E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Antibody Mediated Rejection (AMR) in kidney transplant patients |
|
E.1.1.1 | Medical condition in easily understood language |
Graft rejection in kidney transplant patients. |
|
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 the efficacy of Cinryze administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free intravenous immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of subjects with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of Cinryze administered with given plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg for the treatment of acute AMR of renal allograft in kidney transplant recipients as measured by the proportion of subjects with all cause graft failure at 4 years following treatment of the initial qualifying AMR episode. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Be ≥ 18 and ≤70 years of age.
2.Weigh ≥45 kg with a body mass index (BMI) <35 kg/m2 at screening.
3.Have HLA DSA identified at the time of diagnosis of AMR. If it is anticipated that the local DSA results will not be available within the screening period, previously obtained local DSA results can be used to assess eligibility, if obtained after kidney transplant and within 30 days prior to the qualifying AMR episode. In any instance, a local DSA test
should still be performed at the time of AMR diagnosis.
4.Have a first qualifying episode of AMR in the subject's current renal allograft between 72 hours and 12 months after transplant defined by a renal allograft biopsy demonstrating neutrophil and/or monocyte infiltration in the peritubular capillaries and/or glomeruli with or without evidence of C4d by immunohistopathology according to 2013 Banff criteria for AMR.
5.Have achieved adequate renal function defined as: Pre-AMR baseline eGFRMDRD ≥20 mL/min/1.73m2 for a qualifying AMR episode occurring ≤21 days after transplant or pre-AMR baseline eGFRMDRD ≥30 mL/min/1.73m2 for a qualifying AMR episode occurring >21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value
obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode. If more than one eGFRMDRD value is available, a mean of the 2 highest values (at least 1 day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If no eGFRMDRD was obtained within 30 days prior to biopsy, it can be
evaluated within a 60 day period.
6.Receive first dose of investigational product at least 7 days after kidney transplant and within 7 days after the qualifying renal allograft biopsy procedure that was positive for AMR.
7.Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
8.If female and of child-bearing potential, have a negative urine pregnancy test confirmed by a negative serum beta human chorionic gonadotropin pregnancy test at the Screening Visit and must have a negative urine pregnancy test at the Day 1 visit.
9.Agree to comply with any applicable contraceptive requirements of the protocol. |
|
E.4 | Principal exclusion criteria |
1.Have received pediatric en bloc kidney transplant.
2.Have primary Focal Segmental Glomerulosclerosis, rapidly progressive glomerulonephritis,membrano-proliferative glomerulonephritis type 1 (including C3 Glomerulopathy), "dense deposit disease", or Thrombotic microangiopathy as the cause of native kidney failure.
3.Have prior or concurrent non-renal solid organ transplant or hematopoietic stem cell transplant (HSCT) or have more than 2 completed kidney transplant procedures (note: 1 double kidney transplant procedure is considered to be 1 procedure).
4.Have a known neoplastic lesion in the transplanted allograft.
5.Have, any ongoing infection that causes hemodynamic compromise or as determined by the investigator and/or medical monitor, any surgical or medical condition that could interfere with the administration of investigational product, interpretation of study results, or could compromise patient safety, including (as determined by the transplanting surgeon and documented in the operative report) any major technical complications of the renal artery, renal vein, or ureteral anastomosis.
6.Have ongoing treatment for hepatitits C virus (HCV) infection.
7.Have had a myocardial infarction (MI) within the past 6 months and/or at the time of screening are treated with anticoagulants and/or antiplatelet agents (excluding aspirin) for a previous myocardial infarction.
8.Have a history of abnormal bleeding, clotting events, or disorders (excluding a history of clotted hemodialysis access or superficial thrombophlebitis in the absence of medically-confirmed coagulopathy), any coagulopathy (documented or clinically suspected). For example, patients should be excluded if they have a history of renal allograft arterial or venous thrombosis, deep vein thrombosis, pulmonary embolism, ischemic cerebrovasculara accident (stroke) or transient ischemic attack (TIA), any large vessel thrombosis.
9.Have a history of allergic reaction to CINRYZE or other blood products.
10.Have had any change in androgen therapy (eg, danazol, oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid, or other fibrinolytics within 3 months before the first dose of investigational product.
11.Have participated in the active dosing phase of any other investigational drug study within 30 days prior to dosing with investigational product.
12.Have any of the following local laboratory values reported prior to dosing with investigational product:
Within 24 hours prior to subject dosing, white blood cell count <0.5×10^9/L or >20×10^9/L (the value of >20 x 10^9/L should be excluded if obtained during steroid treatment)
Within 24 hours prior to dosing , platelet count <25×10^9/L or >600×10^9/L
13. Be pregnant or breastfeeding.
14. Have received any of the following agents within 1 month prior to the first dose of investigational product:
Sucrose-containing IVIg
Any C1 INH (plasma-derived [eg, CINRYZE®, Berinert®, Cetor®] or recombinant [eg, Rhucin®])
Eculizumab (Soliris®)
Ecallantide (Kalbitor®) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects with new or worsening TG at 6 months after treatment initiation as determined by Banff criteria. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Proportion of subjects with all-cause graft failure (ie, return to permanent dialysis and/or removal of the transplanted kidney and/or clinical determination of cessation of graft function) at 4 years following treatment of the initial qualifying AMR episode. |
|
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 | 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 | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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.8.4.1 | 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 | 19 |
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 |
Canada |
France |
Germany |
Netherlands |
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
|
Last patient last visit (LPLV) |
|
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 |