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Renal Interstitial FibrosisPhase 3CERTITEMNCT01079143

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

A Phase 3 study testing Certican®, Neoral and Myfortic in people with Renal Interstitial Fibrosis, run by Novartis Pharmaceuticals at 23 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 19 to 75 years
Conditions the study is for
Renal Interstitial Fibrosis
What is being tested?
Certican®, Neoral and Myfortic
Could I receive a placebo?
No, everyone receives an active treatment
How many people
194 participants
Where
23 sitesFrance
Study dates
Sep 2009to Jun 2012
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 31Show fewer
  • 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.

Trial locations and contacts

23 sites in 1 country.

23 sites in 1 country

France23 sites

  • Novartis Investigative Site

    Amiens Cedex1, 80054

  • Novartis Investigative Site

    Angers, France, 49 033

  • Novartis Investigative Site

    Bordeaux, 33076

  • Novartis Investigative Site

    Brest, 29200

  • Novartis Investigative Site

    Caen, Cedex, 14033

  • Novartis Investigative Site

    Créteil, 94010

  • Novartis Investigative Site

    Grenoble, 38043

  • Novartis Investigative Site

    Le Kremlin-Bicêtre, 94275

  • Novartis Investigative Site

    Lille, 59037

  • Novartis Investigative Site

    Lyon, 69 437

  • Novartis Investigative Site

    Nice, 06602

  • Novartis Investigative Site

    Paris, 75015

  • Novartis Investigative Site

    Paris, 75475

  • Novartis Investigative Site

    Paris, 75970

  • Novartis Investigative Site

    Pierre-Bénite, 69495

  • Novartis Investigative Site

    Poitiers, 86000

  • Novartis Investigative Site

    Reims, 51092

  • Novartis Investigative Site

    Saint-Priest-en-Jarez, 42277

  • Novartis Investigative Site

    Strasbourg, 67091

  • Novartis Investigative Site

    Suresnes, France, 92150

  • Novartis Investigative Site

    Toulouse, 31054

  • Novartis Investigative Site

    Tours, 37044

  • Novartis Investigative Site

    Vandoeuvre Les Nancys, 54511

Other trials in France

About this study

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

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

Being tested
Certican®, Neoral, Myfortic, Simulect®, Corticosteroids
Keywords
De Novo renal transplantation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Certican®Drug

    Also called Everolimus, RAD001

    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.

  • NeoralDrug

    Also called Cyclosporine

    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.

  • MyforticDrug

    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®Drug

    Also called basiliximab

    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.

  • CorticosteroidsDrug

    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.

Study groups in NCT01079143
Study groupRoleWhat they receive
Certican EMT+ExperimentalPatients 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®.
Receives: Drug: Certican®; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids
Certican EMT-ExperimentalPatients 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®.
Receives: Drug: Certican®; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids
Neoral EMT+Active comparatorBetween transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Receives: Drug: Neoral; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids
Neoral EMT-Active comparatorBetween transplantation and randomization, all patients have received Neoral®. Treatment had to be initiated within 24 hours post-transplantation in combination with Myfortic®.
Receives: Drug: Neoral; Drug: Myfortic; Drug: Simulect®; Drug: Corticosteroids

What is being measured

The primary outcome is the main question the study is designed to answer.

  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)

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

Secondary outcomes (17)

  1. Interstitial Fibrosis/Tabular Atrophy (IF/TA)

    Incidence and severity of IF/TA according to 2005/2007 Banff classification system grades (grades l to lll). IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (<25%), grade II (25-50%) and grade III (>50% of lesions).

    Measured: M3 and M12 post transplantation

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

    Difference (M12 - M3) in IF/TA grade. IF/TA grade was assessed during centralized reading according to the Banff 2005/2007 classification comprising grade I (<25%), grade II (25-50%) and grade III (>50% of lesions).

    Measured: M3 and M12 post transplantation

  3. Risk Factors of IF/TA Progression

    Composite factors regarding fibrosis progression at 12 months using a logistic regression model; the parameters initially considered concerned the demographic characteristics of both recipient and donor, transplantation characteristics, hypertension, diabetes, study treatments, immunosuppression, EMT, IF/TA, function at M3, the onset of acute rejection, the presence of anti-donor antibodies at M12, infections and BK virus viremia.

    Arteriolar hyaline thickening is thickening of the walls of arterioles by the deposition of homogeneous pink hyaline material.

    BPAR is biopsy proven acute rejection. TEM progression is the increase ≥ 1 of TEM score between Month 3 and Month 12

    Measured: M12 post transplantation

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

    Percentage of IF measured by numerical quantification. The IF percentage was transposed in grade according to the following rule: grade 0 for an IF % ≤5%, grade I for an IF % ranging from >5% to < 25%, grade II for an IF % ranging from 25 to 50%, grade III for an IF % >50%. Interstitial graft fibrosis has been identified as the primary cause of graft loss following death with a functional graft [3-5].

    Measured: M3 and M12 post transplantation

  5. Number of Participants With Progression of Renal Fibrosis Using Numerical Quantification

    Comparisons according to epithelial-mesenchymal transition (EMT) profile and immunosuppressive treatment

    Measured: M3 to M12 post transplantation

  6. Number of Participants With Epithelial-mesenchymal Transition (EMT) Status

    Incidence and severity of EMT status. EMT status was determined centrally using the graft biopsy taken at 3 months. The result was quickly obtained (within 7 to 15 days) and sent to the company in charge of randomization in order to allocate each patient to a treatment group and to provide the investigator with this information without confirming EMT status.

    Measured: M3 and M12 post transplantation

  7. Number of Participants With Epithelial-mesenchymal Transition (EMT) Score

    Incidence and severity of EMT score. The intensity of EMT markers expression present and detectable in the renal graft at an early stage following transplantation is known as EMT score.

    EMT score 0 (the best): <1 EMT score 1 (the better): 1-10% of tubular atrophy EMT score 2: 10-25% of tubular atrophy EMT score 3: 25-50% of tubular atrophy EMT score 4 (the worst): >50% of tubular atrophy

    Measured: M3 and M12 post transplantation

  8. Change in EMT Score

    Change (M12 - M3) in EMT Score. Progression in EMT score is defined as an increase by >=1 of EMT score from M3 to M12.

    EMT score 0 (the best): <1 EMT score 1 (the better) : 1-10% of tubular atrophy EMT score 2 : 10-25% of tubular atrophy EMT score 3 : 25-50% of tubular atrophy EMT score 4 (the worst): >50% of tubular atrophy

    Measured: M3 and M12 post transplantation

  9. Incidence (Number) of Subclinical Rejections and Borderline Lesions

    Incidence of subclinical rejections and borderline lesions with regards to histological evidence of rejection with clinical findings.

    Subclinical rejections: rejection without clinical symptoms which is diagnosed by chance when a graft biopsy is performed.

    Clinically suspected BPAR: rejection suspected because of the presence of clinical symptoms (fever, pain, increase of creatinine) and then confirmed by the graft biopsy.

    Borderline lesions: suspicious for acute T-cell mediated rejection. This category is used when no intimal arteritis is present, but there are foci of tubulitis with minor interstitial infiltration or interstitial infiltration with mild tubulitis.

    Measured: M3

  10. Change From Baseline (M3) in Estimated Glomerular Filtration Rate (eGFR)

    eGFR was calculated according to the abbreviated Modification of Diet in Renal Disease (MDRD) Formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²).

    LOCF = Last observation carried forward

    Measured: M3 (baseline) to M12 post transplantation

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

    The average patient renal function was evaluated on the basis of eGFR was calculated according to the abbreviated MDRD formula and creatinine clearance according to the Cockcroft-Gault formula (mL/min/1.73m²).

    Measured: Baseline (M3), M12

  12. Change in Urine Protein/Creatinine Ratio (Without Imputation)

    One of the factors associated with EMT progression between M3 and M12 according to univariate analysis (ITT biopsies M3 \& M12).

    Measured: Month 3 (baseline), Month 12

  13. Treatment Failures

    A treatment failure is defined as biopsy proven acute rejection (BPAR), a graft loss, a death or a loss to follow up. It was assessed between randomization and 6 and 12 months post-transplantation.

    Measured: M6 and M12 post transplantation

  14. Type of Biopsy Proven Acute Rejection (BPAR)

    A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system.

    Biopsy graded IA: Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Biopsy grade IB: Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising > 25% of the lumenal area.

    Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation).

    Measured: M6 and M12 post transplantation

  15. Severity of BPAR

    A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system.

    Biopsy graded IA: Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Biopsy grade IB: Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells).

    Biopsy grade IIA: Mild to moderate intimal arteritis. Biopsy graded IIB: Severe intimal arteritis comprising > 25% of the lumenal area.

    Biopsy graded III: Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation).

    Measured: M6 and M12 post transplantation

  16. Incidence (Number) of BPAR

    A biopsy proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB or III as per 2005/2007 Banff histological classification system.

    Measured: M6 and M12 post transplantation

  17. Incidence (Number) of Participants With Graft Losses

    If a participant underwent a graft nephrectomy, then the day of nephrectomy was considered as the day of graft loss.

    Measured: M6 and M12 post transplantation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Mar 2010 (estimated)
  2. Study startSep 2009
  3. Primary completionJun 2012
  4. Study completionJun 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
194 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01079143
Sponsor's protocol ID
CRAD001AFR10
Other IDs
2009-011473-33, 2009
Acronym
CERTITEM
Status last verified
Jan 2014
First submitted
1 Mar 2010
Last updated
18 Mar 2014

Publications

  • Truchot A, Lombardi Y, Raynaud M, Aubert O, Divard G, Thalamas T, Astor B, Mandelbrot D, Parajuli S, Newell KA, Larsen CP, Karadkhele G, Orandi B, Friedewald JJ, Gupta G, Akalin E, Jordan SC, Matas AJ, Molnar MZ, Yamauchi J, Fornadi K, Bentall AJ, Stegall MD, Mannon RB, Segev DL, Huang E, Fitzsimmons WE, Loupy A. Performance of the Integrative Box (iBox) Prognostication System in African American Kidney Transplant Recipients. J Am Soc Nephrol. 2026 Sep 10. doi: 10.1681/ASN.0000001247. Online ahead of print.

    PubMed 42720987

  • 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.

    PubMed 31530561

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Certican®, Neoral and Myfortic in people with Renal Interstitial Fibrosis, run by Novartis Pharmaceuticals at 23 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 23 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Mar 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Progression of Renal Graft Fibrosis (Primary Comparison - ITT Population (time frame: Month 3 (M3) and Month 12 (M12) post transplantation). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01079143, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2014.

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