E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Active Antibody-Mediated Rejection (AMR) 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. |
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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 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 In (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 efficacy of clazakizumab in preventing all-cause allograft loss (including death) due to CABMR
2.To evaluate the effects of clazakizumab on loss of allograft function
3.To evaluate the effects of clazakizumab on death-censored allograft loss
4.To evaluate the effects of clazakizumab on albuminuria
5.To evaluate the effects of clazakizumab on DSA titers and mean fluorescence intensity scores
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 incidence of acute rejection episodes (TCMR and ABMR)
8.To evaluate the effects of clazakizumab on overall subject survival
9.To evaluate the PK of clazakizumab following subcutaneous injection in kidney transplant recipients with CABMR (for those subjects in the Pharmacokinetic/Pharmacodynamic Substudy only)
10.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. For eligibility, kidney biopsy must not be older than 12 months and DSA analysis must be performed no longer than 6 months prior to the start of Screening. NOTE: • Within 3 months prior to the start of Screening, treatments for ABMR or TCMR, with the exception of steroids*, are not allowed (see Exclusion Criterion 3).
• If treatment for ABMR (including CABMR) or TCMR (other than steroids*) was given between 3 to 12 months of Screening, a repeat kidney biopsy and DSA analysis are required at least 6 weeks after the end of treatment to confirm continuing CABMR and presence of HLA DSA and to determine eligibility.
* A maximum dose of 2g of methylprednisolone intravenously (or dose equivalent of other steroids), followed by a taper to the original maintenance steroid dose is allowed.
The following histopathologic and serologic diagnostic criteria (based on
Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:
a. Morphologic evidence of chronic tissue injury, as demonstrated by transplant glomerulopathy (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. b. Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following:
i. 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).
ii. At least moderate microvascular inflammation (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 HLA DSA.
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 kidneypancreas 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 tuberculosis 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 composite all-cause allograft loss or irreversible loss of allograft function
Defined as time to first occurrence of any of the following components:
o eGFR < 15 mL/min/1.73 m2*, o return to dialysis*,
o allograft nephrectomy, o retransplantation,
o death from any cause, or
o a sustained (≥ 60 days) 40% decline in eGFR from Baseline.
*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2
AND / OR dialysis ≥ 60 days.
If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after ≥ 60 days from the first measurement.
The primary efficacy endpoint will be analyzed as part of the final analysis when at least 221 composite all-cause allograft loss or irreversible loss of allograft function events have occurred.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 8 years |
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E.5.2 | Secondary end point(s) |
1) Time to composite all-cause allograft loss
2) Incidence and time to irreversible loss of allograft function
3) Incidence of composite all-cause allograft loss or irreversible loss of allograft function
4) Incidence and time to death-censored allograft loss
5) Change in mean estimated glomerular filtration rate (eGFR) from
Baseline to End of Treatment (EOT)
6) Change in spot urine albumin creatinine ratio (UACR) from Baseline to
EOT
7) Change in (Donor-specific antibodies) DSA titers and Mean fluorescence intensity (MFI) scores 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) Incidence of acute rejection episodes of T cell-mediated rejection(TCMR) and Antibody-mediated rejection (ABMR) from Baseline to EOT
10) Overall subject survival
11) Trough concentrations (Ctrough, Ctrough ss) of CSL300
12) Area under the concentration-time curve (AUC0-tau ss) at steady state of CSL300
13) Time of maximum 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 8 years
2) Baseline and up to approximately 8 years
3) Up to approximately 8 years
4) Up to approximately 8 years
5) Baseline and up to approximately 8 years
6) Baseline and up to approximately 8 years
7) Baseline and up to approximately 8 years
8) Up to 52 weeks
9) Baseline and up to approximately 8 years
10) Up to approximately 8 years
11) Up to 21 days
12) Up to 21 days
13) Up to 21 days
14) 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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 |
Colombia |
New Zealand |
Singapore |
Switzerland |
Taiwan |
Australia |
Brazil |
Canada |
Korea, Republic of |
Mexico |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
France |
Germany |
Hungary |
Netherlands |
Spain |
Sweden |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |