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

NCT01079143 | Completed Phase 3 Results

• 2 other identifiers: CRAD001AFR102009-011473-33
• Study Type: interventional
• Target: 194
• Locations: 1 country
• Sites: 23

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

Keywords

De Novo renal transplantation

Outcome Measures

Primary Outcomes (1)

• 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)

  Month 3 (M3) and Month 12 (M12) post transplantation

Secondary Outcomes (17)

• Interstitial Fibrosis/Tabular Atrophy (IF/TA)

  M3 and M12 post transplantation

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

  M3 and M12 post transplantation

• Risk Factors of IF/TA Progression

  M12 post transplantation

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

  M3 and M12 post transplantation

• Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification

  M3 to M12 post transplantation

Study Arms (4)

Certican EMT+

EXPERIMENTAL

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®; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids

Certican EMT-

EXPERIMENTAL

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®; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids

Neoral EMT+

ACTIVE COMPARATOR

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; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids

Neoral EMT-

ACTIVE COMPARATOR

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; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids

Interventions

Certican® 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.

Also known as: Everolimus, RAD001

Certican EMT+; Certican EMT-

Neoral 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.

Also known as: Cyclosporine

Neoral EMT+; Neoral EMT-

Myfortic 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.

Certican EMT+; Certican EMT-; Neoral EMT+; Neoral EMT-

Simulect® 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.

Also known as: basiliximab

Certican EMT+; Certican EMT-; Neoral EMT+; Neoral EMT-

Corticosteroids 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+; Certican EMT-; Neoral EMT+; Neoral EMT-

Eligibility Criteria

• Age: 19 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.
• 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:

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (23)

Novartis Investigative Site

Caen, Cedex, 14033, France

Location

Novartis Investigative Site

Angers, France, 49 033, France

Location

Novartis Investigative Site

Suresnes, France, 92150, France

Location

Novartis Investigative Site

Amiens Cedex1, 80054, France

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Brest, 29200, France

Location

Novartis Investigative Site

Créteil, 94010, France

Location

Novartis Investigative Site

Grenoble, 38043, France

Location

Novartis Investigative Site

Le Kremlin-Bicêtre, 94275, France

Location

Novartis Investigative Site

Lille, 59037, France

Location

Novartis Investigative Site

Lyon, 69 437, France

Location

Novartis Investigative Site

Nice, 06602, France

Location

Novartis Investigative Site

Paris, 75015, France

Location

Novartis Investigative Site

Paris, 75475, France

Location

Novartis Investigative Site

Paris, 75970, France

Location

Novartis Investigative Site

Pierre-Bénite, 69495, France

Location

Novartis Investigative Site

Poitiers, 86000, France

Location

Novartis Investigative Site

Reims, 51092, France

Location

Novartis Investigative Site

Saint-Priest-en-Jarez, 42277, France

Location

Novartis Investigative Site

Strasbourg, 67091, France

Location

Novartis Investigative Site

Toulouse, 31054, France

Location

Novartis Investigative Site

Tours, 37044, France

Location

Novartis Investigative Site

Vandoeuvre Les Nancys, 54511, France

Location

Related Publications (1)

• 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.

  PMID: 31530561 DERIVED

MeSH Terms

Interventions

Everolimus; Cyclosporine; Mycophenolic Acid; Basiliximab; Adrenal Cortex Hormones

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

trialandresults.registries@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2010
• First Posted: March 2, 2010
• Study Start: September 1, 2009
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: March 18, 2014
• Results First Posted: March 18, 2014

Record last verified: 2014-01

Locations

FR (23)