| 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 | 20.0 |
| 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 |
|
| 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 |
| To evaluate patient and functional graft survival in maintenance renal transplant recipients (6-60 Months post transplantation) converted from CNI to belatacept-based immunosupression as compared to those continuing CNI based immunosuppression at 24 months post-randomization. |
|
| E.2.2 | Secondary objectives of the trial |
| Eval effect of conversion from CNI to bela on:Composite of pt/functional graft survival @ 12 mos postrando; incidence/severity of clinically suspected biopsy proven acute rejection @ 12&24 mos postrando; Renal function by:Mean change in (cGFR)(4-variable MDRD equation) from baseline (BL) (def=most recent measurement prior to 1st dose of study drug on D1-12/24 mos postrando (%/absolute), Slopes of cGFR & 1/serum creatinine from BL/Mos 3-12&24 mos postrando, Proportion of sbjcts w/>5%&>10% imprvmnt over BL in cGFR at 12&24 mos postrando, UPCR @ BL/3/6/12/&24 mos postrando; Mean change in systolic & diastolic BP & intensity of antihypertensive trtmnt regimen (def=the total # of antihypertensive meds used to control hypertension) from BL to 12&24 mos postrando, Proportion of sbjcts w/donor spec antibodies(DSA) @ BL/Day 1, 12 & 24 mos postrando, Eval of symptom occurrence/distress measured w/ MTSOSD-59R @ BL, Wk 6 & Mos 3/6/& 12 postrando; Safety/tolerability of bela in a conversion setting |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent a) The subject or legal representative is willing to provide signed written informed consent 2) Target Population a) Adult recipients of a renal allograft from a living donor or a deceased donor between 6-60 mos prior to enrollment. b) Receiving a stable regimen of CNI (CsA or TAC), with MMF or EC-MPS/MPA and daily corticosteroids for ≥ 1 calendar month prior to randomization. CNI trough (C0) levels must be in the range of 50-250 ng/ml for CsA and 4-11 ng/ml for TAC [with regard CNI therapy: "receiving a stable regimen" specifically refers to maintaining a stable level of exposure to CsA or TAC within the protocol-specified ranges, and not to maintaining a stable dose, per se. Thus changes to the CNI dose made during the Screening period to maintain stable exposure do not exclude prospective subjects from study participation, so long as their trough levels remain within the protocol-specified range.] c) Renal function must have remained stable during the 12 week period prior to Screening, in the opinion of the investigator and according to the following criteria:
C1) Absence of new onset proteinuria during the 12-week period prior to enrollment, as documented by ≥ 1+ protein by dipstick or a random-voided urinary protein/creatinine ratio ≥ 0.3 mg protein/mg creatinine (≥ 34 mg protein/mmol creatinine) in a patient without previously diagnosed proteinuria and in the absence of intercurrent illness.
C2) In patients with pre-existing proteinuria (proteinuria known to have been present prior to the 12-week period before enrollment), urinary protein excretion at the time of the Screening evaluation must be:
− ≤ 500 mg/24 hours OR the random urinary protein-to-creatinine ratio (UPr/Cr) must be ≤ 0.5:1 mg protein/mg creatinine (≤ 56.5 mg protein/mmol creatinine) at the Screening evaluation in patients with a history of diabetes mellitus; or
− ≤ 1,000 mg/24 hours OR the random urinary protein-to-creatinine ratio must be ≤ 1.0:1 mg protein/mg creatinine (≤ 113 mg protein/mmol/creatinine) in non-diabetic patients. d) The calculated GFR (cGFR) must be ≥ 30 and ≤ 75 mL/min/1.73 m2, as calculated using the 4-variable MDRD equation 30, on two occasions: once at the Screening evaluation and at one additional time point between 2 and 12 weeks prior to the Screening evaluation. If a historical cGFR value is not available, then a second cGFR must be obtained at least 2 weeks later during the Screening period. Calculated results for cGRF should be rounded to the nearest whole number based upon conventional rounding rules. NOTE: Both serum creatinine determinations should be from the same laboratory unless both labs use IDMS-referenced assays. e) Negative testing for TB by an interferon gamma release assay (IGRA) such as QuantiFERON®-TB Gold test or T- Spot®-TB test, prior to randomization. 3) Age and Reproductive Status. a)Men and women, ages 18 - 75 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. Please note: that according to the US product information for MMF or EC-MPS/MPA, two reliable forms of contraception must be used simultaneously unless abstinence is the chosen method (see package insert). Acceptable methods of highly effective birth control include: • Condom with spermicide; • Diaphragm and spermicide;• Cervical cap and spermicide;• Oral contraceptives; • Intrauterine device (IUD). b) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study medication. c) Women must not be breastfeeding; d) 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. e) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile; see Section 3.2.3 for the definition of WOCBP).
|
|
| E.4 | Principal exclusion criteria |
| Recipients with EBV serostatus negative or unknown; History of any of the following: treated for biopsy proven AR(BPAR) w/i 3 calendar mos prior to enrollment; Antibody mediated AR; Recurrent AR in the current allograft; Banff 97 Grade IIA or greater AR (or equivalent), steroid resistant AR or treatment with lymphocyte-depleting agents, plasmapheresis, or rituximab for AR since the time of transplantation of the current allograft; Subjects with previous graft loss due to BPAR; Subjects with a positive T-cell lymphocytotoxic cross match; Genetically-identical donor recipient pairs (ie identical twins); Donor age < 10 yrs; Subjects with underlying renal disease of: Primary focal segmental glomerulosclerosis, Type I or II membranoproliferative glomerulonephritis, Atypical hemolytic uremic syndrome (HUS) / thrombotic thrombocytopenic purpura (TTP). If subject has ESRD of unknown etiology and/or has no histologically-confirmed diagnosis, the subject may be enrolled into the study as long as, in the opinion of the investigator, the overall history and clinical findings are not consistent with likely diagnosis of underlying primary focal segmental glomerulosclerosis, Type I or II membranoproliferative glomerulonephritis, or atypical HUS/TTP; Subjects with prior non-renal solid organ transplant (subjects undergoing kidney re-transplantation are eligible pending other study criteria being met), or subjects undergoing multi-organ transplants (eg kidney-pancreas) or subjects deemed likely to have a second solid organ or cell transplant (eg pancreas or islet transplant) in the next 3 years by the investigator; Subjects receiving a concurrent solid organ (heart, liver, pancreas) or cell (islet, bone marrow, stem cell) transplant; Subjects receiving paired kidneys (dual or en bloc kidney transplants); Subjects who are or whose allograft donor was known hepatitis C antibody-positive or polymerase chain reaction (PCR)-positive for hepatitis C; Subjects who are or whose allograft donor was known hepatitis B surface antigen-positive or PCR-positive for hepatitis B; Subjects and recipients of a graft from a donor with known human immunodeficiency virus (HIV) infection; Subjects with any active infection [including but not limited to cytomegalovirus CMV), BK or Epstein-Barr virus (as determined by dection of quantifiable viral loads in plasma), BKV associated nephropathy, CMV retinitis, CMV colitis, tuberculosis, etc.]; Subjects with history of active or untreated latent tuberculosis (TB) or radiographic finding consistent with active TB; Subjects must be screened for active and latent tuberculosis prior to entry into the study. Subjects must have a negative chest x-ray (posterior-anterior and lateral views) within the last 6 calendar months prior to screening and a negative IGRA test (such as QuantiFERON®-TB Gold test or T- Spot®- TB) done at screening by the central laboratory. If equipment for incubation prior to shipment to central lab is not available at the site, a local lab IGRA test is acceptable (Refer to Table 5.1-1); Subjects whose life expectancy is severely limited by disease state or other underlying medical condition; Subjects with a history of cancer (other than non-melanoma skin cell cancers cured by local resection) within the last 5 years; 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; 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; Subjects with active peptic ulcer disease, chronic diarrhea, or gastrointestinal malabsorption; Subjects with laboratory values that meet the following criteria are to be excluded from the study: Hemoglobin < 7 g/dL, Platelets < 80,000/mm3, White blood cell (WBC) count < 3000/mm3 (<3 x 109/L), Serum IgG < 400 mg/dl; 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; History of drug or other allergy which in the opinion of the principle investigator makes the subject unsuitable for participation in the study; Women with a positive pregnancy test on enrollment or prior to study drug administration |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who survive with a functional graft at 24 months post randomization |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 months post randomization |
|
| E.5.2 | Secondary end point(s) |
| Patient and Functional Graft Survival; Proportion of subjects who survive with a functional graft at 12 months post randomization; Acute Rejection; The incidence and severity of clinically suspected biopsy proven acute rejection at 12 and 24 months post randomization; Renal Function; Mean change in cGFR (per 4-variable MDRD equation) from baseline to 12 and 24 months post-randomization (% and absolute); Slopes of cGFR and 1/serum creatinine respectively from baseline as well as Month 3 to 12 and 24 months post-randomization; Proportion of subjects with > 5% and > 10% improvement over baseline in cGFR at 12 and 24 months post-randomization; Urine protein/ creatinine ratio (UPCR) at baseline, 3, 6, 12 and 24 months post randomization; Hypertension; Mean change in systolic and diastolic blood pressure and intensity of treatment regimen (defined as the total number of antihypertensive medications used to control hypertension) from baseline to 12 and 24 months post-randomization; Donor Specific Antibodies (DSA); Proportion of subjects with DSA at Basline/Day 1, & months 12 and 24 post-randomization; The frequency of symptom occurrence and symptom distress measured with the MTSOSD-59R at baseline, Week 6, and 3, 6, and 12 months post- randomization; Safety and tolerability of a belatacept in conversion setting; All adverse events; Adverse events of special interest; Clinically significant changes in vital signs; Laboratory test abnormalities; Clinical tolerability of the drug |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Graft survival at 12 mos post rando; Acute rejection: 12 to 24 mos post rando. Renal function & Hypertension: Mean change from baseline to 12 & 24 mos post-rando.; Slopes of cGFR & 1/serum creatinine respectively from baseline as well as Month 3 to 12, 24 mos post rando.; Proportion of subjects with >5% & >10% improvement over baseline in cGFR at 12 & 24 mos post rando.; Urine protein/creatinine ratio (UPCR) at baseline, 3, 6, 12 & 24 mos post rando. Hypertension: intensity of anti-hypertensive trtmnt from baseline to 12 & 24 mos post rando; Proportion of donor specific antibodies (DSA) at Basline/D1 & mos 12 & 24 post rando.; Frequency of symptom occurrence/symptom distress measured with MTSOSD-59R at baseline, Week 6, and 3, 6, 12 mos post rando |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 33 |
| 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 |
| Netherlands |
| Norway |
| Sweden |
| Switzerland |
| United States |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
Print
