| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of kidney allograft rejection |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066543 |
| E.1.2 | Term | Acute allograft rejection |
|
| 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 |
1) To compare the incidence of clinical biopsy-proven acute rejection (BPAR) (as interpreted by the central blinded pathologist) of combination regimens of CP-690,550 and mycophenolate mofetil (MMF) / mycophenolate sodium (MPS) versus a cyclosporine (CsA)-based regimen in recipients of first renal allografts at Month 6 posttransplant
2) To compare glomerular filtration rate (GFR), as measured by iohexol serum clearance, of combination regimens of CP-690,550 and MMF/MPS versus a CsA-based regimen at Month 12 posttransplant |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the safety and tolerability of combination regimens of CP-690,550 and
MMF/MPS, including adverse events, clinically significant infections, malignancies, incidence and duration of delayed graft function, safety laboratory tests and estimated GFR.
2) To compare GFR, as measured by iohexol serum clearance, of combination regimens of CP-690,550 and MMF/MPS vs a CsA-based regimen at Month 6 posttransplant
3) To compare the progression of chronic allograft lesions of combination regimens of
CP-690,550 and MMF/MPS versus a CsA-based regimen at Month 12 posttransplant
4) To evaluate the efficacy of combination regimens of CP-690,550 and MMF/MPS,
including clinical BPAR at Month 12, treated clinical acute rejection, combined Banff rejection categories, graft loss, subject death, and treatment failure
5) To evaluate the PK of CP-690,550 and mycophenolic acid
6) To evaluate the effects of CP-690,550 on lymphocyte subsets and on health outcome assessment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for enrollment into the trial:
1. Subjects must have end-stage renal disease, have been on regular renal replacement therapy (eg, dialysis) or have eGFR (estimated by the Cockcroft-Gault equation) less than or equal to 10 mL/min, and are scheduled to receive a primary kidney transplant from a deceased donor (irrespective of the number of HLA antigen mismatches), or a HLA-mismatched living donor (either living-related or living-unrelated).
2. Between the ages of 18 and 70 years, inclusive;
3. Either female (including women of childbearing potential) or male adults;
4. Subjects must have no known contraindications to the administration of IL-2 receptor antagonist induction, MMF, corticosteroids, or CsA;
5. Subjects must be willing and able to provide written informed consent with evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study;
6. Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures |
|
| E.4 | Principal exclusion criteria |
Subjects with any of the following will not be included in the trial:
1. Subjects who have current PRA >30%, or peak PRA >50% or who have undergone desensitization treatment;
2. Subjects who are recipients of or scheduled for non-renal transplants;
3. Subjects scheduled for double or en bloc kidney transplantation;
4. Subjects with evidence of active infection;
5. Subjects with clinically significant infections within the past 3 months (eg, those requiring hospitalization, or as judged by the Investigator);
6. Subjects with a first-degree relative with a history of hereditary immunodeficiency (eg, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, X-linked agammaglobinemia);
7. Subjects with a history of malignancies with the exception of excised non-metastatic basal cell carcinoma or squamous cell cancer of the skin, or adequately treated cervical carcinoma in situ (preinvasive). Subjects with a history of monoclonal gammopathy of undetermined significance (MGUS) will be excluded;
8. Subjects who have a history of allergy to iodine, betadine, iohexol or other iodinated contrast media;
9. Subjects who have a history of multiple allergies or severe allergy (eg, anaphylaxis) to any substance;
10. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of trial medication;
11. Subjects who are unwilling to refrain from consumption of grapefruit or grapefruit containing juices for the duration of trial medication period;
12. Subjects receiving or are expected to receive concomitant medications on the list of prohibited medications.
13. Subjects with known positive results of the following serological tests: HIV-1 Ab, hepatitis B virus (HBV) surface antigen (HBsAg), or anti-hepatitis C virus antibody (anti-HCV Ab).
Viral load monitoring (HBV DNA PCR and HCV RNA PCR) will be performed by the
central laboratory on a blood sample collected prior to dosing of CP-690,550 or CsA to detect active infection. Positive results in these viral load tests will require subject
discontinuation;
14. Subjects with mental dysfunction or inability to cooperate with the trial;
15. Subjects with the following laboratory parameters at screening: absolute neutrophil count (ANC) <1500/µL or hemoglobin (Hgb) <8 g/dL;
16. Subjects with any condition that may significantly affect drug absorption (eg, gastrectomy or insufficiently treated diabetic gastroenteropathy);
17. Body weight <90 lbs (<41 kg) or subjects who are morbidly obese at the time of transplant with a body mass index BMI >40.
18. [no longer applicable per Amendment #2]
19. Males who are unwilling to abstain from sexual intercourse or use a condom with pregnant or lactating women. Non-vasectomized males unwilling to use a condom in addition to having their female partner use another form of contraception such as an IUD, diaphragm with spermicide, oral contraceptive, injectable progesterone, sub-dermal implant or a tubal ligation if the female partner could become pregnant from the time of the first dose of trial medication until completion of follow-up procedures;
20. Women of childbearing potential who are either pregnant, lactating, planning to become pregnant in the next 12 months, or with a positive serum or urine pregnancy test. Women of childbearing potential must be willing to agree to contraceptive practices;
21. Subjects with evidence of clinically significant disease (eg, gastrointestinal or hepatic disorders) that places the subject at increased risk for participating in the trial and/or will confound the results of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) First clinical BPAR episode (as interpreted by the central blinded pathologist) within
6 months posttransplant. Clinical BPAR is defined as a BPAR associated with an
increase in serum creatinine of more than or equal to 0.3 mg/dL and more than or equal to 20% from pre-rejection baseline.
2) GFR, measured by iohexol serum clearance, at Month 12. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| partially blinded, open label to the sponsor |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Placebo tablet is used for blinding purposes |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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