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

NCT ID: NCT01079143

Last Updated: 2014-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 194 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2012-06-30

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

Conditions

Renal Interstitial Fibrosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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®.

Group Type: EXPERIMENTAL

Certican®

Intervention Type: DRUG

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.

Myfortic

Intervention Type: DRUG

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.

Simulect®

Intervention Type: DRUG

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.

Corticosteroids

Intervention Type: DRUG

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.

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®.

Group Type: EXPERIMENTAL

Certican®

Intervention Type: DRUG

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.

Myfortic

Intervention Type: DRUG

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.

Simulect®

Intervention Type: DRUG

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.

Corticosteroids

Intervention Type: DRUG

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.

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®.

Group Type: ACTIVE_COMPARATOR

Neoral

Intervention Type: DRUG

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.

Myfortic

Intervention Type: DRUG

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.

Simulect®

Intervention Type: DRUG

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.

Corticosteroids

Intervention Type: DRUG

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.

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®.

Group Type: ACTIVE_COMPARATOR

Neoral

Intervention Type: DRUG

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.

Myfortic

Intervention Type: DRUG

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.

Simulect®

Intervention Type: DRUG

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.

Corticosteroids

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Everolimus; RAD001; Cyclosporine; basiliximab

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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

Randomization criteria:

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

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

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

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

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Caen, Cedex, France

Novartis Investigative Site

Angers, France, France

Novartis Investigative Site

Suresnes, France, France

Novartis Investigative Site

Amiens Cedex1, , France

Novartis Investigative Site

Bordeaux, , France

Novartis Investigative Site

Brest, , France

Novartis Investigative Site

Créteil, , France

Novartis Investigative Site

Grenoble, , France

Novartis Investigative Site

Le Kremlin-Bicêtre, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Lyon, , France

Novartis Investigative Site

Nice, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Pierre-Bénite, , France

Novartis Investigative Site

Poitiers, , France

Novartis Investigative Site

Reims, , France

Novartis Investigative Site

Saint-Priest-en-Jarez, , France

Novartis Investigative Site

Strasbourg, , France

Novartis Investigative Site

Toulouse, , France

Novartis Investigative Site

Tours, , France

Novartis Investigative Site

Vandoeuvre Les Nancys, , France

Countries

France

References

Loupy A, Aubert O, Orandi BJ, Naesens M, Bouatou Y, Raynaud M, Divard G, Jackson AM, Viglietti D, Giral M, Kamar N, Thaunat O, Morelon E, Delahousse M, Kuypers D, Hertig A, Rondeau E, Bailly E, Eskandary F, Bohmig G, Gupta G, Glotz D, Legendre C, Montgomery RA, Stegall MD, Empana JP, Jouven X, Segev DL, Lefaucheur C. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019 Sep 17;366:l4923. doi: 10.1136/bmj.l4923.

Reference Type: DERIVED

PMID: 31530561 (View on PubMed)

Other Identifiers

2009-011473-33

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001AFR10

Identifier Type: -

Identifier Source: org_study_id