Efficacy and Safety of Everolimus With Enteric-Coated Mycophenolate Sodium (EC-MPS) in a Cyclosporine Microemulsion-free Regimen Compared to Standard Therapy in de Novo Renal Transplant Patients

NCT00154310 | Completed Phase 4 Results

• 1 other identifier: CRAD001A2418
• Study Type: interventional
• Target: 300
• Locations: 2 countries
• Sites: 3

Brief Summary

The purpose of this study is to assess whether a calcineurin inhibitor (CNI)-free regimen with enteric-coated mycophenolate sodium (EC-MPS) and everolimus is as safe and well-tolerated as the standard regimen containing enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion, but results in better renal function.

Conditions

Renal Transplantation

Keywords

Renal transplantation, everolimus, immunosuppressants, CNI-free

Outcome Measures

Primary Outcomes (1)

• Renal Function (Nankivell Formula) at Month 12 Post Transplantation.

  Renal function at the end of the trial assessed as mean absolute values of the glomerular filtration rate (GFR) calculated by Nankivell formula 12 months after renal transplantation. The Nankivell formula: GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)\^2 + C ; where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. Estimated GFR is expressed in mL/min per 1.73m\^2.

  at Month 12 post transplantation

Secondary Outcomes (4)

• Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death

  Up to Month 12

• Number of Participants With Occurrence of Treatment Failures

  up to or at Month 12

• Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12

  Month 4.5 and Month 12

• Number of Participants Who Experienced an Adverse Event or Serious Adverse Event

  Aes from end of core study period (month 12) to end of follow-up period (month 60)

Study Arms (2)

Everolimus + Mycophenolate sodium

EXPERIMENTAL

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Drug: Everolimus; Drug: Enteric-coated mycophenolate sodium; Drug: Corticosteroids

Cyclosporine + Mycophenolate sodium

ACTIVE COMPARATOR

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Drug: Cyclosporine; Drug: Enteric-coated mycophenolate sodium; Drug: Corticosteroids

Interventions

Everolimus DRUG

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL.

Also known as: certican

Everolimus + Mycophenolate sodium

Cyclosporine DRUG

Tablets orally twice a day to maintain protocol specific target blood levels

Also known as: Sandimmun Optoral

Cyclosporine + Mycophenolate sodium

Enteric-coated mycophenolate sodium DRUG

Enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day.

Also known as: Myfortic

Cyclosporine + Mycophenolate sodium; Everolimus + Mycophenolate sodium

Corticosteroids DRUG

Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Cyclosporine + Mycophenolate sodium; Everolimus + Mycophenolate sodium

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or females, aged 18 - 65 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 BL 1, 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
• Of all patients included into the study at BL 1 (prior to transplantation), those who continued into the randomized study period had to meet the following condition at BL 2, prior to randomization:
• Patients had to be on an immunosuppressive regimen with EC-MPS (target dose; 1440 mg/day, if tolerated; minimal dose: 720 mg/day), cyclosporine and corticosteroids
• Patients with an actual serum creatinine =\< 3.0 mg/dl

You may not qualify if:

• More than one previous renal transplantation
• Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney
• Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation)
• Patients who are recipients of A-B-O incompatible transplants
• Patients with a historical or current peak PRA of \> 25%
• Patients with already existing antibodies against the HLA-type of the receiving transplant
• Females of childbearing potential who are planning to become pregnant, who are pregnant and/or lactating, who are unwilling to use effective means of contraception
• Of all patients included into the study at BL 1 (prior to transplantation), those who met one or more of the following criteria at BL 2, prior to randomization, should not continue into the randomized study period:
• Graft loss or death
• Changes to the immunosuppressive regimen prior to randomization due to immunologic reasons
• Patients who suffered from severe rejection (\>= BANFF II acute rejection), recurrent acute rejection, or steroid resistant acute rejection
• Proteinuria \> 1g/day

Sponsors & Collaborators

• Novartis: lead

Study Sites (3)

Novartis Investigational Sites

Nuremberg, Germany

Location

Novartis Pharma AG

Basel, Switzerland

Location

Novartis Investigational Sites

Bern, Switzerland

Location

Related Publications (4)

• 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.

  PMID: 30231851 DERIVED

• Eisenberger U, Budde K, Lehner F, Sommerer C, Reinke P, Witzke O, Wuthrich RP, Stahl R, Heller K, Suwelack B, Muhlfeld A, Hauser IA, Nadalin S, Porstner M, Arns W; ZEUS Study Investigators. Histological findings to five years after early conversion of kidney transplant patients from cyclosporine to everolimus: an analysis from the randomized ZEUS study. BMC Nephrol. 2018 Jun 28;19(1):154. doi: 10.1186/s12882-018-0950-1.

  PMID: 29954336 DERIVED

• Lehner F, Budde K, Zeier M, Wuthrich RP, Reinke P, Eisenberger U, Muhlfeld A, Arns W, Stahl R, Heller K, Witzke O, Wolters HH, Suwelack B, Klehr HU, Stangl M, Hauser IA, Nadalin S, Porstner M, May C, Paulus EM, Sommerer C; ZEUS Study Investigators. Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study. Transpl Int. 2014 Nov;27(11):1192-204. doi: 10.1111/tri.12411. Epub 2014 Aug 20.

  PMID: 25070687 DERIVED

• Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F; ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011 Mar 5;377(9768):837-47. doi: 10.1016/S0140-6736(10)62318-5. Epub 2011 Feb 19.

  PMID: 21334736 DERIVED

MeSH Terms

Interventions

Everolimus; Cyclosporine; Mycophenolic Acid; Adrenal Cortex Hormones

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis

  Novartis

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2005
• First Posted: September 12, 2005
• Study Start: June 1, 2005
• Primary Completion: September 1, 2008
• Study Completion: September 1, 2008
• Last Updated: November 13, 2013
• Results First Posted: May 24, 2011

Record last verified: 2013-10

Locations

CH (2); DE (1)