E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prophylaxis of graft rejection in adults who have received a renal transplant |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of rejection of transplanted kidneys in adults |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050436 |
E.1.2 | Term | Prophylaxis against renal transplant rejection |
E.1.2 | System Organ Class | 100000022818 |
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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 compare cardiovascular(CV) risk estimated by a renal transplant specific CV calculator in renal transplant recipients (RTR) randomized to belatacept or CNI-based immunosuppression. |
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E.2.2 | Secondary objectives of the trial |
•Comparison of individual components of CV risk in RTR randomized to belatacept vs. CNI-based immunosuppression – blood pressure, fasting lipids, fasting glucose and eGFR.
•Differences in vascular function measured by EndoPAT in RTR randomized to belatacept vs. CNI-based immunosuppression.
•Changes in biomarkers of ageing (bio-ageing) in RTR randomized to belatacept vs. CNI-based immunosuppression. These will include peripheral markers (leukocyte telomere length, CDKN2A); and RNA expression profiling in peripheral blood leukocytes.
•Analyses of transplant biopsy specimens in a subset of patients (histology, RNA expression) targeting chronic allograft nephropathy in CNI treated patients vs. patients switched to belatacept.
•Safety analyses – adverse events, mortality, rejection episodes and graft losses.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
2. Target Population:
2.a Renal transplant recipients of living donor or deceased donor kidney transplant.
2.b Stable renal graft with no need for exploratory examination (eGFR >20 ml/min)
2.c Tacrolimus or CsA (Cyclosporine A) standard treatment since transplantation
2.d 3 – 60 months post-transplantation at randomization
3. Age and Sex:
3.a Men and women, aged 18 to 80 years, both inclusive.
3.b Women of childbearing potential (WOCBP) must be using adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of study drug to minimize the risk of pregnancy. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not postmenopausal. Post-menopause is defined as:
•Amenorrhea that has lasted for >= 12 consecutive months without another cause, or
•For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL. Women who are using oral contraceptives, other hormonal
contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (e.g. vasectomy) should be considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product (belatacept). |
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E.4 | Principal exclusion criteria |
1. Sex and Reproductive Status
1.a WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug.
1.b Women who are pregnant or breastfeeding.
1.c Women with a positive pregnancy test.
2. Target Disease Exceptions
Subjects who are EBV IgG negative or have unknown IgG status for EBV.
3. Medical History and Concurrent Diseases
3.a De novo or recurrent underlying renal disease that, in the Investigator's opinion, could adversely influence the current allograft
3.b History of vascular or antibody-mediated rejection in the present transplant
3.c Ongoing serious infections, as per Investigator's opinion
3.d Signs of post-transplant lymphoproliferative disorder
3.e History of tuberculosis. If the patient has a history of active TB or a history of latent untreated TB, the patient must be excluded from the study. If the patient has a history of latent treated TB, the patient can be included
3.f Signs of malignancy. Exceptions are BCC/SCC or non-malignant melanoma
3.g History of malignancy, unless subject has been considered to have fully recovered from malignancy more than 1 year ago, without any signs of relapse
3.h Life expectancy < 3 years at the time of randomization
4. Allergies and Adverse Drug Reactions
4.a Hypersensitivity to belatacept
4.b Previous/ongoing use of rituximab in connection with the current transplant.
5. Other Exclusion Criteria
5.a Prisoners, or subjects who are involuntarily incarcerated.
5.b Subjects who are compulsorily detained for treatm |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point is the estimated risk of major adverse cardiovascular events (MACE). The natural logarithm of the estimated CV risk for MACE will be calculated as previously described by Soveri et al. (2012) as a linear function of the following variables: age, previous coronary heart disease, smoking, serum creatinine, diabetes mellitus, LDL-cholesterol and number of transplants. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be a comparison of the log of the estimated CV risk between treatment groups (CNI vs. belatacept based immunosuppression) at one year.
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E.5.2 | Secondary end point(s) |
The secondary end-points are the comparisons between treatments arms for:
• individual components of CV risk in RTR: blood pressure, fasting lipid profiles, fasting glucose and eGFR.
• vascular function measured by EndoPAT.
• biomarkers of ageing (bio-ageing) in RTR: leukocyte telomere length, CDKN2A levels, leukocyte RNA expression profile.
• renal transplant biopsy IFTA scores (Banff criteria)
• expression of graft fibrosis markers, and other measures of chronic renal transplant markers in kidney biopsies
• acute rejection
• allograft losses
• CV events occurring during the study, i.e.
o cardiovascular death (due to myocardial infarction (MCI), heart failure or stroke),
o non fatal MCI
o non fatal stroke
o hospitalization due to congestive heart failure
o hospitalization due to angina pectoris
o coronary intervention
• patient survival
• safety and tolerability |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | Yes |
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) | 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) | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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Last visit of the last subject |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |