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Study Investigating a Standard Regimen in de Novo Kidney Transplant Patients Versus a Calcineurin Inhibitor (CNI)-Free Regimen and a CNI-low Dose Regimen

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00514514
First received: August 9, 2007
Last updated: November 21, 2016
Last verified: November 2016
  Purpose
The purpose of this study is to compare renal function of immunosuppressive regimens with different relevance of the calcineurin inhibitor (CNI) cyclosporine: standard dose CNI, low dose CNI, CNI free in de novo kidney transplant patients after 12 months of therapy.

Condition Intervention Phase
Kidney Transplantation
Drug: Everolimus
Drug: Myfortic
Drug: Sandimmun Optoral
Drug: Simulect®
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Multi-center, Open-label, Prospective, Randomized, Parallel Group, Long-term Study Investigating a Standard Regimen in de Novo Kidney Transplant Patients Versus a CNI-free Regimen and a CNI-low Dose Regimen

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen [ Time Frame: From randomization at BL2 (Month 3) to Month 12 post-transplant ]
    Demonstrate superiority of CNI-Free vs Standard Regimen in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. P-values are not adjusted


Secondary Outcome Measures:
  • GFR Via Nankivell Formula at Month 12 - All Regimens [ Time Frame: From randomization at BL2 (Month 3) to Month 12 post-transplant ]
    Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.

  • GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method [ Time Frame: From randomization at BL2 (Month 3) to Month 12 post-transplant ]

    Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat:

    For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.


  • GFR at Month 12 Utilizing Cockcroft-Gault Formula [ Time Frame: From randomization at BL2 (Month 3) to Month 12 post-transplant ]
    Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

  • Mean Change in Serum Creatinine From Month 3 to Month 12 [ Time Frame: From randomization at BL2 (Month 3) to Month 12 post-transplant ]
    Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

  • Efficacy Event Data From Baseline 2 (Month 3) to Month 6 [ Time Frame: From Baseline 2 (Month 3) to Month 6 ]
    Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).

  • Efficacy Event Data Baseline 2 (Month 3) to Month 12 [ Time Frame: From Baseline 2 (Month 3) to Month 12 ]
    Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).

  • Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) [ Time Frame: From Baseline 2 (Month 3) to Month 12 ]
    The Framingham Score (based on LDL cholesterol level) estimates the coronary heart disease risk (%) of developing one of the following coronary heart diseases: angina pectoris, myocardial infarction, or coronary disease death, over the course of 10 years.

  • GFR Calculated Via Nankivell Formula at Month 60 [ Time Frame: From randomization at BL2 (Month 3) to Month 60 ]
    Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.

  • GFR at Month 60 Utilizing Cockcroft-Gault Formula [ Time Frame: From randomization at BL2 (Month 3) to Month 60 post-transplant ]
    Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl) For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

  • GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method [ Time Frame: From randomization at BL2 (Month 3) to Month 60 post-transplant ]

    Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat:

    For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.


  • Mean Change in Serum Creatinine From Month 3 to Month 60 [ Time Frame: From randomization at BL2 (Month 3) to Month 60 post-transplant ]
    Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

  • Efficacy Event Data After Month 12 to Month 60 [ Time Frame: Events starting after Month 12 ]
    Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).


Enrollment: 802
Study Start Date: July 2007
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: CNI standard regimen
Myfortic, Sandimmun Optoral and corticosteroids
Drug: Myfortic

1 tablet containing 180 mg or 360 mg

Dosing schedule:

Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen) According to blood level 1440 mg/day (2 x 720 mg), if tolerated. Dose reduction possible in case of side effects (min. dose at BL2 (Month 3): 720 mg/day)

Other Name: Enteric Coated Mycophenolate Sodium
Drug: Sandimmun Optoral
1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level
Other Name: Cyclosporine A
Drug: Simulect®
Lyophilisate in vials with ampoules of sterile water for injection (5 ml). Dosing: 1 vial containing 20 mg lyophilisate. Dosing schedule: 2 x 20 mg to be applied as 10 sec. bolus injection, i.v. on Day 0 (2 h before transplant) and on Day 4
Other Name: Basiliximab
Experimental: CNI free regimen

CNI free regimen: comprising the following steps for switching treatment:

Step 1 at BL2 + 1 day: Myfortic, Certican 1.5 mg, Sandimmun Optoral (50% of standard dose) and corticosteroids Step 2 at BL2 + 8 days: Myfortic, Certican 3 mg and corticosteroids

Drug: Everolimus
Tablet containing 0.5 mg or 0.75 mg. Dosing schedule: Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen
Other Name: Certican
Drug: Myfortic

1 tablet containing 180 mg or 360 mg

Dosing schedule:

Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen) According to blood level 1440 mg/day (2 x 720 mg), if tolerated. Dose reduction possible in case of side effects (min. dose at BL2 (Month 3): 720 mg/day)

Other Name: Enteric Coated Mycophenolate Sodium
Drug: Sandimmun Optoral
1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level
Other Name: Cyclosporine A
Active Comparator: CNI low regimen

CNI low regimen: comprising the following steps for switching treatment:

Step 1 at BL2 + 1 day: Certican 1.5 mg, Sandimmun Optoral and corticosteroids Step 2 at BL2 + 8 days: Certican 1.5 mg, Sandimmun Optoral (low dose) and corticosteroids

Drug: Everolimus
Tablet containing 0.5 mg or 0.75 mg. Dosing schedule: Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen
Other Name: Certican
Drug: Sandimmun Optoral
1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level
Other Name: Cyclosporine A

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Males or females, aged 18 - 70 years
  • Recipients of de novo cadaveric, living unrelated or living related kidney transplants
  • Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, and are required to practice an approved method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility.
  • Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.

Exclusion criteria

  • More than one previous renal transplantation
  • Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney
  • Patients receiving a kidney from a non-heart beating donor
  • Donor age: < 5 years or > 70 years
  • Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation)
  • Other protocol-defined inclusion/exclusion criteria may apply
  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: NCT00514514

Locations
Germany
Novartis Investigative Site
Aachen, Germany, 52074
Novartis Investigative Site
Berlin, Germany, 10117
Novartis Investigative Site
Berlin, Germany, 13353
Novartis Investigative Site
Erlangen, Germany, 91054
Novartis Investigative Site
Essen, Germany, 45122
Novartis Investigative Site
Frankfurt am Main, Germany, 60596
Novartis Investigative Site
Freiburg, Germany, 79106
Novartis Investigative Site
Hamburg, Germany, 20246
Novartis Investigative Site
Hannover Muenden, Germany, 34346
Novartis Investigative Site
Hannover, Germany, 30625
Novartis Investigative Site
Heidelberg, Germany, 69120
Novartis Investigative Site
Kaiserslautern, Germany, 67655
Novartis Investigative Site
Koeln, Germany, 51109
Novartis Investigative Site
Lubeck, Germany, 23538
Novartis Investigative Site
Munchen, Germany, 81377
Novartis Investigative Site
München, Germany, 81675
Novartis Investigative Site
Regensburg, Germany, 93053
Switzerland
Novartis Investigative Site
Bern, Switzerland, 3010
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Study Director: Novartis Novartis
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00514514     History of Changes
Other Study ID Numbers: CRAD001ADE13
2006-007021-32
Study First Received: August 9, 2007
Results First Received: June 3, 2016
Last Updated: November 21, 2016

Keywords provided by Novartis:
Everolimus
mycophenolate
CNI-free
kidney transplantation

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

ClinicalTrials.gov processed this record on April 24, 2017