) | 0 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Clinically suspected BPAR - Missing (N=68, 84) | 1 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - No (n=68,84) | 71 Participants |
| Neoral EMT+ | Incidence (Number) of Subclinical Rejections and Borderline Lesions | Borderline lesions - Yes (n=68,84) | 13 Participants |
Secondary
Interstitial Fibrosis/Tabular Atrophy (IF/TA)
Incidence and severity of IF/TA according to 2005/2007 Banff classification system grades (grades l to lll). IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (\<25%), grade II (25-50%) and grade III (\>50% of lesions).
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | Interstitial Fibrosis/Tubular Atrophy (IF/TA) | 13 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade 1 | 11 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IFTA grade at M3 at grade II | 2 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade III | 0 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade 0 | 9 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IT/TA grade at M12 at grade I | 8 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade II | 6 Number of participants |
| Certican EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade III | 3 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IT/TA grade at M12 at grade I | 18 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade 0 | 20 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade 1 | 5 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade III | 0 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade II | 5 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade III | 0 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IFTA grade at M3 at grade II | 0 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | Interstitial Fibrosis/Tubular Atrophy (IF/TA) | 38 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade II | 9 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IFTA grade at M3 at grade II | 1 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade III | 1 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade 0 | 7 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IT/TA grade at M12 at grade I | 15 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade III | 1 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | Interstitial Fibrosis/Tubular Atrophy (IF/TA) | 13 Number of participants |
| Neoral EMT+ | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade 1 | 17 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IFTA grade at M3 at grade II | 0 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade III | 0 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M3 at grade 1 | 9 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | Interstitial Fibrosis/Tubular Atrophy (IF/TA) | 44 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade 0 | 31 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade III | 1 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IF/TA grade at M12 at grade II | 6 Number of participants |
| Neoral EMT- | Interstitial Fibrosis/Tabular Atrophy (IF/TA) | IT/TA grade at M12 at grade I | 15 Number of participants |
Secondary
Number of Participants With Epithelial-mesenchymal Transition (EMT) Score
Incidence and severity of EMT score. The intensity of EMT markers expression present and detectable in the renal graft at an early stage following transplantation is known as EMT score. EMT score 0 (the best): \<1 EMT score 1 (the better): 1-10% of tubular atrophy EMT score 2: 10-25% of tubular atrophy EMT score 3: 25-50% of tubular atrophy EMT score 4 (the worst): \>50% of tubular atrophy
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M12 (n= 25,41,32, 53) | 7 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M12 (n= 25,41,32, 53) | 1 participants | 1.06 |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M3 (n= 26,43,32, 53) | 9 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M12 (n= 25,41,32, 53) | 3 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M3 (n= 26,43,32, 53) | 0 participants | 0.49 |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M12 (n= 25,41,32, 53) | 4 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M12 (n= 25,41,32, 53) | 10 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M3 (n= 26,43,32, 53) | 17 participants | — |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Missing Score at M12 (n= 25,41,32, 53) | 1 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M12 (n= 25,41,32, 53) | 2 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M3 (n= 26,43,32, 53) | 26 participants | 0.49 |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M3 (n= 26,43,32, 53) | 17 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M12 (n= 25,41,32, 53) | 13 participants | 1.17 |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M12 (n= 25,41,32, 53) | 11 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M12 (n= 25,41,32, 53) | 11 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M12 (n= 25,41,32, 53) | 4 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Missing Score at M12 (n= 25,41,32, 53) | 2 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M12 (n= 25,41,32, 53) | 4 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M12 (n= 25,41,32, 53) | 0 participants | 1.02 |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M3 (n= 26,43,32, 53) | 20 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M12 (n= 25,41,32, 53) | 9 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M3 (n= 26,43,32, 53) | 0 participants | 0.72 |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M12 (n= 25,41,32, 53) | 10 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M12 (n= 25,41,32, 53) | 9 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M3 (n= 26,43,32, 53) | 8 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Missing Score at M12 (n= 25,41,32, 53) | 0 participants | — |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M3 (n= 26,43,32, 53) | 4 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Missing Score at M12 (n= 25,41,32, 53) | 0 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M12 (n= 25,41,32, 53) | 19 participants | 1.03 |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 4 at M12 (n= 25,41,32, 53) | 1 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M12 (n= 25,41,32, 53) | 4 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M12 (n= 25,41,32, 53) | 17 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 1 at M3 (n= 26,43,32, 53) | 25 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 0 at M3 (n= 26,43,32, 53) | 28 participants | 0.5 |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 3 at M3 (n= 26,43,32, 53) | 0 participants | — |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Score | EMT Score 2 at M12 (n= 25,41,32, 53) | 12 participants | — |
Secondary
Number of Participants With Epithelial-mesenchymal Transition (EMT) Status
Incidence and severity of EMT status. EMT status was determined centrally using the graft biopsy taken at 3 months. The result was quickly obtained (within 7 to 15 days) and sent to the company in charge of randomization in order to allocate each patient to a treatment group and to provide the investigator with this information without confirming EMT status.
Time frame: M3 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3-Negative (n=26,43,32,53) | 0 Participants |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3- Positive (n=26,43,32,53) | 26 Participants |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3 - Not done (n=26,43,32,53) | 0 Participants |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Negative (n=25,41,32,53) | 8 Participants |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Positive (n=25,41,32,53) | 17 Participants |
| Certican EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Not done (n=25,41,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Not done (n=25,41,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Negative (n=25,41,32,53) | 24 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3-Negative (n=26,43,32,53) | 43 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3 - Not done (n=26,43,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3- Positive (n=26,43,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Positive (n=25,41,32,53) | 17 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3- Positive (n=26,43,32,53) | 32 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3 - Not done (n=26,43,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Negative (n=25,41,32,53) | 9 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Not done (n=25,41,32,53) | 0 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Positive (n=25,41,32,53) | 23 Participants |
| Neoral EMT+ | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3-Negative (n=26,43,32,53) | 0 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Positive (n=25,41,32,53) | 17 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Not done (n=25,41,32,53) | 0 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3- Positive (n=26,43,32,53) | 0 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M12- Negative (n=25,41,32,53) | 36 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3-Negative (n=26,43,32,53) | 53 Participants |
| Neoral EMT- | Number of Participants With Epithelial-mesenchymal Transition (EMT) Status | EMT Status at M3 - Not done (n=26,43,32,53) | 0 Participants |
Secondary
Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification
Comparisons according to epithelial-mesenchymal transition (EMT) profile and immunosuppressive treatment
Time frame: M3 to M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis Progression - No (n=24, 42, 31, 53) | 18 Participants |
| Certican EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Missing (n=24, 42, 31, 53) | 2 Participants |
| Certican EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Yes (n=24, 42,31,43) | 6 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis Progression - No (n=24, 42, 31, 53) | 30 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Missing (n=24, 42, 31, 53) | 1 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Yes (n=24, 42,31,43) | 12 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Yes (n=24, 42,31,43) | 12 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis Progression - No (n=24, 42, 31, 53) | 19 Participants |
| Neoral EMT+ | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Missing (n=24, 42, 31, 53) | 0 Participants |
| Neoral EMT- | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis Progression - No (n=24, 42, 31, 53) | 42 Participants |
| Neoral EMT- | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Missing (n=24, 42, 31, 53) | 0 Participants |
| Neoral EMT- | Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification | Fibrosis progression - Yes (n=24, 42,31,43) | 11 Participants |
Secondary
Risk Factors of IF/TA Progression
Composite factors regarding fibrosis progression at 12 months using a logistic regression model; the parameters initially considered concerned the demographic characteristics of both recipient and donor, transplantation characteristics, hypertension, diabetes, study treatments, immunosuppression, EMT, IF/TA, function at M3, the onset of acute rejection, the presence of anti-donor antibodies at M12, infections and BK virus viremia. Arteriolar hyaline thickening is thickening of the walls of arterioles by the deposition of homogeneous pink hyaline material. BPAR is biopsy proven acute rejection. TEM progression is the increase ≥ 1 of TEM score between Month 3 and Month 12
Time frame: M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment. Among the 194 participants in the ITT group, 58 patients in the EMT+ group completed the study providing a graft biopsy for analysis at M3 and M12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Risk Factors of IF/TA Progression | Donor Age - <=50 years | 28 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 0 (n=66, 85) | 52 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Expanded Criteria donor: NO | 40 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 1 (n=66, 85) | 14 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Delayed graft function: Yes | 15 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 2 (n=66, 85) | 0 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Donor Sex - Female | 22 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 0 | 36 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | CC at M3 <50 mL/min/1.73m^2 | 40 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 1 | 15 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Expanded Criteria Donor: Yes | 27 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 2 | 10 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | CC at M3 >=50 mL/min/1.73m^2 (n=67, 85) | 27 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 3 | 6 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix increase at M3 - 0 (n=64, 85) | 59 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | BPAR - No | 55 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Donor Age - >50 years | 39 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | BPAR - Yes | 12 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix (mm) increase at M3: 1 (n=64, 85) | 2 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: No (n=67, 83) | 26 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Delayed graft function: No | 52 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: Yes (n=67, 83) | 41 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix increase at M3: 2 (n=64, 85) | 3 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: Missing (n=67, 83) | 0 Participants |
| Certican EMT+ | Risk Factors of IF/TA Progression | Donor Sex - Male | 45 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: Missing (n=67, 83) | 3 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Donor Sex - Male | 48 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Donor Sex - Female | 38 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Donor Age - <=50 years | 48 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Donor Age - >50 years | 38 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Expanded Criteria donor: NO | 63 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Expanded Criteria Donor: Yes | 23 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Delayed graft function: No | 76 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | CC at M3 >=50 mL/min/1.73m^2 (n=67, 85) | 50 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Delayed graft function: Yes | 10 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | CC at M3 <50 mL/min/1.73m^2 | 35 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix increase at M3 - 0 (n=64, 85) | 84 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix (mm) increase at M3: 1 (n=64, 85) | 1 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Mesangial matrix increase at M3: 2 (n=64, 85) | 0 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 0 (n=66, 85) | 55 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 1 (n=66, 85) | 27 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Interstitial fibrosis (ci) at M3: 2 (n=66, 85) | 3 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 0 | 56 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 1 | 21 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 2 | 8 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | Arteriolar hyaline thickening (ah) at M3: 3 | 1 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | BPAR - No | 79 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | BPAR - Yes | 7 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: No (n=67, 83) | 57 Participants |
| Neoral EMT+ | Risk Factors of IF/TA Progression | TEM Progression fron M3-M12: Yes (n=67, 83) | 26 Participants |
Secondary
Severity of BPAR
A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system. Biopsy graded IA: Significant interstitial infiltration (\> 25% of parenchyma) and foci of moderate tubulitis (\> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (\> 25% of parenchyma) and foci of severe tubulitis (\> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising \> 25% of the lumenal area. Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation).
Time frame: M6 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Severity of BPAR | M12: Banff type Grade IA | 2 Participants |
| Certican EMT+ | Severity of BPAR | M6: Banff type Grade IB | 0 Participants |
| Certican EMT+ | Severity of BPAR | M12: Banff type Grade IB | 2 Participants |
| Certican EMT+ | Severity of BPAR | M6: Banff type Grade IIA | 1 Participants |
| Certican EMT+ | Severity of BPAR | M12: Banff type Grade IIA | 1 Participants |
| Certican EMT+ | Severity of BPAR | M12: Banff type Grade IIB | 0 Participants |
| Certican EMT+ | Severity of BPAR | M6: Banff type Grade IIB | 0 Participants |
| Certican EMT+ | Severity of BPAR | M12: Banff type Grade III | 0 Participants |
| Certican EMT+ | Severity of BPAR | M6: Banff type Grade III | 0 Participants |
| Certican EMT+ | Severity of BPAR | M6: Banff type Grade IA | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IIA | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IA | 7 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IIB | 1 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade III | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade III | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IB | 5 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IIB | 1 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IB | 4 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IA | 2 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IIA | 1 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IA | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IB | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IIB | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade III | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IIA | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade IIB | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IIA | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M6: Banff type Grade III | 0 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IA | 1 Participants |
| Neoral EMT+ | Severity of BPAR | M12: Banff type Grade IB | 0 Participants |
| Neoral EMT- | Severity of BPAR | M12: Banff type Grade III | 0 Participants |
| Neoral EMT- | Severity of BPAR | M6: Banff type Grade IA | 0 Participants |
| Neoral EMT- | Severity of BPAR | M6: Banff type Grade IB | 0 Participants |
| Neoral EMT- | Severity of BPAR | M6: Banff type Grade IIB | 0 Participants |
| Neoral EMT- | Severity of BPAR | M6: Banff type Grade III | 0 Participants |
| Neoral EMT- | Severity of BPAR | M12: Banff type Grade IA | 0 Participants |
| Neoral EMT- | Severity of BPAR | M12: Banff type Grade IB | 0 Participants |
| Neoral EMT- | Severity of BPAR | M12: Banff type Grade IIA | 1 Participants |
| Neoral EMT- | Severity of BPAR | M12: Banff type Grade IIB | 0 Participants |
| Neoral EMT- | Severity of BPAR | M6: Banff type Grade IIA | 0 Participants |
Secondary
Treatment Failures
A treatment failure is defined as biopsy proven acute rejection (BPAR), a graft loss, a death or a loss to follow up. It was assessed between randomization and 6 and 12 months post-transplantation.
Time frame: M6 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Treatment Failures | M6: BPAR - No | 33 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Loss to follow-up - Yes | 0 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Graft Loss - No | 36 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: BPAR - Yes | 7 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: BPAR -Yes | 3 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Loss to follow-up - Yes | 0 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: BPAR - No | 29 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Death - Yes | 0 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Treatment Failure- Yes | 3 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Loss to follow-up - No | 36 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Death - No | 36 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Death - Yes | 0 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Treatment Failure- No | 29 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Loss to follow-up - No | 36 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Death - No | 36 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Graft Loss - Yes | 1 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Treatment Failure- Yes | 7 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Treatment Failure- No | 33 Number of Participants |
| Certican EMT+ | Treatment Failures | M12: Graft Loss - No | 35 Number of Participants |
| Certican EMT+ | Treatment Failures | M6: Graft Loss - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Death - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Treatment Failure- No | 52 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Treatment Failure- Yes | 8 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Treatment Failure- No | 42 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Treatment Failure- Yes | 18 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: BPAR - No | 52 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: BPAR -Yes | 8 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: BPAR - No | 43 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Loss to follow-up - No | 60 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: BPAR - Yes | 17 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Graft Loss - No | 60 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Graft Loss - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Graft Loss - No | 56 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Graft Loss - Yes | 4 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Death - No | 60 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Death - No | 60 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Death - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Loss to follow-up - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Loss to follow-up - No | 59 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Loss to follow-up - Yes | 1 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Graft Loss - No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Loss to follow-up - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Graft Loss - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Treatment Failure- Yes | 3 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Graft Loss - No | 38 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Graft Loss - Yes | 1 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Treatment Failure- No | 36 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Death - No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Loss to follow-up - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Death - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Treatment Failure- Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Loss to follow-up - No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Death - No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: BPAR -Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: Death - Yes | 0 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Loss to follow-up - No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: BPAR - No | 37 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: Treatment Failure- No | 39 Number of Participants |
| Neoral EMT+ | Treatment Failures | M12: BPAR - Yes | 2 Number of Participants |
| Neoral EMT+ | Treatment Failures | M6: BPAR - No | 39 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Loss to follow-up - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Graft Loss - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Treatment Failure- Yes | 3 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Death - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: BPAR - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Graft Loss - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: BPAR - Yes | 3 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Loss to follow-up - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Loss to follow-up - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Graft Loss - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Treatment Failure- No | 56 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Death - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Death - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Graft Loss - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Treatment Failure- No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: Loss to follow-up - Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: BPAR -Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Death - No | 59 Number of Participants |
| Neoral EMT- | Treatment Failures | M6: Treatment Failure- Yes | 0 Number of Participants |
| Neoral EMT- | Treatment Failures | M12: BPAR - No | 56 Number of Participants |
Secondary
Type of Biopsy Proven Acute Rejection (BPAR)
A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system. Biopsy graded IA: Significant interstitial infiltration (\> 25% of parenchyma) and foci of moderate tubulitis (\> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IB: Significant interstitial infiltration (\> 25% of parenchyma) and foci of severe tubulitis (\> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising \> 25% of the lumenal area. Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation).
Time frame: M6 and M12 post transplantation
Population: ITT population: All patients randomized in the study who received at least one dose of the study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Certican EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - No | 30 Participants |
| Certican EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - Yes | 6 Participants |
| Neoral EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - Yes | 14 Participants |
| Neoral EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - No | 46 Participants |
| Neoral EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - No | 38 Participants |
| Neoral EMT+ | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - Yes | 1 Participants |
| Neoral EMT- | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - No | 58 Participants |
| Neoral EMT- | Type of Biopsy Proven Acute Rejection (BPAR) | Cellular AR - Yes | 1 Participants |