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A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With EC-MPS Compared to Standard Treatment Combination Tacrolimus and EC-MPS in de Novo Liver Transplant Recipients (SIMCER)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01625377
First received: June 19, 2012
Last updated: March 25, 2016
Last verified: March 2016
  Purpose

The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS.

The renal function was estimated by glomerular filtration rate.


Condition Intervention Phase
Liver Transplantation
Drug: tacrolimus
Drug: everolimus
Drug: Basiliximab
Drug: Mycophenolic Acid
Drug: Corticosteroids
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A National, Multi-center, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Everolimus Combined With Enteric-coated Mycophenolate Sodium Compared to the Standard Treatment Combining Tacrolimus and Enteric-coated Mycophenolate Sodium in de Novo Liver Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline (Randomization) in Renal Function [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]

    Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula.

    GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.



Secondary Outcome Measures:
  • Number of Patients With Treatment Failures [ Time Frame: At week 12 and week 24 ] [ Designated as safety issue: No ]

    Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification >3, graft loss or death at 6 months.

    Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.

    The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.


  • Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) [ Time Frame: at 12 week and 24 week ] [ Designated as safety issue: No ]
    Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.

  • Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification [ Time Frame: at 12 week and 24 week ] [ Designated as safety issue: No ]

    Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.

    The severity of BPAR was categorized as :

    Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.


  • Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]

    Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.

    The patients with treated or untreated BPAR having RAI score > 3 were reported in this end point.


  • Number of Patients With Death or Graft Loss [ Time Frame: at week 24 ] [ Designated as safety issue: No ]
    The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.

  • Change From Baseline (Randomization) in Serum Creatinine [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]

    Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function.

    Baseline was Day 28 visit.


  • Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio [ Time Frame: Baseline, week 24 ] [ Designated as safety issue: No ]
    Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.

  • Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit.

  • Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]

    Change in glomerular filtration rate was calculated using the MDRD abbreviated formula.

    GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.


  • Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]

    GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula:

    eGFR (mL/min/1.73m^2) = 141 * min(C/K,1)^ α * max(C/K,1)^-1.209 * 0.993^A * 1.1018 (if male) * 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit.


  • Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System [ Time Frame: At Week 24 ] [ Designated as safety issue: No ]

    Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m^2) :

    Stage 1 : GFR >= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was < 15 (or dialysis)


  • Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: Yes ]
    Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.


Enrollment: 188
Study Start Date: December 2012
Study Completion Date: March 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tacrolimus
From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids
Drug: tacrolimus
Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.
Other Name: Prograf®
Drug: Basiliximab
Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4
Other Name: Simulect®
Drug: Mycophenolic Acid
Dose of 1440 mg/day from transplantation to month 6 post- transplantation
Other Name: Myfortic®
Drug: Corticosteroids
Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice
Experimental: Everolimus (RAD001)

From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids.

From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).

Drug: tacrolimus
Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.
Other Name: Prograf®
Drug: everolimus
Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation
Other Name: Certican® / RAD001
Drug: Basiliximab
Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4
Other Name: Simulect®
Drug: Mycophenolic Acid
Dose of 1440 mg/day from transplantation to month 6 post- transplantation
Other Name: Myfortic®
Drug: Corticosteroids
Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver

Key Exclusion Criteria:

  • Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant
  • Recipient of a liver from a living donor or cadaveric non heart beating donor
  • ABO incompatible transplant graft
  • Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis
  • Estimated glomerular filtration rate ≤ 30ml/min at selection
  • History of malignancy within the 5 past years, other than non-metastatic basal or squamous cell carcinoma and hepatocellular carcinoma
  • Alpha-foeto-protein > 1000 ng/ml (only in case of hepatocellular carcinoma)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01625377

Locations
France
Novartis Investigative Site
Besancon cedex, France, 25030
Novartis Investigative Site
Bordeaux Cedex, France, 33076
Novartis Investigative Site
Chambray les Tours, France, 37044
Novartis Investigative Site
Clichy, France, 92110
Novartis Investigative Site
Creteil, France, 94010
Novartis Investigative Site
Grenoble, France, 38043
Novartis Investigative Site
Lille Cedex, France, 59037
Novartis Investigative Site
Marseille, France, 13385
Novartis Investigative Site
Montpellier, France, 34295
Novartis Investigative Site
Nice, France, 06202
Novartis Investigative Site
Paris Cedex 13, France, 75651
Novartis Investigative Site
Rennes Cedex, France, 35033
Novartis Investigative Site
Toulouse Cedex 4, France, 31054
Novartis Investigative Site
Villejuif, France, 94800
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01625377     History of Changes
Other Study ID Numbers: CRAD001HFR02  2012-000137-39 
Study First Received: June 19, 2012
Results First Received: March 25, 2016
Last Updated: March 25, 2016
Health Authority: France: L'Agence nationale de sécurité du médicament et des produits de santé (ANSM)

Keywords provided by Novartis:
Everolimus,
liver transplantation,
early introduction,
renal function

Additional relevant MeSH terms:
Everolimus
Sirolimus
Mycophenolic Acid
Tacrolimus
Mycophenolate mofetil
Basiliximab
Antibodies, Monoclonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 02, 2016