Paroxysmal Nocturnal Hemoglobinuria
Conditions
Keywords
HS-10542, paroxysmal nocturnal hemoglobinuria（PNH）, CFB
Brief summary
This was a phase 1b/2,open label, multi-center study to assess efficacy and safety of HS-10542 in adulte patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.
Detailed description
HS-10542 is a novel oral small molecular weight compound that inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral HS-10542 has the potential to prevent both intra - and extravascular hemolysis. This study consists of a dose exporation(Ph1b) and a dose expansion(Ph 2): Phase Ib:In participants with paroxysmal nocturnal hemoglobinuria (PNH), two dose levels of HS-10542 will be explored (low dose; high dose randomized 1:1), stratified by whether the patient is currently receiving C5 complement inhibitor therapy. Based on an integrated assessment of interim data on the safety, efficacy, and PK/PD profile of HS-10542 in the target population, the recommended Phase II dose (RP2D) will be determined. Phase II:Based on the safe and effective dose identified in Phase Ib, the efficacy and safety of HS-10542 will be evaluated in participants with PNH who have an inadequate response to C5 complement inhibitor therapy.
Interventions
DRUGHS-10542
HS-10542 low dose,QD
Sponsors
Jiangsu Hansoh Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Men or women aged more than or equal to (≥) 18 years, and less than (≤) 75 years. 2. It was confirmed to be PNH during screening, and the clone size of red blood cells or/and granulocytes or/and monocytes was detected by flow cytopy ≥10% 3. Stable use of C5 complement inhibitor ikuzumab/covalimab for the first 6 months of random treatment 4. Have at least one blood transfusion record within the last 4 months, or sustain a hemoglobin level below 100g/L the last 4 months prior to screening. 5. The average hemoglobin level from two tests conducted by the laboratory at the time of screening is less than 100 g/L, or hemoglobin level \<100g/L before transfusion. 6. LDH \> 1.5 x Upper Limit of Normal (ULN) at the time of screening 7. Inoccution of Neisseris meningitis and Streptococcus pneumoniae vaccine at least 2 weeks before the first administration of HS-10542; 8. if HS-10542 treatment must begin less than 2 weeks after vaccination, preventive antibiotic treatment must begin at least 2 weeks after vaccination. 9. Male and female subjects with fertility must agree to adopt efficient contraceptive measures with their partners within 60/120 days from the signing of the informed consent form to the last administration, 10. Male subjects who are infertile (such as those who have undergone effective sterilization surgery) must take additional efficient contraceptive measures when it is uncertain whether they have sperm，
Exclusion criteria
1. Known or suspected hereditary or acquired complement deficiency 2. Currently active primary or secondary immunodeficiency 3. History of infection with pod bacteria (such as Neisseris meningitis, Streptococcus pneumoniae, etc.) 4. Patients with laboratory evidence of bone marrow failure (reticulocytes \<100x109/L; platelets \<30x109/L; neutrophils \<0.5x109/L); 5. Presence of a bone marrow failure disorder (e.g., aplastic anemia, myelodysplastic syndrome, myelofibrosis) 6. Presence of active anemia unrelated to PNH, such as renal anemia or anemia due to blood loss. 7. There is or is suspected of systemic active bacteria, virus or fungal infection 2 weeks before the first administration of HS-10542 (according to the researcher's judgment) 8. During screening, there are advanced heart disease (such as NYHA level IV), 9. unstable thrombosis events that may exist for other causes, 10. Abnormal ECG: The absolute value of QTcF (QT interval corrected by Fridericia 's formula \> 450 msec for males and \> 470 msec for females; or other clinically significant abnormalities as judged by the investigator. 11. Major surgery within 3 months prior to the first dose. \*Note: See Appendix for definitions of Grade 3/4 surgeries. 12. Known active infection requiring systemic therapy 13. Diagnosed malignant tumors in the past 5 years 14. Those who have a history of splenectomy or History of bone marrow/hematopoietic stem cells or solid organ transplantation 15. Severe or poorly controlled hypertension 16. poorly controlled diabetes 17. Those who are suspected of being allergic to experimental drugs or any ingredient in experimental drugs 18. Use any of the following drugs, unless there is a stable treatment plan before screening: a) erythropoietin (ESA), hypoxic-inducing factor proaminoyl hydroxylase inhibitor (HIF-PHI) or immunosuppressant for at least 8 weeks b) Systemic use of glucocorticoids (≤15 mg/day Prednisone or equivalent doses of glucocorticoids) at least 4 weeks c) Vitamin K antagonists (such as warfarin) have a stable international standardized ratio (INR) at least 4 weeks d) Low molecular weight heparin, oral anticoagulants such as aspirin, rvaroxaban, apifloxaban, etc. at least 4 weeks e) Iron supplements , vitamin B12, folic acid or androgen for at least 4 weeks 19. Except for C5 complement inhibitors (including but not limited to ecucizumab and covalizumab), the situation of participating in other clinical trials or using other study drugs or approved therapies for experimental use before screening, and the trial drug is still within 5 half-lives or 2 weeks 20. Participants who have previously received B-factor inhibitor treatment, with a treatment duration of no more than one week and having stopped taking the drug for more than five half-lives before screening, may not be excluded 21. During screening, there are serious concurrent diseases, such as severe kidney disease (such as eGFR\<30 mL/min/1.73 m2, dialysis), 22. ALT/ALP\>3×ULN, 23. Screening positive blood pregnancy test and breastfeeding women at the time of the visit,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1b: Incidence and severity of adverse events | 12 weeks |
| Phase 2: In the absence of red blood cell infusion the proportion of subjects with at least 3 times of ≥120 g/L of hemoglobin level measured 4 times between weeks 18 and 24 | From the 18th to the 24th week |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: In the absence of red blood cell infusion the proportion of subjects of ≥120 g/L of hemoglobin level between weeks 3 and 12 | From the 3th to the 12th week | — |
| Phase 1b: the Proportion of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 20g/L in the Absence of Red Blood Cell Transfusions | hemoglobin between Day 15 and Day 84 and absence of transfusions | — |
| Phase 1b: The proportion of subjects who did not receive red blood cell infusion from week 3 to week 12 | From the 3th to the 12th week | — |
| Phase 1b: Change in LDH level from baseline | 12 weeks | — |
| Ph1b:change from baseline in hemoglobin concentration | 12 weeks | — |
| Phase 1b: Change From Baseline in Hgb.LDH.free-Hgb. haptoglobin and ferritin | by week 2 and week 4 | — |
| Phase 1b: The number of red blood cell units transfused by the participants who received blood transfusions | 12 weeks | — |
| Phase 1b: The average change of the score of Chronic Disease Treatment Function Assessment (FACIT) compared to the baseline | Baseline and week 2, week 4, week 8, week 12 | The FACIT-F is a 13 -item, self-reported PRO measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health-related QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue. |
| Phase 1b: The incidence of breakthrough hemolysis(BTH)from Week 1 to week 12 | From the 1th to the 12th week | — |
| Phase 1b: The incidence of Major Adverse Vascular Events(MAVEs) from Week 1 to week 12 | From the 1th to the 12th week | MAVEs are recorded on the AE page/. MAVEs include but are not limited to the following conditions:Acute peripheral vascular occlusion; Gangrene, amputation (non-traumatic, non-diabetic participants); Transient ischemic attack; Cerebral artery/vein occlusion/cerebrovascular accident; Hepatic/portal vein thrombosis (Budd-Chiari syndrome); Mesenteric/visceral artery or vein thrombosis; Unstable angina; Myocardial infarction; Pulmonary embolism; Renal artery/vein thrombosis; Thrombophlebitis/deep vein thrombosis. |
| Phase 2: the Proportion of Participants With Sustained Increase in Hemoglobin Levels From Baseline of ≥ 20 g/L in the Absence of Red Blood Cell Transfusions | From the 18th to the 24th week | — |
| Phase 2: The proportion of subjects who did not receive red blood cell infusion from week 3 to week 24 | From the 3th to the 24th week | — |
| Phase 2: the average change of Hemoglobin compared to the baseline | From the 18th to the 24th week | — |
| Phase 2: the average change of Ret compared to the baseline | From the 18th to the 24th week | — |
| Phase 2: the average change of LDH compared to the baseline | From the 18th to the 24th week | — |
| Phase 2: Chronic Disease Treatment Function Assessment (FACIT) from weeks 18 to 24- the average change of the score compared to the baseline | From the 18h to the 24th week | The FACIT-F is a 13 -item, self-reported PRO measure assessing an individual's level of fatigue during their usual daily activities over the past week. This questionnaire is part of the FACIT measurement system, a compilation of questions measuring health-related QoL in patients with cancer and other chronic illnesses. The FACIT-fatigue assesses the level of fatigue using a 4-point Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher scores indicating greater fatigue. |
| Phase 2: Incidence and severity of adverse events | From the 1th to the 24th week | — |
Countries
China
Contacts
CONTACTYan Hong Tong
Outcome results
None listed