Full title of the trial : Multi-center, open-label, prospective, randomized, parallel group study investigating a CNI-free regimen with Myfortic® and Certican® in comparison to standard therapy with Myfortic® and Sandimmun® Optoral in de novo renal transplant patients - ZEUS

• Register: EUCTR
• Last refreshed on: 3 December 2012
• Main ID: EUCTR2004-004346-40-DE
• Date of registration: 08/03/2005
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma GmbH
• Public title: Full title of the trial : Multi-center, open-label, prospective, randomized, parallel group study investigating a CNI-free regimen with Myfortic® and Certican® in comparison to standard therapy with Myfortic® and Sandimmun® Optoral in de novo renal transplant patients - ZEUS
• Scientific title: Full title of the trial : Multi-center, open-label, prospective, randomized, parallel group study investigating a CNI-free regimen with Myfortic® and Certican® in comparison to standard therapy with Myfortic® and Sandimmun® Optoral in de novo renal transplant patients - ZEUS
• Date of first enrolment: 02/05/2005
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-004346-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Germany

Key inclusion & exclusion criteria

Inclusion criteria:
- 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 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.

To be fulfilled at Baseline 2 (prior to randomization)
In addition to the above criteria the following must be met at BL2 prior to randomization.

- Patients have to be on an immunosuppressive regimen with Myfortic® (target dose: 1440 mg/day, if tolerated; minimal dose: 720 mg/day), Sandimmun® Optoral, and corticosteroids.
- Patients with an actual serum creatinine = 3.0 mg/dl
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 and < 65 years
- 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
- Patients with any known hypersensitivity to Simulect®, Certican®, mycophenolic acid, cyclosporine A, other drugs similar to Certican® (e.g., macrolides), or other components of the formulations (e.g. lactose)
- Patients who have received an investigational immunosuppressive drug within four weeks prior to study entry (Baseline visit 1)
- Patients with thrombocytopenia (platelets < 75,000/mm³), with an absolute neutrophil count of < 1,500/mm³ or leucopenia (leucocytes < 2,500/mm³), or hemoglobin < 6 g/dL
- Patients with symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, who are unlikely to comply with the study requirements, or who are unable to give informed consent
- Patients with a history of malignancy during the last five years, except squamous or basal cell carcinoma of the skin
- Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C virus positive. Recipients of organs from donors who test positive for Hepatitis B surface antigen or Hepatitis C are excluded.
- Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin > 3 times UNL)
- Presence of a clinically significant infection requiring continued therapy, severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus that in the opinion of the investigator would interfere with the appropriate conduct of the study
- Patients receiving drugs known to interact with CsA and/or everolimus according to the list provided in Appendix 3 to this protocol.

To be fulfilled at Baseline 2 (prior to randomization)
In addition to the above criteria the following must be met at BL2 prior to randomization.

- Graft loss or death
- Changes to the immunosuppressive regimen prior to randomization due to immunologic reasons.
- Patients who suffered from severe rejection (more than or equal to BANFF II acute rejection), recurrent acute rejection, or steroid resistant acute rejection.
- Patients with thrombocytopenia (platelets < 75,000/mm³), with an absolute neutrophil count of < 1,500/mm³ or leucopenia (leucocytes < 2,500/mm³), or hemoglobin < 6 g/dL
- Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin > 3 times ULN)
- Proteinuria > 1g/day
- Dialysis dependency at randomization visit (Visit 5, BL2).
- Patients with clinically significant infection requiring continued therapy which would interfere with the objectives of the study
- Presence of intractable immunosuppressant complications or side effects (e.g., severe gastrointestinal adverse events) at randomization visit (Visit 5, BL2)



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

de novo kidney transplantation (cadaveric, living unrelated or living related)
MedDRA version: M15 Level: LLT Classification code 10023438

Intervention(s)

Trade Name: Certican 0.5mg Tabletten
Product Name: Certican Tabletten
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
Current Sponsor code: RAD001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Certican 0.75mg Tabletten
Product Name: Certican Tabletten
Pharmaceutical Form: Tablet
INN or Proposed INN: Everolimus
Current Sponsor code: RAD001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.75-

Trade Name: Sandimmun Optoral 10 mg Kapseln
Product Name: Sandimmun Optoral
Pharmaceutical Form: Capsule*
INN or Proposed INN: Ciclosporin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: Sandimmun Optoral 25 mg Kapseln
Product Name: Sandimmun Optoral
Pharmaceutical Form: Capsule*
INN or Proposed INN: Ciclosporin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: Sandimmun Optoral 50 mg Kapseln
Product Name: Sandimmun Optoral
Pharmaceutical Form: Capsule*
INN or Proposed INN: Ciclosporin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Sandimmun Optoral 100 mg Kapseln
Product Name: Sandimmun Optoral
Pharmaceutical Form: Capsule*
INN or Proposed INN: Ciclosporin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Primary end point(s): Renal function assessed as glomerula filtration rate (GFR) – Nankivell method – 12 months after renal transplantation

Secondary Objective: - To assess renal function by GFR – Cockcroft-Gault and MDRD method – at Month 12 post Tx
- To assess efficacy (biopsy proven acute rejection, graft loss, death) at Month 6 and 12
- To assess occurrence of treatment failures up to or at Month 12, while treatment failure is defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up and discontinuations due to lack of efficacy or toxicity or conversion to another regimen (at least one condition must be present)
- To assess evolution of renal function between Month 4.5 and 12 (creatinine slope)
- To assess safety and tolerability at Month 4.5 and 12 (acc. to safety parameters specified in chapter 7.5)
- To assess changes in cardiovascular risk (according to Framingham Score) between Month 4.5 and 12

Main Objective: The primary objective of this trial is to show superiority of a CNI-free regimen with respect to the renal function at Month 12 post Tx assessed by glomerular filtration rate – Nankivell method – as compared to the standard CNI-based regimen in de novo renal transplant patients.

Secondary ID(s)

CRAD001A2418