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

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

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.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: Myfortic; Drug: Sandimmun Optoral; Drug: Simulect®; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Actual): 802
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • 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, Germany, 30625
    • Novartis Investigative Site
  • Hannover Muenden, Germany, 34346
    • 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
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Enteric Coated Mycophenolate Sodium; Drug: Sandimmun Optoral; 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level; Other Names: 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 Names: 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: 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 Names: Enteric Coated Mycophenolate Sodium; Drug: Sandimmun Optoral; 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level; Other Names: Cyclosporine A; 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 Names: Certican
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: Sandimmun Optoral; 1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level; Other Names: Cyclosporine A; 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 Names: Certican

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Sommerer C, Witzke O, Lehner F, Arns W, Reinke P, Eisenberger U, Vogt B, Heller K, Jacobi J, Guba M, Stahl R, Hauser IA, Kliem V, Wuthrich RP, Muhlfeld A, Suwelack B, Duerr M, Paulus EM, Zeier M, Porstner M, Budde K; ZEUS and HERAKLES study investigators. Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials. BMC Nephrol. 2018 Sep 19;19(1):237. doi: 10.1186/s12882-018-1031-1.
• Budde K, Zeier M, Witzke O, Arns W, Lehner F, Guba M, Jacobi J, Kliem V, Reinke P, Hauser IA, Vogt B, Stahl R, Rath T, Duerr M, Paulus EM, May C, Porstner M, Sommerer C; HERAKLES Study Group. Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial. Nephrol Dial Transplant. 2017 Jun 1;32(6):1060-1070. doi: 10.1093/ndt/gfx075.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: August 9, 2007
• First Submitted That Met QC Criteria: August 9, 2007
• First Posted (ESTIMATE): August 10, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): January 18, 2017
• Last Update Submitted That Met QC Criteria: November 21, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: kidney transplantation; Everolimus; mycophenolate; CNI-free
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Everolimus; Basiliximab; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ADE13; 2006-007021-32