| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects who received a kidney transplant |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
| 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 primary objective is to assess the effects of a belatacept-based immunosuppressive regimen relative to a CNI-based immunosuppressive regimen on the change in calculated GFR from baseline to 12 months post-randomization.
Protocol Amendment 04 - Long-Term Extension:
To assess the long-term safety and tolerability of belatacept in subjects who have completed 12 months of treatment in the main study IM103-010 |
|
| E.2.2 | Secondary objectives of the trial |
• Assess the incidence and severity of acute rejection (AR) at 6 and 12 months post-randomization
• Assess the change in calculated glomerular filtration rate (GFR) from baseline to 6 months
• Assess the incidence of discontinuation of study medication or dose alteration due to declining renal function at 6 and 12 months
• Assess the incidence of death and graft loss at 6 and 12 months
• Assess the change in serum creatinine (SCr) from baseline to 6 and 12 months
• Assess the incidence of new onset diabetes at 6 and 12 months
• Assess the incidence of human leukocyte antigen (HLA) antibodies at baseline (randomization) and at 6 and 12 months
• Assess QoL at baseline (randomization) and at 6 and 12 months
• Assess safety and tolerability
• Overall safety and tolerability of a belatacept-based immunosuppressive regimen
+ Additional assessments as per Protocol Amendment 04 - Long-Term Extension (see Protocol Appendix 4, section 2.2) |
|
| 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 |
Comprehensive PK assessment will be performed under a separate sub-study protocol.
The PK parameters related to this sub-study will be reported separately.
Sparse PK samples will be collected from all belatacept-treated subjects in the main study at the following time points:
• Pre-dose serum samples at Weeks 4, 24, and 52
• One hour after start of infusion (ie, 30 minutes after infusion) at Week 20.
Additionally, a blood sample for PK analysis should be obtained at any time a rejection episode is suspected. If a rejection is suspected at the time of an infusion, obtain the PK sample prior to belatacept infusion. |
|
| E.3 | Principal inclusion criteria |
1)Signed Written Informed Consent
a) Subjects willing to sign the informed consent for this sub-study. Informed consent will be obtained prior to any samples analyzed and reported. PK samples were collected as a standard of care in the clinical management of renal transplant recipients receiving MMF.
2) Target Population
a) Subjects that are currently participating in the main study and either taking Belatacept or remaining on their CNI immunosuppressive regimen
Subjects must be a recipient of a renal allograft from a living donor or a
deceased donor at least 6 months, but not longer than 36 months, prior to enrollment
3) Age & Sex
a)Men and women ages 18 years and older, inclusive, Subjects must be receiving a CNI-based (CsA [any formulation] or TAC) immunosuppressive regimen
4) Study medication,
a) Subjects must be receiving adjunctive background maintenance
immunosupression with MMFThe dose of CNI must have been stable over the month prior to randomization
b) Subjects must be currently taking belatacept or CNI (CsA or TAC) in the IM103010 clinical trial
a) For subjects receiving CsA, trough serum concentration at the time of enrollment must be 100-250 ng/mL (based on screening/baseline local laboratory results)
b) For subjects receiving TAC, trough serum concentration at the time of enrollment must be 5-10 ng/mL (based on screening/baseline local laboratory results)
5) Subjects must be receiving adjunctive background maintenance immunosuppression with MMF, MPA, SRL, or AZA
a) Subjects receiving MMF must have received a minimum total daily dose of 1.5 g for the month prior to randomization (up to 3 missed doses are acceptable provided doses were not missed due to drug intolerance)
b) Subjects receiving MPA must have received a minimum total daily dose of 1080 mg for the month prior to randomization (up to 3 missed doses are acceptable provided doses were not missed due to drug intolerance)
c) Subjects receiving AZA must have received a minimum daily dose of 50 mg for the month prior to randomization (up to 3 missed doses are acceptable provided doses were not missed due to drug intolerance)
d) Subjects receiving SRL must have a trough serum concentration at the time of enrollment of 5-15 ng/mL (based on screening/baseline local laboratory results)
6) If subjects are receiving concomitant corticosteroids (steroid use is not required), the dose of corticosteroid must have been stable over the month prior to randomization with no anticipated dose alteration in the next 12 months unless a change in the medical condition warrants
adjustment.
7) Subjects must have a calculated GFR ≥ 35 and ≤ 75 mL/min/1.73 m2 (MDRD formula) at the time of enrollment (based on screening/baseline central laboratory results)
8) Men and women, ages 18 years and older, inclusive
9) WOCBP must be using an adequate method of contraception 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.
Inclusion criteria for participation to Protocol Amendment 4 - Long-Term
Extension:
11) Subjects must be willing to participate and provide signed, written
informed consent for this long-term extension phase.
12) Subjects must have completed 1 year in the IM103010 study
(through Month 12) aand remained on study treatment
13) Subjects must be willing and able to continue therapy with MMF,
MPA, sirolimus (SRL) or azathioprine (AZA). If a subject is unable to
tolerate minimum therapeutic doses of their current adjunctive
background maintenance immunosuppression, another adjuvant agent
may be substituted.
14) Women of childbearing potential (WOCBP) must be using an
adequate method of contraception to avoid pregnancy throughout the
study and for up to 8 weeks after the last dose of study drug in such a
manner that the risk of pregnancy is minimized.
15) Subjects originally assigned to the CNI treatment group must be
willing and able to continue therapy with CsA or TAC |
|
| E.4 | Principal exclusion criteria |
1) WOCBP 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 medication. It should be noted that according to the US product information for mycophenolate mofetil (CellCept®) and mycophenolic acid (Myfortic®), “two reliable forms of contraception be used simultaneously unless abstinence is the chosen method”
2) WOCBP using a prohibited contraceptive method
3) Women who are pregnant or breastfeeding
4) Women with a positive pregnancy test on enrollment or prior to study drug administration
5) Subjects with underlying renal disease of:
a) Primary focal segmental glomerulosclerosis
b) Type I or II membranoproliferative glomerulonephritis
c) Hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura syndrome
Subjects :
6) expected to undergo weaning of immunosuppressive therapy during the period of the study
8) with previous graft loss due to acute rejection (AR)
9) whose SCr at enrollment is over 30% higher than 3 months (± 4 weeks) prior to randomization
10) with an episode of AR in the last 3 months. Subjects who have had an episode of AR are required to have had clinical resolution for at least 3 months prior to randomization
11) who have had a Banff 97 Grade IIA or greater AR (or equivalent), steroid-resistant AR or have received lymphocyte-depleting agents, plasmapheresis, or rituximab for the treatment of AR since transplantation of current allograft
12) who have experienced more than 1 episode of rejection of the current allograft
13) with a biopsy of the current allograft staining C4d positive. Neither a biopsy nor C4d staining is required for entry into the study
14) who have experienced complications of anastomotic stenosis or stricture (vascular or ureteral)
15) who had a positive T-cell or B-cell crossmatch
16) who have documented BK virus (polyoma virus) nephropathy (biopsy is not required for enrollment)
17) who have documented evidence of recurrence of the primary cause of end-stage renal disease (ESRD) in their current or in a past renal allograft
18) with multiple solid organ or cell transplants
19) who received paired kidneys (dual or en bloc kidney transplants)
20) who are known hepatitis C antibody-positive or PCR-positive for hepatitis C (neither hepatitis C antibody or PCR for hepatitis C testing is required for study entry)
21) who are known hepatitis B surface antigen-positive or PCR-positive for hepatitis B (neither hepatitis B surface antigen or PCR for hepatitis B testing is required for study entry)
22) with known HIV infection. HIV testing is not required for study entry
23) with a chest radiograph (posterior-anterior and lateral views) consistent with an acute lung parenchymal process, malignancy, or active tuberculosis. Subjects must have a chest radiograph within 2 months prior to randomization
24) with any significant infection
Medical History and Concurrent Diseases
25) Subjects whose life expectancy is severely limited by disease state or other underlying medical condition
26) Subjects with a history of cancer (other than non-melanoma skin cell cancers cured by local resection) within the last 5 years
27) Subjects with a history of substance abuse (drug or alcohol) within the past 5 years, or psychotic disorders that are not compatible with adequate study follow-up
Physical and Laboratory Test Findings
28) Subjects with laboratory values that meet the following criteria:
Urine Assay:
• Proteinuria > 1,000 mg/day or
• Urine protein : creatinine ratio > 1
Hematology:
• Hemoglobin < 7 g/dL
• Platelets < 80,000/mm3
• White blood cell count < 3000/mm3 (3 x 109/L)
Chemistry:
• Bilirubin >1.5 x upper limit of normal range (ULN); Subjects who have Gilbert’s syndrome and have a normal direct bilirubin are permitted
• Aspartate aminotransferase (AST) ≥ 2 x ULN
• Alanine aminotransferase (ALT) ≥ 2 x ULN
29) All women 50 years or older must have a screening mammogram or provide results of a mammogram performed within 6 months of enrollment. Subjects with a mammogram that is suspicious for malignancy and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory, or other diagnostic evaluations will be excluded.
Women of any age who have a first degree relative with a history of breast cancer or who have other risk factors for breast cancer must undergo increased surveillance for breast cancer according to local practice.
30) Subjects who have difficult i.v. access
Prohibited Therapies and/or Medications
31) Subjects who have used any investigational drug within 30 days prior to the Day 1 visit
32) Subjects previously treated with belatacept or previously enrolled in a belatacept trial with their present allograft
33) Prisoners or subjects who are compulsorily detained
+ For participation to Protocol Amendment 4 - Long-Term Extension:
See Protocol Appendix 4, section 5.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Assess the change in calculated GFR (MDRD formula) from baseline to 12 months post-randomization.
Protocol Amendment 4 - Long-Term Extension:
Overall safety of a belatacept- based immunosuppressive regimen |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from baseline to 12 months post randomization |
|
| E.5.2 | Secondary end point(s) |
- Assess the incidence/severity of acute rejection
- death and graft loss
- discontinuation or dose alteration due to declining renal function
- quality of life and overall safety and tolerability of a belatacept-based
immunosuppression regimen |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 |
| Immunogenicity Analyses; QoL; Biomarkers; Tolerability |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Australia |
| Belgium |
| Brazil |
| Canada |
| France |
| Germany |
| India |
| Mexico |
| Spain |
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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