CERTITEM: 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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01079143
• Collaborator: (none)
• Enrollment: 194
• Locations: 23
• Arms: 4
• Duration (Months): 33
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Renal Interstitial Fibrosis	Drug: Certican®; Drug: Neoral; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 194 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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®.	Drug: Certican®; 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.; Other Names: Everolimus RAD001 ; Drug: Myfortic; 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.; Drug: Simulect®; 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.; Other Names: basiliximab ; Drug: Corticosteroids; 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.
Experimental: 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®.	Drug: Certican®; 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.; Other Names: Everolimus RAD001 ; Drug: Myfortic; 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.; Drug: Simulect®; 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.; Other Names: basiliximab ; Drug: Corticosteroids; 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.
Active Comparator: 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®.	Drug: Neoral; 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.; Other Names: Cyclosporine ; Drug: Myfortic; 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.; Drug: Simulect®; 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.; Other Names: basiliximab ; Drug: Corticosteroids; 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.
Active Comparator: 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®.	Drug: Neoral; 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.; Other Names: Cyclosporine ; Drug: Myfortic; 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.; Drug: Simulect®; 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.; Other Names: basiliximab ; Drug: Corticosteroids; 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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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).

3. 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

4. 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].

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

6. 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.

7. 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

8. 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

9. 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.

10. 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

11. 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).

12. 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).

13. 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.

14. 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).

15. 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).

16. 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.

17. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Caen	Cedex	France	14033
2	Novartis Investigative Site	Amiens cedex1		France	80054
3	Novartis Investigative Site	Angers		France	49 033
4	Novartis Investigative Site	Bordeaux Cedex		France	33076
5	Novartis Investigative Site	Brest		France	29200
6	Novartis Investigative Site	Creteil		France	94010
7	Novartis Investigative Site	Grenoble		France	38043
8	Novartis Investigative Site	Le Kremlin Bicetre		France	94275
9	Novartis Investigative Site	Lille Cedex		France	59037
10	Novartis Investigative Site	Lyon		France	69 437
11	Novartis Investigative Site	Nice Cedex 1		France	06602
12	Novartis Investigative Site	Paris cedex 15		France	75015
13	Novartis Investigative Site	Paris		France	75475
14	Novartis Investigative Site	Paris		France	75970
15	Novartis Investigative Site	Pierre Benite Cedex		France	69495
16	Novartis Investigative Site	Poitiers		France	86000
17	Novartis Investigative Site	Reims		France	51092
18	Novartis Investigative Site	St Priest en Jarez Cedex		France	42277
19	Novartis Investigative Site	Strasbourg		France	67091
20	Novartis Investigative Site	Suresnes		France	92150
21	Novartis Investigative Site	Toulouse Cedex 4		France	31054
22	Novartis Investigative Site	Tours Cedex		France	37044
23	Novartis Investigative Site	Vandoeuvre Les Nancys		France	54511

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01079143
• Other Study ID Numbers: CRAD001AFR10; 2009-011473-33
• First Posted: Mar 2, 2010
• Last Update Posted: Mar 18, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Novartis Pharmaceuticals: De Novo renal transplantation
• Additional relevant MeSH terms: Lung Diseases, Interstitial; Fibrosis; Cyclosporine; Mycophenolic Acid; Everolimus; Cyclosporins; Basiliximab

Study Results

Participant Flow

Pre-assignment Detail	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

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Period Title: Overall Study
STARTED	36	60	39	59
Exposed	36	60	39	59
Month 3 (M3) Biopsies	36	59	39	59
Month 12 (M12) Biopsies	26	43	32	53
M3 and M12 Biopsies	26	43	32	53
COMPLETED	27	43	34	54
NOT COMPLETED	9	17	5	5

Baseline Characteristics

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-	Total
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Total of all reporting groups
Overall Participants	36	60	39	59	194
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.2 (10.7)	46.4 (12.9)	50.0 (10.0)	50.7 (11.7)	49.3 (11.7)
Sex: Female, Male (Count of Participants)
Female	17 47.2%	17 28.3%	16 41%	16 27.1%	66 34%
Male	19 52.8%	43 71.7%	23 59%	43 72.9%	128 66%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.3 (4.6)	26.0 (4.6)	25.6 (4.0)	25.3 (4.2)	25.4 (4.4)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Neoral EMT+
Arm/Group Description	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	32
Participants with an IF/TA grade <= II at M3	26 72.2%	31 51.7%
Participants with Fibrosis progression, M3 to M12	12 33.3%	16 26.7%

2. Secondary Outcome

Title	Interstitial Fibrosis/Tabular Atrophy (IF/TA)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
Interstitial Fibrosis/Tubular Atrophy (IF/TA)	13 36.1%	38 63.3%	13 33.3%	44 74.6%
IF/TA grade at M3 at grade 1	11 30.6%	5 8.3%	17 43.6%	9 15.3%
IFTA grade at M3 at grade II	2 5.6%	0 0%	1 2.6%	0 0%
IF/TA grade at M3 at grade III	0 0%	0 0%	1 2.6%	0 0%
IF/TA grade at M12 at grade 0	9 25%	20 33.3%	7 17.9%	31 52.5%
IT/TA grade at M12 at grade I	8 22.2%	18 30%	15 38.5%	15 25.4%
IF/TA grade at M12 at grade II	6 16.7%	5 8.3%	9 23.1%	6 10.2%
IF/TA grade at M12 at grade III	3 8.3%	0 0%	1 2.6%	1 1.7%

3. Secondary Outcome

Title	Change in Interstitial Fibrosis/Tabular Atrophy (IF/TA) Grade
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
Difference in IF/TA grade -1	5 13.9%	1 1.7%	7 17.9%	2 3.4%
Difference in IF/TA grade 0	9 25%	21 35%	9 23.1%	33 55.9%
Difference in IF/TA grade 1	7 19.4%	18 30%	11 28.2%	13 22%
Difference in IF/TA grade 2	3 8.3%	3 5%	5 12.8%	5 8.5%
Difference in IF/TA grade 3	2 5.6%	NA NaN	0 0%	NA NaN

4. Secondary Outcome

Title	Risk Factors of IF/TA Progression
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Yes- Fibrosis Progression	No- No Fibrosis Progression
Arm/Group Description	Participants who experienced fibrosis progression based on IF/TA (univariate analysis)	Participants who did not experience fibrosis progression based on IF/TA (univariate analysis)
Measure Participants	67	86
Donor Sex - Male	45 125%	48 80%
Donor Sex - Female	22 61.1%	38 63.3%
Donor Age - <=50 years	28 77.8%	48 80%
Donor Age - >50 years	39 108.3%	38 63.3%
Expanded Criteria donor: NO	40 111.1%	63 105%
Expanded Criteria Donor: Yes	27 75%	23 38.3%
Delayed graft function: No	52 144.4%	76 126.7%
Delayed graft function: Yes	15 41.7%	10 16.7%
CC at M3 <50 mL/min/1.73m^2	40 111.1%	35 58.3%
CC at M3 >=50 mL/min/1.73m^2 (n=67, 85)	27 75%	50 83.3%
Mesangial matrix increase at M3 - 0 (n=64, 85)	59 163.9%	84 140%
Mesangial matrix (mm) increase at M3: 1 (n=64, 85)	2 5.6%	1 1.7%
Mesangial matrix increase at M3: 2 (n=64, 85)	3 8.3%	0 0%
Interstitial fibrosis (ci) at M3: 0 (n=66, 85)	52 144.4%	55 91.7%
Interstitial fibrosis (ci) at M3: 1 (n=66, 85)	14 38.9%	27 45%
Interstitial fibrosis (ci) at M3: 2 (n=66, 85)	0 0%	3 5%
Arteriolar hyaline thickening (ah) at M3: 0	36 100%	56 93.3%
Arteriolar hyaline thickening (ah) at M3: 1	15 41.7%	21 35%
Arteriolar hyaline thickening (ah) at M3: 2	10 27.8%	8 13.3%
Arteriolar hyaline thickening (ah) at M3: 3	6 16.7%	1 1.7%
BPAR - No	55 152.8%	79 131.7%
BPAR - Yes	12 33.3%	7 11.7%
TEM Progression fron M3-M12: No (n=67, 83)	26 72.2%	57 95%
TEM Progression fron M3-M12: Yes (n=67, 83)	41 113.9%	26 43.3%
TEM Progression fron M3-M12: Missing (n=67, 83)	0 0%	3 5%

5. Secondary Outcome

Title	Change in Percentage of Interstitial Fibrosis (IF) by Numerical Quantification
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
Percentage of IF at M3 (n=26,43,32,53)	22.8 (8.9)	15.9 (7.5)	23.4 (9.5)	17.8 (8.2)
Percentage of IF at M12 (n=24,42,32,53)	27.6 (12.2)	20.9 (10.1)	27.4 (11.5)	20.4 (9.1)
Change in Percentage of IF (n=24,42,32,53)	5.1 (12.4)	4.9 (12.2)	3.9 (12.3)	2.7 (9.7)

6. Secondary Outcome

Title	Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification
Description	Comparisons according to epithelial-mesenchymal transition (EMT) profile and immunosuppressive treatment
Time Frame	M3 to M12 post transplantation

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
Fibrosis Progression - No (n=24, 42, 31, 53)	18 50%	30 50%	19 48.7%	42 71.2%
Fibrosis progression - Yes (n=24, 42,31,43)	6 16.7%	12 20%	12 30.8%	11 18.6%
Fibrosis progression - Missing (n=24, 42, 31, 53)	2 5.6%	1 1.7%	0 0%	0 0%

7. Secondary Outcome

Title	Number of Participants With Epithelial-mesenchymal Transition (EMT) Status
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
EMT Status at M3-Negative (n=26,43,32,53)	0 0%	43 71.7%	0 0%	53 89.8%
EMT Status at M3- Positive (n=26,43,32,53)	26 72.2%	0 0%	32 82.1%	0 0%
EMT Status at M3 - Not done (n=26,43,32,53)	0 0%	0 0%	0 0%	0 0%
EMT Status at M12- Negative (n=25,41,32,53)	8 22.2%	24 40%	9 23.1%	36 61%
EMT Status at M12- Positive (n=25,41,32,53)	17 47.2%	17 28.3%	23 59%	17 28.8%
EMT Status at M12- Not done (n=25,41,32,53)	0 0%	0 0%	0 0%	0 0%

8. Secondary Outcome

Title	Number of Participants With Epithelial-mesenchymal Transition (EMT) Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
EMT Score 0 at M3 (n= 26,43,32, 53)	0 (0.49) 0%	26 (0.49) 43.3%	0 (0.72) 0%	28 (0.5) 47.5%
EMT Score 1 at M3 (n= 26,43,32, 53)	0 0%	17 28.3%	0 0%	25 42.4%
EMT Score 2 at M3 (n= 26,43,32, 53)	17 47.2%	0 0%	20 51.3%	0 0%
EMT Score 3 at M3 (n= 26,43,32, 53)	9 25%	0 0%	8 20.5%	0 0%
EMT Score 4 at M3 (n= 26,43,32, 53)	0 0%	0 0%	4 10.3%	0 0%
EMT Score 0 at M12 (n= 25,41,32, 53)	1 (1.06) 2.8%	13 (1.17) 21.7%	0 (1.02) 0%	19 (1.03) 32.2%
EMT Score 1 at M12 (n= 25,41,32, 53)	7 19.4%	11 18.3%	9 23.1%	17 28.8%
EMT Score 2 at M12 (n= 25,41,32, 53)	10 27.8%	11 18.3%	10 25.6%	12 20.3%
EMT Score 3 at M12 (n= 25,41,32, 53)	4 11.1%	4 6.7%	9 23.1%	4 6.8%
EMT Score 4 at M12 (n= 25,41,32, 53)	3 8.3%	2 3.3%	4 10.3%	1 1.7%
EMT Missing Score at M12 (n= 25,41,32, 53)	1 2.8%	2 3.3%	0 0%	0 0%

9. Secondary Outcome

Title	Change in EMT Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	26	43	32	53
Mean (Standard Deviation) [scores on a scale]	-0.3 (1.22)	0.9 (1.09)	-0.3 (1.05)	0.6 (0.99)

10. Secondary Outcome

Title	Incidence (Number) of Subclinical Rejections and Borderline Lesions
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican	Neoral
Arm/Group Description	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®.	Between transplantation adn randomization, all patients have received Neoral. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic.
Measure Participants	69	85
Subclinical rejections-No (n=68, 84)	67 186.1%	84 140%
Subclinical rejections- Yes (n=68, 84)	1 2.8%	0 0%
Subclinical rejections- missing (n=68, 84)	1 2.8%	1 1.7%
Clinically suspected BPAR - No (N=68, 84)	68 188.9%	84 140%
Clinically suspected BPAR - Yes (N=68, 84)	0 0%	0 0%
Clinically suspected BPAR - Missing (N=68, 84)	1 2.8%	1 1.7%
Borderline lesions - No (n=68,84)	62 172.2%	71 118.3%
Borderline lesions - Yes (n=68,84)	6 16.7%	13 21.7%
Borderline lesions - Missing (n=68,84)	1 2.8%	1 1.7%

11. Secondary Outcome

Title	Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR)
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican	Neoral
Arm/Group Description	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	71	87
without imputation	6.99 (1.66)	2.54 (1.5)
imputation by LOCF(96, 97)	5.96 (1.39)	2.15 (1.37)

12. Secondary Outcome

Title	Change in Estimated Glomerular Filtration Rate (eGFR) at M12 From Baseline (M3) - ANCOVA Model
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	27	44	34	53
without imputation	8.6 (15.21)	5.6 (18.73)	1.5 (9.49)	3.8 (10.99)
imputation by LOCF (36, 60, 39, 58)	-11.9 (27.78)	27.3 (138.44)	5.1 (40.80)	-4.9 (29.09)

13. Secondary Outcome

Title	Change in Urine Protein/Creatinine Ratio (Without Imputation)
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	17	28	19	36
Mean (Standard Deviation) [mg/mmol]	44.4 (188.99)	3.5 (48.37)	16.0 (41.53)	29.8 (189.41)

14. Secondary Outcome

Title	Treatment Failures
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	36	60	39	59
M6: Treatment Failure- No	33 91.7%	52 86.7%	39 100%	59 100%
M6: Treatment Failure- Yes	3 8.3%	8 13.3%	0 0%	0 0%
M12: Treatment Failure- No	29 80.6%	42 70%	36 92.3%	56 94.9%
M12: Treatment Failure- Yes	7 19.4%	18 30%	3 7.7%	3 5.1%
M6: BPAR - No	33 91.7%	52 86.7%	39 100%	59 100%
M6: BPAR -Yes	3 8.3%	8 13.3%	0 0%	0 0%
M12: BPAR - No	29 80.6%	43 71.7%	37 94.9%	56 94.9%
M12: BPAR - Yes	7 19.4%	17 28.3%	2 5.1%	3 5.1%
M6: Graft Loss - No	36 100%	60 100%	39 100%	59 100%
M6: Graft Loss - Yes	0 0%	0 0%	0 0%	0 0%
M12: Graft Loss - No	35 97.2%	56 93.3%	38 97.4%	59 100%
M12: Graft Loss - Yes	1 2.8%	4 6.7%	1 2.6%	0 0%
M6: Death - No	36 100%	60 100%	39 100%	59 100%
M6: Death - Yes	0 0%	0 0%	0 0%	0 0%
M12: Death - No	36 100%	60 100%	39 100%	59 100%
M12: Death - Yes	0 0%	0 0%	0 0%	0 0%
M6: Loss to follow-up - No	36 100%	60 100%	39 100%	59 100%
M6: Loss to follow-up - Yes	0 0%	0 0%	0 0%	0 0%
M12: Loss to follow-up - No	36 100%	59 98.3%	39 100%	59 100%
M12: Loss to follow-up - Yes	0 0%	1 1.7%	0 0%	0 0%

15. Secondary Outcome

Title	Type of Biopsy Proven Acute Rejection (BPAR)
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	36	60	39	59
Cellular AR - No	30 83.3%	46 76.7%	38 97.4%	58 98.3%
Cellular AR - Yes	6 16.7%	14 23.3%	1 2.6%	1 1.7%

16. Secondary Outcome

Title	Severity of BPAR
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	36	60	39	59
M6: Banff type Grade IA	0 0%	2 3.3%	0 0%	0 0%
M6: Banff type Grade IB	0 0%	4 6.7%	0 0%	0 0%
M6: Banff type Grade IIA	1 2.8%	0 0%	0 0%	0 0%
M6: Banff type Grade IIB	0 0%	1 1.7%	0 0%	0 0%
M6: Banff type Grade III	0 0%	0 0%	0 0%	0 0%
M12: Banff type Grade IA	2 5.6%	7 11.7%	1 2.6%	0 0%
M12: Banff type Grade IB	2 5.6%	5 8.3%	0 0%	0 0%
M12: Banff type Grade IIA	1 2.8%	1 1.7%	0 0%	1 1.7%
M12: Banff type Grade IIB	0 0%	1 1.7%	0 0%	0 0%
M12: Banff type Grade III	0 0%	0 0%	0 0%	0 0%

17. Secondary Outcome

Title	Incidence (Number) of BPAR
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	36	60	39	59
M6 - No	33 91.7%	52 86.7%	39 100%	59 100%
M6 - Yes	3 8.3%	8 13.3%	0 0%	0 0%
M12 - No	29 80.6%	43 71.7%	37 94.9%	56 94.9%
M12 - Yes	7 19.4%	17 28.3%	2 5.1%	3 5.1%

18. Secondary Outcome

Title	Incidence (Number) of Participants With Graft Losses
Description	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

Outcome Measure Data

Analysis Population Description

ITT population: All patients randomized in the study who received at least one dose of the study treatment.

Arm/Group Title	Certican EMT+	Certican EMT-	Neoral EMT+	Neoral EMT-
Arm/Group Description	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®.	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®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Measure Participants	36	60	39	59
M6 - No	36 100%	60 100%	39 100%	59 100%
M6 - Yes	0 0%	0 0%	0 0%	0 0%
M12 - No	35 97.2%	56 93.3%	38 97.4%	59 100%
M12 - Yes	1 2.8%	4 6.7%	1 2.6%	0 0%

Adverse Events

Arm/Group Title	Neoral		Certican
Arm/Group Description	Between transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.		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®.
All Cause Mortality
	Neoral		Certican
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Neoral		Certican
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/98 (39.8%)		46/96 (47.9%)
Blood and lymphatic system disorders
Agranulocytosis	0/98 (0%)		1/96 (1%)
Anaemia	1/98 (1%)		2/96 (2.1%)
Febrile neutropenia	0/98 (0%)		1/96 (1%)
Leukopenia	1/98 (1%)		0/96 (0%)
Neutropenia	2/98 (2%)		0/96 (0%)
Pancytopenia	2/98 (2%)		0/96 (0%)
Cardiac disorders
Acute coronary syndrome	1/98 (1%)		0/96 (0%)
Gastrointestinal disorders
Aphthous stomatitis	1/98 (1%)		2/96 (2.1%)
Colitis	0/98 (0%)		2/96 (2.1%)
Colitis ulcerative	0/98 (0%)		1/96 (1%)
Dental necrosis	0/98 (0%)		1/96 (1%)
Diarrhoea	3/98 (3.1%)		3/96 (3.1%)
Gastritis	1/98 (1%)		0/96 (0%)
Hernial eventration	0/98 (0%)		1/96 (1%)
Oesophageal ulcer	1/98 (1%)		0/96 (0%)
Periodontitis	0/98 (0%)		1/96 (1%)
General disorders
Asthenia	1/98 (1%)		1/96 (1%)
Chills	1/98 (1%)		0/96 (0%)
General physical health deterioration	0/98 (0%)		1/96 (1%)
Hyperthermia	1/98 (1%)		1/96 (1%)
Oedema peripheral	0/98 (0%)		1/96 (1%)
Pain	1/98 (1%)		0/96 (0%)
Pyrexia	5/98 (5.1%)		5/96 (5.2%)
Sudden death	1/98 (1%)		0/96 (0%)
Hepatobiliary disorders
Hepatitis	0/98 (0%)		1/96 (1%)
Immune system disorders
Amyloidosis	1/98 (1%)		0/96 (0%)
Kidney transplant rejection	0/98 (0%)		4/96 (4.2%)
Transplant rejection	1/98 (1%)		0/96 (0%)
Infections and infestations
Abdominal abscess	1/98 (1%)		0/96 (0%)
Bacillus infection	1/98 (1%)		0/96 (0%)
Bacterial pyelonephritis	3/98 (3.1%)		2/96 (2.1%)
Bronchitis	0/98 (0%)		2/96 (2.1%)
Cytomegalovirus infection	0/98 (0%)		1/96 (1%)
Diarrhoea infectious	0/98 (0%)		2/96 (2.1%)
Escherichia bacteraemia	0/98 (0%)		1/96 (1%)
Escherichia infection	0/98 (0%)		1/96 (1%)
Eye infection toxoplasmal	0/98 (0%)		1/96 (1%)
Gastroenteritis	1/98 (1%)		0/96 (0%)
Gastroenteritis yersinia	0/98 (0%)		1/96 (1%)
Hepatic cyst infection	1/98 (1%)		0/96 (0%)
Lung infection	0/98 (0%)		1/96 (1%)
Orchitis	1/98 (1%)		0/96 (0%)
Pneumocystis jiroveci pneumonia	0/98 (0%)		1/96 (1%)
Pneumonia	1/98 (1%)		0/96 (0%)
Polyomavirus-associated nephropathy	1/98 (1%)		0/96 (0%)
Pseudomonal sepsis	1/98 (1%)		0/96 (0%)
Pyelonephritis	2/98 (2%)		3/96 (3.1%)
Pyelonephritis acute	1/98 (1%)		3/96 (3.1%)
Renal cyst infection	0/98 (0%)		1/96 (1%)
Sinusitis	1/98 (1%)		0/96 (0%)
Staphylococcal infection	1/98 (1%)		0/96 (0%)
Transplant abscess	0/98 (0%)		1/96 (1%)
Urinary tract infection	2/98 (2%)		4/96 (4.2%)
Viral pharyngitis	1/98 (1%)		0/96 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/98 (1%)		0/96 (0%)
Arteriovenous fistula site complication	0/98 (0%)		1/96 (1%)
Arteriovenous fistula thrombosis	2/98 (2%)		0/96 (0%)
Graft loss	1/98 (1%)		1/96 (1%)
Head injury	1/98 (1%)		0/96 (0%)
Overdose	1/98 (1%)		2/96 (2.1%)
Post procedural haematuria	1/98 (1%)		0/96 (0%)
Spinal fracture	1/98 (1%)		0/96 (0%)
Toxicity to various agents	1/98 (1%)		0/96 (0%)
Ureteric anastomosis complication	1/98 (1%)		0/96 (0%)
Vascular graft complication	1/98 (1%)		0/96 (0%)
Investigations
Blood creatinine increased	3/98 (3.1%)		2/96 (2.1%)
Blood pressure increased	0/98 (0%)		1/96 (1%)
Weight decreased	0/98 (0%)		2/96 (2.1%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/98 (1%)		0/96 (0%)
Gout	1/98 (1%)		0/96 (0%)
Hypercreatininaemia	1/98 (1%)		1/96 (1%)
Hypoglycaemia	1/98 (1%)		0/96 (0%)
Malnutrition	1/98 (1%)		0/96 (0%)
Musculoskeletal and connective tissue disorders
Fistula	1/98 (1%)		0/96 (0%)
Pain in extremity	1/98 (1%)		0/96 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Multiple myeloma	1/98 (1%)		0/96 (0%)
Nervous system disorders
Cerebrovascular accident	0/98 (0%)		1/96 (1%)
Dizziness	1/98 (1%)		0/96 (0%)
Headache	1/98 (1%)		0/96 (0%)
Status epilepticus	1/98 (1%)		0/96 (0%)
Syncope	1/98 (1%)		0/96 (0%)
Psychiatric disorders
Depression	1/98 (1%)		1/96 (1%)
Neurosis	1/98 (1%)		0/96 (0%)
Renal and urinary disorders
Glomerulonephritis	1/98 (1%)		0/96 (0%)
Haematuria	1/98 (1%)		0/96 (0%)
Hydronephrosis	1/98 (1%)		0/96 (0%)
Proteinuria	1/98 (1%)		1/96 (1%)
Renal failure acute	4/98 (4.1%)		2/96 (2.1%)
Renal tubular disorder	1/98 (1%)		0/96 (0%)
Renal tubular necrosis	1/98 (1%)		0/96 (0%)
Vesicoureteric reflux	0/98 (0%)		1/96 (1%)
Reproductive system and breast disorders
Metrorrhagia	1/98 (1%)		0/96 (0%)
Prostatitis	1/98 (1%)		0/96 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/98 (0%)		1/96 (1%)
Dyspnoea	0/98 (0%)		2/96 (2.1%)
Lung disorder	1/98 (1%)		1/96 (1%)
Pulmonary oedema	0/98 (0%)		2/96 (2.1%)
Respiratory distress	0/98 (0%)		1/96 (1%)
Skin and subcutaneous tissue disorders
Capillaritis	1/98 (1%)		0/96 (0%)
Rash maculo-papular	0/98 (0%)		1/96 (1%)
Surgical and medical procedures
Hip arthroplasty	0/98 (0%)		1/96 (1%)
Vascular disorders
Haematoma	1/98 (1%)		0/96 (0%)
Haemorrhage	0/98 (0%)		1/96 (1%)
Iliac artery stenosis	1/98 (1%)		0/96 (0%)
Orthostatic hypotension	1/98 (1%)		0/96 (0%)
Phlebitis	0/98 (0%)		1/96 (1%)
Subclavian artery stenosis	1/98 (1%)		0/96 (0%)
Venous thrombosis limb	1/98 (1%)		0/96 (0%)
Other (Not Including Serious) Adverse Events
	Neoral		Certican
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/98 (60.2%)		59/96 (61.5%)
Blood and lymphatic system disorders
Anaemia	6/98 (6.1%)		7/96 (7.3%)
Leukopenia	7/98 (7.1%)		2/96 (2.1%)
Neutropenia	6/98 (6.1%)		6/96 (6.3%)
Gastrointestinal disorders
Aphthous stomatitis	3/98 (3.1%)		17/96 (17.7%)
Diarrhoea	3/98 (3.1%)		7/96 (7.3%)
Gingival hypertrophy	8/98 (8.2%)		0/96 (0%)
General disorders
Oedema peripheral	17/98 (17.3%)		14/96 (14.6%)
Infections and infestations
Bronchitis	6/98 (6.1%)		5/96 (5.2%)
Cytomegalovirus infection	7/98 (7.1%)		2/96 (2.1%)
Urinary tract infection	5/98 (5.1%)		7/96 (7.3%)
Metabolism and nutrition disorders
Dyslipidaemia	6/98 (6.1%)		9/96 (9.4%)
Respiratory, thoracic and mediastinal disorders
Cough	5/98 (5.1%)		1/96 (1%)
Skin and subcutaneous tissue disorders
Acne	1/98 (1%)		6/96 (6.3%)
Rash	0/98 (0%)		7/96 (7.3%)
Vascular disorders
Hypertension	6/98 (6.1%)		5/96 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.