E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Allograft Rejection in Adult Subjects After Renal Transplantation. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
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 |
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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 |
Efficacy: To estimate the change in naive B cells following belimumab 10 mg/kg (or placebo) in addition to standard of care immunosuppressants in renal transplant patients from the time of transplantation up to 24 weeks.
Safety: To assess the safety and tolerability of belimumab 10 mg/kg (or placebo) in renal transplant patients in addition to standard of care immunosuppressants. |
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E.2.2 | Secondary objectives of the trial |
To further assess the pharmacodynamic effect of belimumab in addition to standard of care immunosuppressants in renal transplant patients at 24 weeks
To assess the phenotype and tolerogenic profile of the repopulating B cells after belimumab therapy at week 52.
To further assess the potential for efficacy of belimumab in addition to standard of care immunosuppressants in reducing the incidence of renal allograft rejection using biomarker and clinical outcomes. |
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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 |
Title:
Pharmacogenetic Research
Objective:
The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship response to Belimumab. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with Belimumab that may be attributable to genetic variations of subjects, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:
- Pharmacokinetics and/or pharmacodynamics of study treatment
- Safety and/or tolerability
- Efficacy |
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E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Eligible for kidney transplantation: Considered eligible for transplantation
after undergoing multidisciplinary evaluation at the institution at which transplantation will be performed
2. Donor characteristics: Receiving a deceased donor kidney or a living donor kidney allograft
3. Age & Gender: Male or female between 18 and 75 years of age, inclusive, at the time of signing the informed consent
4. Female Subjects: Not pregnant or nursing and at least one of the following conditions apply:
a. Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. In the absence of confirmatory laboratory assessments [(a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/ml (<147 pmol/L)] in questionable cases, female subjects will be required to use one of the contraception methods described in Section 7.1,
Contraception Requirements, until confirmatory results become available.
b. Questionable post-menopausal status and agrees to use one of the contraception methods listed in Section 7.1, Contraception Requirements, from Day 0 until 16 weeks after the last dose of investigational product or until postmenopausal status is confirmed with a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/ml and estradiol < 40 pg/ml (<147 pmol/L). Females with questionable post-menopausal status who are using hormone replacement therapy (HRT) will be required to use one of the contraception methods in Section 7.1,
Contraception Requirements, until post-menopausal status is confirmed. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
c. Child-bearing potential and agrees to use one of the contraception methods listed in Section 7.1, Contraception Requirements, from Day 0 until 16 weeks after the last dose of investigational product.
5. Liver function (most recent values available before transplantation): ALT < 2xULN; bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
6. Immunosuppressants: at the time of transplantation, planned to receive a combination of immunosuppressants including basiliximab, mycophenolate mofetil, tacrolimus, prednisolone. |
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E.4 | Principal exclusion criteria |
1. Donor characteristics: receiving a kidney allograft from a donor with any of the following characteristics
a.cold ischemic time exceeding 36 hours
b.age < 5 years old
c.for donors after brain death (DBD), age >70 years old,
d. for donors after cardiac death (DCD) age > 70 years old.
e.ABO blood type incompatible against the recipient
f.0 0 0 HLA-A -B -DR mismatch against the recipient by NHSBT criteria
g.T- and/or B-cell positive crossmatch by complement dependent cytotoxicity or flow cytometry against the recipient
Note: - (In some situations it may be that a pre existing T- and/or B-cell positive crossmatch by complement dependant cytotoxicity and flowcytometry against the recipient will only be fully revealed immediately after transplant; in such situations they will be recorded as having met exclusion criteria and withdraw from further involvement in the study.
h.serology positive for hepatitis B (except hepatitis B surface antibody and prior vaccination), hepatitis C or human immunodeficiency virus (HIV)
2. Transplant other than kidney: has previously received a hematopoietic stem cell/marrow transplant or an organ transplant other than a kidney (with the exception of corneal transplantation)
3. Planned immunosuppressant regimen: are being considered for steroid-free or alemtuzumab induction
4.Prior therapy at any time: has ever received any of the following:
a. B-cell targeted therapy (e.g., rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI fragment, crystallizable (Fc), or belimumab)
5. 364 Day prior therapy: has received any of the following within 364 days before Day 0:
a.Cyclophosphamide
b. Abatacept
c. A biologic investigational agent other than B-cell targeted therapy [e.g.,
abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC 131;
investigational agent applies to any drug not approved for sale in the country in which it is being used]
6. 90 Day prior therapy: has received any of the following within 364 days before Day 0:
a. Anti-TNF or anti-IL-6 therapy (e.g., adalimumab, etanercept, infliximab,
tocilizumab)
b. Interleukin-1 receptor antagonists (e.g., anakinra)
c. IVIG
d. Plasmapheresis, leukapheresis
7. 60 Day prior therapy: has received any of the following within 60 days before Day 0:
a. A non-biologic investigational agent (investigational agent applies to any drug not approved for sale in the country in which it is being used)
b. Any new immunosuppressive/immunomodulatoryagent; tacrolimus, MMF,
and corticosteroids are permitted. Inhaled steroids and new topical
immunosuppressive agents (e.g., eye drops, topical creams) are also allowed.
8. 30 Day prior therapy: has received any of the following within 30 days before Day 0:
a. A live vaccine
b. An increase in dose of an immunosuppressive/immunomodulatory agent
(decreases in dose or discontinuations are permitted). Increases in doses of
tacrolimus, MMF, and corticosteroids are permitted.
9. Malignancy: has a history of malignancy in the past 5 years except for
adequately treated cancers of the skin (basal or squamous cell) or carcinoma in
situ of the uterine cervix.
Please see Protocol page 32 for complete exclusion criteria.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline in naïve B cells from baseline to Week 24
• AEs and SAEs, including AEs of special interest (opportunistic infections, malignancies, hypersensitivity and infusion reactions, all cause mortality and suicidality)
• Incidence and severity of infections
• Change from baseline and number of subjects outside the normal range for blood pressure, heart rate, and temperature
• Change from baseline and number of subjects outside the normal range for clinical chemistry and haematology parameters, with particular attention to white blood cell count and immunoglobulin levels |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Weeks 1, 2, 4, 8, 12, 16, 20, 24 (End of Treatment), 36 (Safety Follow-up), and Week 52 (Exit Visit) |
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E.5.2 | Secondary end point(s) |
• Percent change from baseline in memory B cells
•Activated memory B cells, transitional B cells
• Activated T cells, regulatory T cells, and ratio of activated: regulatory T cells
• All HLA-specific and donor HLA-specific antibody levels
• Proportion of subjects with episodes of acute rejection
• Serum creatinine
• Estimated glomerular filtration rate (eGFR)
• Immunosuppressant/corticosteroid use |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, Weeks 1, 2, 4, 8, 12, 16, 20, 24 (End of Treatment), 36 (Safety Follow-up), and Week 52 (Exit Visit) |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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.8.5 | The trial involves multiple Member States | No |
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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The end of the study is defined as the last subject’s last visit (LSLV). The last visit will be at Week 52 for subjects irrespective of whether they complete all scheduled infusions. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |