E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
complement 3 glomerulopathy immunoglobulin A nephropathy primary membranous nephropathy |
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E.1.1.1 | Medical condition in easily understood language |
C3 G IgA nephropathy primary membranous nephropathy |
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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 | 10021263 |
E.1.2 | Term | IgA nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027170 |
E.1.2 | Term | Membranous nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 | 10077827 |
E.1.2 | Term | C3 glomerulopathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
To evaluate the therapeutic potential of BCX9930 as assessed by proteinuria measures |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of BCX9930 To evaluate the therapeutic potential of BCX9930 as assessed by other measures of clinical benefit To evaluate effects on kidney biopsy morphologic findings To characterize the effects of BCX9930 on blood and urine biomarkers of complement activation and consumption To evaluate the correlation of BCX9930-associated changes in blood and urine biomarkers of complement activation and consumption with changes in proteinuria |
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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 |
PK / PD sub-study - within the main protocol |
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E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent 2. Male or non-pregnant, non-lactating female subjects ≥ 18 years of age 3. Body weight ≥ 40 kg. 4. Primary diagnosis of C3G, IgAN, or PMN with evidence of disease activity as, confirmed by central pathology review of digital images and pathology reports of renal biopsy samples 5. For subjects with C3G only, documentation of duration of illness of at least 90 days by either a prior biopsy collected ≥ 90 days prior to screening confirming a diagnosis of C3G OR a clinical diagnosis of C3G with at least one documented proteinuria assessment ≥ 90 days prior to initial screening visit. 6. For subjects with C3G only, proteinuria defined as ≥ 1 g of urinary protein per 24 hours at screening that has not shown a ≥ 25% decrease from the most recent documented proteinuria assessment, which was collected ≥ 30 days prior to and ≤ 180 days of initial screening visit. 7. For subjects with IgAN only, proteinuria defined as 1 g to ≤ 4 g of urinary protein per 24 hours at screening that has not shown a ≥ 25% decrease from the most recent documented proteinuria assessment, which was collected ≥ 30 days prior to and ≤ 180 days of initial screening visit. 8. For subjects with PMN only, an anti-phospholipase A2 receptor antibody (aPLA2Rab) Immunoglobulin G (IgG) titer of ≥ 150 U/mL and 3.5 g to ≤11 g of urinary protein per 24 hours at screening that has not shown a ≥ 25% decrease from the most recent documented proteinuria assessment, which was collected ≥ 30 days prior to and ≤ 180 days of initial screening visit. 9. An eGFR ≥ 50 mL/min/1.73 m2 (or ≥ 30 mL/min/1.73 m2 after DMC recommendation) 10. Resting supine vital signs within the following ranges: • Systolic blood pressure, 80 to 150 mm Hg, inclusive, for adults • Systolic blood pressure below the 90th percentile, for adolescents per Section 12.10.1 • Diastolic blood pressure ≤ 90 mm Hg 11. Treatment with a stable, maximum recommended or maximum tolerated dose of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 60 days prior to the Day 1 12. Contraception requirements - WOCBP and female partners of male subjects to use highly effective contraception methods 13. Documentation of current vaccination against N. meningitidis Types A, C, W and Y, and S. pneumoniae vaccine, or must be vaccinated or willingness to start vaccination series at least 14 days prior to Day 1 14. In the opinion of the investigator, the subject is expected to comply adequately with all required study procedures and restrictions for the study |
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E.4 | Principal exclusion criteria |
1. Known congenital deficiency of C1s, C1r, C1q, C2, C4. Known variants in complement factor H, complement factor I, C3, and complement factor B or genomic rearrangements in the complement factor-H-related proteins are not exclusionary. 2. Receiving hemodialysis or peritoneal dialysis or anticipated to receive dialysis during the duration of this study. 3. History of hematopoietic cell transplant or solid organ transplant or anticipated candidate for transplantation during the study. 4. History of transfusion with blood or blood products, or plasmapheresis or plasma exchange, within 30 days prior to screening. 5. Myocardial infarction or cerebrovascular accident within 30 days prior to screening, or current and uncontrolled clinically significant cardiovascular or cerebrovascular condition, including unstable angina, severe congestive heart failure, unexplained syncope, arrhythmia, and critical aortic stenosis. 6. History of malignancy within 5 years prior to the screening visit, with the exception of adequately treated non-melanoma skin or superficial bladder cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor deemed by the investigator and medical monitor to be at low risk for recurrence. 7. Any clinical or pathological evidence of monoclonal gammopathy of unclear or renal significance, lupus or other systemic autoimmune disease, or other conditions (eg, infection-associated disease or associated with another systemic disease, anti-phospholipid antibody syndrome with significant clinical disease, immune complex glomerulonephritis, immunoglobulin A [IgA] vasculitis with nephritis [Henoch-Schönlein purpura] or morphologic features of secondary membranous nephropathy). Presence of C3 or C5 nephritic factors (eg, autoantibodies directed at C3 or C5 convertase), in the absence of known infection or other systemic disease, are not exclusionary for this study. 8. Treatment with azathioprine, canakinumab, cyclophosphamide, cyclosporine, eculizumab, everolimus, hydroxychloroquine, infliximab, sirolimus, ravulizumab, systemic corticosteroids(including budesonide), tacrolimus, or any other systemic immunosuppressive or immunomodulatory therapies (eg. complement inhibitors)within 90 days OR mycophenolate mofetil/mycophenolate soldium treatment within 60 days for anti-CD20 antibody therapies (eg, rituximab) within 180 days, prior to the screening visit. a. For subjects with C3G only, ongoing treatment with a stable dosing regimen of mycophenolate mofetil/mycophenolate sodium for at least 6 months prior to Day 1 Visit is allowed. 9. Treatment with renin inhibitors (eg, aliskiren) or sodium-glucose-cotransporter 2 (SGLT2) inhibitors within 60 days prior to Day 1. 10. Current participation in any other investigational drug study or participation in an investigational drug study within 30 days prior to the screening visit, or 5.5 half-lives of the investigational drug, whichever is longer. 11. Any of the following at screening: Hb < 8.5 g/dL; WBC < 2.5 × 109/L; ANC < 1.0 × 109/L; platelet count < 90 × 109/L; ALT, AST, ALP or total bilirubin > 1.5 × ULN; serum albumin < 1.5 g/dL; or international normalized ratio (INR) > 1.4. a. Subjects with Grade 1 elevated bilirubin due to Gilbert’s syndrome are allowed to enroll 12. Any laboratory parameter at screening that is clinically significant and would represent a safety concern. 13. Clinically significant abnormal electrocardiogram (ECG) prior to dosing at the Day 1 Visit, including a QT interval corrected (QTcF) > 450 msec in males and QTcF > 470 msec in females, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping. 14. Current use of a prohibited concomitant medication within 7 days prior to Day 1 15. Active serious bacterial, viral, or fungal infection or any other serious infection within 14 days of screening 16. Positive serology for HIV, or active infection with HBV or HCV 17. Positive drugs of abuse screen during screening 18. Pregnant, planning to become pregnant, or breastfeeding. 19. Known hypersensitivity to BCX9930 or any of its formulation excipients 20. History of severe hypersensitivity to any medicinal product 21. Any clinically significant medical or psychiatric condition that would interfere with the subject’s ability to participate in the study or increase the risk of participation for that subject |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in 24-hour urinary protein excretion normalized to urine creatinine as measured by percentage change in uPCR from baseline |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Number and proportion of subjects with a uPCR response defined as: - Partial remission, ≥ 50% reduction from baseline - Complete remission, ≤ 500 mg/g - Normalization, ≤ 200 mg/g • Change from baseline in 24-hour urinary protein excretion as measured by percentage change in urinary protein from baseline • Change from baseline in estimated glomerular filtration rate (eGFR) • Change from baseline in serum albumin • Number and proportion of subjects with the following parameters: - Protein ≥ 3.5 g in a 24-hour urine collection - Serum albumin ≤ 2.5 g/dL • Number and proportion of subjects with a morphologic response in each of the following categories: - Decreased endocapillary hypercellularity, mesangial hypercellularity, active crescents (if present) glomerular leukocyte infriltration, fibrinoid necrosis membranoproliferative glomerulonephritis pattern. - Decreased acute tubular injury, interstitial inflammation, interstitial edema - Reduction in C3 glomerular staining - Reduction in the extent of deposits, clearing of deposits, or no additional active deposits as assessed by electron microscopy (EM) - No progression of chronic changes (ie, global, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, arteriosclerosis) • Change from baseline in constitutive blood levels of complement biomarkers, including but not limited to C3, Factor Bb, and soluble C5b-9 (sC5b-9) • Change from baseline in single void urine levels of complement biomarkers, including but not limited to Ba, C3a, and sC5b-9 normalized to urine creatinine • Change from baseline in complement biomarker measurements of ex vivo stimulation assays • Number and proportion of subjects with a treatment-emergent adverse event (TEAE) • Number and proportion of subjects who discontinue due to a TEAE • Number and proportion of subjects who experience a treatment-emergent serious adverse event (TESAE) • Number and proportion of subjects who experience a Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 TEAE • Number and proportion of subjects who experience a CTCAE treatment-emergent Grade 3 or 4 laboratory abnormality |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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) | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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 | No |
E.8.2.3 | Other | No |
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 | 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 |
France |
Germany |
Hungary |
Italy |
United Kingdom |
Romania |
Spain |
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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 | 2 |
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 | 2 |