| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Maintenance of renal transplant recipients. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients who have had kidney transplant. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023439 |
| E.1.2 | Term | Kidney transplant rejection |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 primary objective is to assess the incidence of clinically-suspected
and biopsy proven acute rejection (CSBPAR) at 6 months post-transplant in de novo renal allograft recipients treated with thymoglobulin induction, rapid corticosteroid withdrawal, and maintenance belatacept in combination with EVL, or maintenance TAC in combination with MMF. |
|
| E.2.2 | Secondary objectives of the trial |
The effects of each immunosuppressant regimen on the rates of acute
rejection, subject and allograft survival and allograft function will be
evaluated as follows : The frequency and severity of acute rejection at
6, 12 and 24 months post-transplant/Rates of subject and allograft survival at 6, 12 and 24 months post-transplant/Changes in renal function and severity of proteinuria at 3, 6, 12 and 24 months post-transplant/The frequency and type of donor-specific anti-HLA antibodies (DSA) detectable prior to, and at 12 and 24 months post-transplant/The safety and tolerability of each treatment regimen, as based upon the results of vital signs and safety laboratory assessments, and cumulative rates of adverse events reported at 6, 12, and 24 months post-transplant/ The frequency of cardiovascular and metabolic co-morbidities reported at 3, 6, 12, and 24 months post-transplant. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Signed Written informed Consent, the subject or legal representative is
willing to provide signed written informed consent. Adults with endstage renal disease (ESRD) scheduled to undergo transplantation of a non-HLA identical, living or standard criteria deceased (SCD) donor
kidney; Subjects with serological evidence of prior exposure to EBV.
Evidence of prior exposure is to be determined locally by positive testing
for IgG antibodies directed against EBV firal capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA). Historical results are acceptable. •
Men and women, 18to 75 at Screening, inclusive; Women of childbearing
potential (WOCBP) must use highly effective methods of birth control to
avoid pregnancy throughout the study and for up to 8 weeks after the
study in such a manner that the risk of pregnancy is minimized;
Acceptable methods of highly effective birth control include: Condom
with spermicide, Diaphragm and spermicide, Cervical cap and
spermicide, Oral contraceptives, Intrauterine device (IUD); It should be
noted that according to the US product information for mycophenolate
mofetil (CellCept®), two reliable forms of contraception must be used
simultaneously unless abstinence is the chosen method; WOCBP must
have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of beta-human chorionic gonadotropin [β-HCG])
within 24 hours prior to the start of study medication; Women must not
be breastfeeding; Sexually active fertile men must use highly effective
birth control if their partners are WOCBP. Men who are sexually active
with WOCBP must follow instructions for birth control for the entire
duration of the study and a minimum of 8 weeks post study drug has
been completed; Women who are not of childbearing potential (ie, who
are postmenopausal or surgically sterile; see Section 3.3.3 for the
definition of WOCBP) and azoospermic men do not require
contraception. |
|
| E.4 | Principal exclusion criteria |
Subjects who are seronegative for prior exposure to EBV or those whose EBV serologic status is unknown at randomization. Genetically-identical donor recipient pairs (ie, identical twins) Subjects with a recent (within 3 months prior to transplant) PRA more than or equal to 20%. Subjects with a past history of, or current need for desensitization therapy. Subjects with previous graft loss due to acute rejection Subjects with a positive T-cell or lymphocytotoxic cross match or any detectable donor specific antibodies prior to transplantation. Recipients of kidneys from donors < 10 years old. Recipients of an extended criteria deceased donor (ECD) kidney, defined as: -Donors more than or equal to 60 years old, or -Donors aged 50 – 59 years with any 2 of the following: death from cerebrovascular accident; hypertension; serum creatinine > 1.5 mg/dL;or -Recipients of kidneys donated after cardiac death. Subjects with prior or concurrent non-renal solid organ or cell (eg, pancreas or kidneypancreas, islet transplant or stem-cell) transplants and those deemed by the Investigator as being likely to require a non-renal transplant in the
next 3 years.Subjects receiving paired (dual or en bloc kidney
transplants). CMV negative subjects scheduled to receive a kidney from
a CMV positive donor. Subjects with ESDR due to any of the following underlying conditions : primary focal segmental glomerulosclerosis, type I or II membranoproliferative glomerulonephritis,hemolytic uremic syndrome/Thrombotic Thrombocytopenic Purpura Hepatitis C virus (HCV): subjects or donors known to be positive for anti-HCV antibody or for HCV RNA detectable by polymerase chain reaction (PCR). Hepatitis B virus (HBV): subjects or donors known to be positive for hepatitis B surface antigen or for HBV DNA detectable PCR. Human immunodeficiency virus (HIV): subjects or donors known to be HIV positive. Subjects with current evidence or past history of active or inadequately treated latent TB infection: Subjects must have documentation of a chest x-ray (posterior-anterior and lateral views) that is negative for radiographic evidence of pulmonary TB within
the last 6 months prior to transplant.A negative screening test for latent TB infection (LTBI) [intradermal PPD, or interferon-gamma release assay (IGRA) such as QuantiFERON TB Gold test or T-Spot-TB] that was performed at any time prior to the current transplant. Those subjects who do not have documented negative result specifically from an IGRA test performed within the last 3 months prior to randomization, must be screened for latent TB with an Interferon gamma release assay (IGRA) test performed during the Screening visit- TB. Results of IGRA are not required for randomization when the results from a historical negative screening test (PPD or IGRA) are available. If equipment for sample preparation prior to shipment to central lab is not available at the site, a local lab IGRA test is acceptable. If a historical negative screening test (PPD or IGRA) result for LTBI was available and the patient was randomized on that basis, but the Screening Visit IGRA is subsequently reported (post-transplant) to be positive, treatment for latent TB must be initiated upon receipt of the test result by the Investigator. Treatment may consist of isoniazid (INH, isonicotinic acid hydrazide), 300 mg p.o. once daily for 9 months or an alternative that is consistent with the local standard of care. History of biopsy-confirmed malignancy (other than nonmelanoma skin cancer cured by resection) within the previous 5
years prior to current transplant. Subjects with a body mass index (BMI)
at screening > 35 kg/m2 for nondiabetic subjects or > 30 kg/m2 for
diabetic subjects (due to higher risk of wound complications). Subjects
whose life expectancy is severely limited ( < 6 months). Subjects with a
current or past history of substance abuse (drug or alcohol) within the
past 5 years, or psychotic disorders that are not compatible with
adequate study adherence and follow-up. Subjects with active peptic
ulcer disease, chronic diarrhea, or gastrointestinal malabsorption.
Subjects with any active infection or other contraindication that would
normally preclude transplantation. Female subjects who had a breast
cancer screening that is suspicious for malignancy, and in whom the
possibility of malignancy cannot be reasonably excluded following
additional clinical, laboratory, or other diagnostic evaluations.
History of drug or other allergy which in the opinion of PI makes the subject unsuitable for the study. WOCB ho are unwilling or unable tio use an acceptabel method to avoid pregnancy for the entire study period and for up to 8 weeks after the last infusion. Prisoners or involuntarily incarcerated ; subjects compusorily deteained for treatment of Psychiatric or Physical illness.Subjects receiveing immunosuppresive treatments or who have used any investigational drug within 30 days prior to Day 1 visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The incidence of CSBPAR at 6 months post-transplant, in the individual treatment groups: Belatacept + EVL; TAC + MMF.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months post-transplant. |
|
| E.5.2 | Secondary end point(s) |
| 1.Frequency and severity of acute rejection at 12 and 24 months post -transplant 2. Rates of subject and allograft survival at 6, 12 and 24 months post-transplant 3. Changes in renal function and severity of proteinuria at 3, 6, 12 and 24 months post-transplant 4. The frequency and type of donor specific anti-HLA antibodies (DSA) detectable prior to, and at 12 and 24 months post-transplant 5. Safety and tolerability of each treatment regimen 6. The frequency of cardiovascular and metabolic co-morbidities reported at 3, 6, 12, and 24 months post-transplant. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 3, 6, 12 and 24 months post transplant. |
|
| 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 | Yes |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | No |
| 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 |
| Argentina |
| Austria |
| Colombia |
| Germany |
| United States |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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