E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prophylaxis of rejection in recipients of first or second cadaveric, living unrelated or living related kidney transplants |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main aim of the study is to confirm the hypothesis than an initially intensified dosing regimen of mycophenolic acid administered as Myfortic® during the first 6 weeks post transplantation will provide therapeutical benefit as compared to a standard dosing regimen of Myfortic®, and is as safe and well-tolerated as the standard dosing regimen of Myfortic®. |
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E.2.2 | Secondary objectives of the trial |
To compare proportion of patients with treatment failure (defined as biopsy proven rejection, graft failure or death) at days 21 and 84 post-transplantation.
To compare renal function as assessed by serum creatinine and glomerular filtration rate.
To compare safety/tolerability as the proportion of patients with Myfortic® dose reductions and interruptions due to AEs, within 6 months post-transplantation.
To explore changes in patient-reported gastro intestinal symptom burden using the Gastrointestinal Symptom Rating Scale (GSRS) total score at visits baseline, day 10, day 21, day 56, and day 84 post-transplantation.
To explore changes in patient-reported health status measured by EQ-5D in at visits baseline, day 10, day 21, day 56, day 84 and day 180 post-transplantation.
To compare the proportion of patients with treatment failure between treatment arms combining this study data with the data from CERL080ADE12 and with in-house historical data. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Pharmacokinetic substudy (18-Aug-2006)
To explore the pharmacokinetics of mycophenolic acid, mycophenolic acid glucuronide and free MPA in a subgroup of de novo renal transplant patients (in selected centers only).
2. Pharmacogenetic substudy (18-Aug-2006)
To explore the influence of uridine diphosphate-glucuronosyltranferase 1A9 (UGT1A9) and multidrug resistance protein 2 (MRP2) single nucleotide polymorphisms (SNPs) on the risk of acute rejection due to an early under-exposure in the standard Myfortic® dosing regimen versus the initially intensified Myfortic® dosing regimen as well as to explore the role of these SNPs on the risk for developing MPA-related side-effects.
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E.3 | Principal inclusion criteria |
1. Males or females, aged between 18 and 65 years 2. Recipients of first or second cadaveric, living unrelated or living related kidney transplants 3. Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 1), and are required to practice an approved method of birth control for the duration of the study and for a period of 3 months following discontinuation of study medication, even where there has been a history of infertility 4. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained
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E.4 | Principal exclusion criteria |
1. Graft loss due to immunological reasons in the first year after the first transplantation (in case of secondary transplantation) 2. Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney 3. Patients receiving a kidney from a non-heart beating donor 4. Patients who are recipients of A-B-O incompatible transplants 5. Patients with a current peak PRA of > 10% 6. Patients with already existing antibodies against the HLA-type of the receiving transplant 7. Patients with any known hypersensitivity to mycophenolic acid or cyclosporine micro-emulsion, or other components of the formulations (e.g. lactose, see also SmPCs) 8. Use of other investigational drugs or a non-protocol immunosuppressant at randomization, or within 30 days or 5 half-lives prior to randomization, whichever is longer 9. Patients with thrombocytopenia (platelets < 100,000/mm³), with an absolute neutrophil count of < 2,000/mm³ or leucopenia (leucocytes < 3,000/mm³), or hemoglobin < 6 g/dL 10. Patients with symptoms of significant 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 11. Patients with a history of malignancy during the last five years, except squamous or basal cell carcinoma of the skin 12. Patients who are HIV positive or Hepatitis B surface antigen positive. 13. Evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin > 3 times UNL) 14. 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 (see also section 8.2) 15. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, unless they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy or are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation, hysterectomy), hormonal contraception (implantable, patch, oral), and double- barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation 16. 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 17. Evidence of drug or alcohol abuse 18. Patients receiving drugs known as strong inhibitors or inducers of CsA and/or Myfortic® drug metabolism (for drug interactions see Appendix 3 to this protocol). 19. Patients with chronic bowel inflammatory disease.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the proportion of patients with treatment failure defined as biopsy-proven acute rejection (BPAR), graft loss (GFL) or death at 6 months post-transplantation.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
patient reported outcomes and quality of life |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard dose of myfortic |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 24 |