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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Everolimus
* Drug: Myfortic
* Drug: Sandimmun Optoral
* Drug: Simulect®


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CNI standard regimen<br>Myfortic, Sandimmun Optoral and corticosteroids | Drug: Myfortic<br>* 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)<br>* Other names: Enteric Coated Mycophenolate Sodium;Drug: Sandimmun Optoral<br>* 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level<br>* Other names: Cyclosporine A;Drug: Simulect®<br>* 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<br>* Other names: Basiliximab;|
| Experimental: CNI free regimen<br>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<br>* 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<br>* Other names: Certican;Drug: Myfortic<br>* 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)<br>* Other names: Enteric Coated Mycophenolate Sodium;Drug: Sandimmun Optoral<br>* 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level<br>* Other names: Cyclosporine A;|
| Active Comparator: CNI low regimen<br>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<br>* 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<br>* Other names: Certican;Drug: Sandimmun Optoral<br>* 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level<br>* Other names: Cyclosporine A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen | 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 | From randomization at BL2 (Month 3) to Month 12 post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GFR Via Nankivell Formula at Month 12 - All Regimens | 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. | From randomization at BL2 (Month 3) to Month 12 post-transplant | 
| GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 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. | From randomization at BL2 (Month 3) to Month 12 post-transplant | 
| GFR at Month 12 Utilizing Cockcroft-Gault Formula | 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 | From randomization at BL2 (Month 3) to Month 12 post-transplant | 
| Mean Change in Serum Creatinine From Month 3 to Month 12 | Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model | From randomization at BL2 (Month 3) to Month 12 post-transplant | 
| Efficacy Event Data 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). | From Baseline 2 (Month 3) to Month 6 | 
| Efficacy Event Data 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). | From Baseline 2 (Month 3) to Month 12 | 
| Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | 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. | From Baseline 2 (Month 3) to Month 12 | 
| GFR Calculated Via Nankivell Formula at 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. | From randomization at BL2 (Month 3) to Month 60 | 
| GFR at Month 60 Utilizing Cockcroft-Gault Formula | 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 | From randomization at BL2 (Month 3) to Month 60 post-transplant | 
| GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 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. | From randomization at BL2 (Month 3) to Month 60 post-transplant | 
| Mean Change in Serum Creatinine From Month 3 to Month 60 | Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model | From randomization at BL2 (Month 3) to Month 60 post-transplant | 
| Efficacy Event Data After Month 12 to Month 60 | 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). | Events starting after Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Everolimus, mycophenolate, CNI-free, kidney transplantation