E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Active Antibody-Mediated Rejection (CABMR) in Kidney Transplant Recipients |
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E.1.1.1 | Medical condition in easily understood language |
Kidney rejection after transplant cause by specific antibodies. This needs to be established in blood and biopsy investigations. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate the efficacy of clazakizumab in preventing all-cause composite allograft loss (including death) due to CABMR. 2. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 (MDRD4) equation) (Interim Analysis #2 (IA #2)). 3. To evaluate the safety of clazakizumab.
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effects of clazakizumab on loss of allograft function (defined as a 40% decline in eGFR from Baseline that is sustained for at least 60 days). 2. To evaluate the effects of clazakizumab on death-censored allograft loss. 3. To evaluate the effects of clazakizumab on albuminuria. 4. To evaluate the effects of clazakizumab on DSA titers and mean fluorescence intensity (MFI) scores. 5. To evaluate the effects of clazakizumab on incidence of acute rejection episodes (TCMR and ABMR). 6. To evaluate the effects of clazakizumab on the histology of kidney biopsies according to the Banff 2015 lesion grading scores. 7. To evaluate the effects of clazakizumab on overall patient survival. 8. To evaluate the PK of clazakizumab following subcutaneous injection in kidney transplant recipients with CABMR (for those in the PK/PD substudy only). 9. To evaluate the immunogenicity of clazakizumab in kidney transplant recipients with CABMR. |
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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 |
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E.3 | Principal inclusion criteria |
1. Age 18-75 years. 2.Living donor/deceased donor kidney transplant recipients ≥6 months from time of transplant. 3. Diagnosis of CABMR determined by kidney biopsy and the presence of HLA DSA using single-antigen bead-based assays. NOTE: If conducted within 12 months (+3 weeks) prior to the start of the screening period and no intervening treatments have been administered, the biopsy does not need to be repeated at Screening. If conducted within 6 months (+ 3 weeks) prior to the start of Screening, the DSA analysis do not need to be repeated at screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed at least 2 months ± 2 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR and presence of HLA DSA. In addition, with the exception of steroids, treatments for ABMR or TCMR are not allowed within 3 months prior to the start of screening (see Exclusion Criterion 3). The following histopathologic and serologic diagnostic criteria (based on Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion: • Morphologic evidence of chronic tissue injury, as demonstrated by TG (cg>0). Biopsies without evidence of chronic tissue injury on light microscopy, but with glomerular basement membrane double contours on electron microscopy (cg1a) are eligible. • Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following. • Linear C4d staining in peritubular capillaries or medullary vasa recta (Banff scores C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections). • At least moderate microvascular inflammation ([g + glomerulitis score, [g] + peritubular capillaritis score [ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥ 1. NOTE: The local pathologist's diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. Biopsies with other histopathologic changes (eg, BKV nephropathy or recurrent glomerulonephritis) may be eligible if concurrent CABMR changes (as detailed above) are present and determined to be the predominant cause of renal dysfunction. c. Serologic evidence of circulating DSA to HLA. NOTE: The local laboratory DSA results must be reviewed and confirmed by the central HLA reviewer during the screening period. 4. Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures. |
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E.4 | Principal exclusion criteria |
1. Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient. 2. Treatment for ABMR (including CABMR) or TCMR within 3 months prior to the start of screening with the exception of steroids. 3. Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of screening. 4. Pregnant, breastfeeding, or unwillingness to practice adequate contraception. 5. Active tuberculosis (TB) or history of active TB. 6. History of human immunodeficiency virus (HIV) infection or positive for HIV. 7. Seropositive for hepatitis B surface antigen (HBsAg) 8. Hepatitis C virus (HCV) RNA positive. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to all-cause composite allograft loss Defined as: o eGFR < 15 mL/min/1.73 m2*, o eGFR < 15 mL/min/1.73 m2*, o return to dialysis*, o allograft nephrectomy, o retransplantation, or o death from any cause (Final Analysis), *total cumulative duration of eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. An eGFR < 15 mL/min/1.73 m2 must be confirmed by a repeat measurement. The time window for confirmation of an eGFR < 15 mL/min/1.73 m2 is ≥ 60 days from when initially noted. The date of the initial eGFR < 15 mL/min/1.73 m2 is the date when first determined from local or central laboratories. The primary efficacy endpoint will be analyzed as part of the final analysis when at least 221 all-cause composite allograft loss events have occurred.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 7 years |
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E.5.2 | Secondary end point(s) |
1) Incidence and time to loss of allograft function as defined by a 40% decline in eGFR from Baseline 2) Incidence and time to all-cause composite allograft loss 3) Incidence and time to death-censored allograft loss 4) Change in mean estimated glomerular filtration rate (eGFR) from Baseline to End of Treatment (EOT) 5) Change in spot urine albumin creatinine ratio (UACR) from Baseline to EOT 6) Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores from Baseline to EOT 7) Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT 8) Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment to post‑treatment (Week 52) kidney biopsies 9) Overall patient survival 10) Maximum serum concentration (Cmax, Cmax ss) of CSL300 11) Trough serum concentrations (Ctrough, Ctrough ss) of CSL300 12) Area under the concentration-time curve (AUC0-tau) at steady state of CSL300 13) Time of maximum serum concentration (Tmax, Tmax ss) of CSL300 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline and up to approximately 7 years 2-7) Up to approximately 7 years 8) Up to 52 weeks 9) Up to approximately 7 years 10-13) Up to 21 days |
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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 | 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 | 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) | 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 | 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.8.4.1 | 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 | 45 |
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 |
Brazil |
Canada |
Korea, Republic of |
Mexico |
New Zealand |
Taiwan |
United States |
Austria |
France |
Sweden |
Netherlands |
Spain |
Switzerland |
Czechia |
Germany |
Belgium |
Hungary |
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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
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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 | 10 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 4 |