| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Paroxysmal Nocturnal Hemoglobinuria |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10034042 |
| E.1.2 | Term | Paroxysmal nocturnal haemoglobinuria |
| 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 determine the efficacy of oral BCX9930 monotherapy administered for 24 weeks, compared to continued complement component 5 (C5) inhibitor therapy, in subjects with paroxysmal nocturnal hemoglobinuria (PNH) with an inadequate response to C5 inhibitor therapy
• To evaluate the long-term safety and tolerability of oral BCX9930 monotherapy administered over a 28- to 52 week treatment period in subjects with PNH with an inadequate response to C5 inhibitor therapy |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of BCX9930 monotherapy administered for 24 weeks, as compared to continued C5 inhibitor therapy
• To characterize the effects of BCX9930 monotherapy, as compared to continued C5 inhibitor therapy, using clinical and laboratory measurements, including complement and thrombosis biomarkers, PNH clone size, and C3-opsonization of red blood cells
• To evaluate the effects of BCX9930 monotherapy, as compared to continued C5 inhibitor therapy, on the FACIT-Fatigue scale and other patient-reported outcomes (PROs)
• To assess the effectiveness of BCX9930 monotherapy in the treatment of PNH
• To characterize the effects of BCX9930 monotherapy using clinical and laboratory measurements, including complement and thrombosis biomarkers, PNH clone size, and C3 opsonization of RBCs
• To evaluate the effects of BCX9930 monotherapy on FACIT-Fatigue scale and other PROs
• To characterize BCX9930 PK parameters |
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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 substudy - within the same protocol, |
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| E.3 | Principal inclusion criteria |
1. Male or female, aged ≥ 18 years old.
2. Body weight ≥ 40 kg.
3. Documented diagnosis of PNH confirmed by flow cytometry with a PNH granulocyte or monocyte clone size of ≥ 10% during screening.
4. Treated with a stable regimen of eculizumab for ≥ 3 months prior to the screening visit or ravulizumab for ≥ 6 months prior to the screening visit.
5. Recorded the following results during screening:
a. Hb of ≤ 105 g/L (≤ 10.5 g/dL).
b. ARC of ≥ 100 × 109 cells/L (≥ 100,000 cells/µL; ≥ 100 G/L).
c. Absolute neutrophil count of ≥ 0.75 × 109 cells/L (≥ 750 cells/µL; ≥ 0.75 × G/L).
d. Platelet count of ≥ 30 × 109/L (≥ 30,000/µL; ≥ 30 G/L).
e. Adequate iron reserve based on ferritin ≥ LLN or total iron binding capacity ≤ upper limit of the normal reference range (ULN).
f. Estimated glomerular filtration rate of ≥ 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey and Stevens 2010) and no evidence of clinically relevant abnormal renal function unrelated to underlying PNH disease.
6. Contraception requirements: WOCBP and partners of male subjects to use highly effective contraception
7. Documentation of current vaccinations against Neisseria meningitidis types A, C, W, and Y, and Streptococcus pneumoniae, or willingness to start vaccination series at least 14 days prior to Day 1.
(Note: Vaccination for N. meningitidis type B and for H. influenzae type B (Hib) is strongly encouraged where authorized and available.)
8. In the opinion of the investigator, the subject is expected to adequately comply with all required study procedures and restrictions for the study, including compliance with the twice daily dosing schedule for BCX9930.
9. Willing and able to provide written informed consent
|
|
| E.4 | Principal exclusion criteria |
1. Known history of or existing diagnosis of hereditary complement deficiency.
2. History of hematopoietic cell transplant or solid organ transplant or anticipated candidate for transplantation during the study.
3. 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.
4. History of malignancy within 5 years prior to the screening visit, with 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.
5. Active bacterial, viral, or fungal infection or any other serious infection within 14 days prior to screening.
(Note: Suspected or confirmed coronavirus disease [COVID-19]; persistent or recurrent positive test(s) for severe acute respiratory syndrome coronavirus 2 [SARS CoV 2] nucleic acids or antigens; and worsening of dyspnea not due to PNH, vasculitic rash, and persistent fever or other symptoms consistent with multisystem inflammatory syndrome in adults [MIS A] are exclusionary.)
6. 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.
7. Treatment with anti-thymocyte globulin within 180 days prior to the screening visit.
8. Initiation of treatment with an erythropoiesis-stimulating agent (eg, erythropoietin), a thrombopoietin receptor agonist (eg, eltrombopag), or danazol within 28 days prior to the screening visit.
(Note: Treatment with these medications initiated > 28 days prior to the screening visit is not exclusionary, if the dose is stable and there is a reasonable expectation that treatment will be continued.)
9. Receiving iron supplementation with an unstable dose in the 28 days prior to the screening visit.
10. Clinically significant abnormal electrocardiogram (ECG) at the screening visit.
(Note: This includes, but is not limited to, a QT interval corrected using Fridericia’s method [QTcF] of > 450 msec in males or > 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.)
11. Subjects with any of the following results at the screening visit:
a. Alanine aminotransferase (ALT; also serum glutamic-pyruvic transaminase [SGPT]) > 3 × ULN.
b. Aspartate aminotransferase (AST; also serum glutamic-oxaloacetic transaminase [SGOT]) > 3 × ULN.
(Note: Subjects may be enrolled with AST > 3 × ULN if explained by hemolysis.)
c. Total serum bilirubin > 2 × ULN
(Note: Subjects may be enrolled with total serum bilirubin > 2 × ULN if explained by hemolysis or Gilbert’s syndrome. In the case of hemolysis, total serum bilirubin must be < 5 × ULN and in the case of Gilbert’s syndrome, total serum bilirubin must be < 11 × ULN.)
12. Current use of a prohibited concomitant medication within 7 days prior to Day 1 as detailed in Section 9.8.1.
13. Positive serology for human immunodeficiency virus, or active infection with hepatitis B virus or hepatitis C virus, unless receiving antiviral therapy and viral load is undetectable.
14. Positive drugs of abuse screen, unless by prescription.
15. Pregnant, planning to become pregnant, or breastfeeding.
16. Known hypersensitivity to BCX9930 or any of its formulation excipients.
17. History of severe hypersensitivity to any medicinal product, which was associated with swelling, severe rash requiring treatment/hospitalization, or anaphylaxis.
18. Any other clinically significant medical or psychiatric condition that, in the opinion of the investigator or sponsor, 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 from baseline (CFB) in hemoglobin (Hb)
• Number and proportion of subjects with a TEAE
• Number and proportion of subjects who discontinue due to a TEAE
• Number and proportion of subjects who experience a TESAE
• Number and proportion of subjects who experience a CTCAE Grade 3 or Grade 4 TEAE
• Number and proportion of subjects who experience a treatment-emergent CTCAE Grade 3 or Grade 4 laboratory abnormality
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 - mean of values at Weeks 12, 16, 20, and 24
others - week 52 |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of subjects who are transfusion-free
2. Number of units of packed red blood cells (pRBCs) transfused
3. CFB in FACIT-Fatigue scale score
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. - week 24
2. - week 24
3. - mean of values at Weeks 12, 16, 20, and 24 |
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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 | 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 | 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 | 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) | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Brazil |
| Canada |
| China |
| Colombia |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| European Union |
| Turkey |
| United Kingdom |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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