A Phase Ib Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of VSA012 Injection in Subjects With Paroxysmal Nocturnal Hemoglobinuria Who Are Complement Inhibitor Naïve or Have Not Received Complement Inhibitor Recently and Have Persistent Anemia Despite Previous Stable Use of C5 Complement Inhibitor
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Number of Participants with Treatment-Emergent Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
研究概览
简要总结
The complement system is an important component of the innate immune system. Abnormal activation, inadequate regulation and control of the complement system, as well as impaired and dysfunctional effector functions, underlie complement mediated diseases including PNH. VSA012 targeting complement system has the potential to treat a variety of diseases associated with abnormal activation of the complement system.The purpose of VSA012-1002 is to evaluate the safety, tolerability, pharmacokinetic, pharmacodynamics and efficacy of VSA012 Injection in subjects with PNH.
详细描述
This is a multi-center, non-randomized, open-label Phase 1b study to evaluate the safety and tolerability, pharmacokinetic and pharmacodynamic profiles of VSA012 Injection in Chinese subjects with PNH, as well as to explore preliminary efficacy.
The VSA012 60 mg dose group and VSA012 120 mg dose group were initially proposed in this study; adjustments will be made based on data obtained in a single ascending dose study in healthy adult Chinese subjects (VSA012-1001) and stepwise data from this study, taking full account of subject safety. Enrollment in the 60 mg dose group of this study was not initiated until 15 days postdose safety assessments were completed for subjects in the 60 mg dose group of Study VSA012-1001; enrollment in the 120 mg dose group of Study VSA012-1001 was not initiated until 15 days postdose safety assessments were completed for subjects in the 120 mg dose group.
About 8 subjects with PNH will be enrolled in each group in this study and will receive VSA012 Injection 60 mg or V SA012 Injection 12 0 mg on D1 and D29, respectively; based on full consideration of the safety of subjects, the dosing regimen may be adjusted in combination with the data gradually obtained from the VSA012-1001 study and this study. Participants may receive concomitant supportive care permitted in this study throughout the study and continue to be followed for 24 weeks following completion of D29 dosing.
This study includes: Screening Period, Treatment Period, Follow-up Period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion and
排除标准
- •for Groups 1-4
- •Participants voluntarily participate in this clinical study, and voluntarily sign the ICF;
- •BMI ≥ 18.0 kg/m2; male or female; 18 to 75 years of age;
- •Confirmed diagnosis of PNH by clinical manifestation and flow cytometry; granulocyte clone size ≥ 10%;
- •Presence of one or more of PNH-related signs or symptoms within 3 months prior to screening;
- •Hb < 100 g/L;
- •LDH value > 1.5 × ULN;
- •One of the following criteria for prior drug therapy for PNH must be met:
- •Having never received any complement inhibitor therapy;
- •Having received C5, C3, or CFB complement inhibitors and having discontinued the complement inhibitor for more than 5 half-lives or 3 months prior to screening;
- •Participants are willing to receive meningococcal vaccine and pneumococcal vaccine at least 14 days prior to dosing.
- •Inclusion and Exclusion Criteria for Groups 5
- •Participants voluntarily participate in this clinical study, and voluntarily sign the ICF;
- •BMI ≥ 18.0 kg/m2; male or female; 18 to 75 years of age;
- •Confirmed diagnosis of PNH by clinical manifestation and flow cytometry; granulocyte clone size ≥ 10%;
- •Participants who have been on a stable dose and interval of a C5 complement inhibitor (approved locally) for at least 3 months prior to the first dose of VSA012;
- •Within the 3 months prior to screening, have a documented Hb level of < 105 g/L while on C5 complement inhibitor therapy;
- •Hb < 105 g/L;
- •Participants are willing to receive meningococcal vaccine and pneumococcal vaccine at least 14 days prior to dosing.
- •Exclusion Criteria for Groups 1-4
- •History of hypersensitivity to VSA012 or its excipients;
- •Use of any complement inhibitors within 3 months prior to screening
- •Use of any targeted small interfering RNA (siRNA) within 18 months prior to screening, or any antisense oligonucleotide molecule within 6 months prior to screening;
- •Supportive care for PNH does not meet the stable-dose requirements:
- •Participants have infections;
- •Laboratory tests meet the following criteria:
- •Reticulocyte count < 100 × 109/L;
- •Platelet count < 30 × 109/L;
- •Neutrophil count < 0.5 × 109/L;
- •Creatinine clearance < 30 mL/min (calculated by the Cockcroft-Gault formula);
- •Exclusion Criteria for Groups 5
- •History of hypersensitivity to VSA012 or its excipients;
- •Use of any targeted small interfering RNA (siRNA) within 18 months prior to screening, or any antisense oligonucleotide molecule within 6 months prior to screening;
- •Supportive care for PNH does not meet the stable-dose requirements:
- •Participants have infections;
- •History of splenectomy;
- •Previous suspected/confirmed hereditary complement deficiency;
- •History of recurrent invasive infections with capsular bacteria, e.g., meningococcus or pneumococcus;
- •Laboratory tests meet the following criteria:
- •Reticulocyte count < 100 × 109/L;
- •Platelet count < 30 × 109/L;
- •Neutrophil count < 0.5 × 109/L;
- •Creatinine clearance < 30 mL/min (calculated by the Cockcroft-Gault formula);
研究组 & 干预措施
VSA012 dose B
干预措施: VSA012 (Drug)
VSA012 dose A
干预措施: VSA012 (Drug)
VSA012 dose C
干预措施: VSA012 (Drug)
VSA012 dose D
干预措施: VSA012 (Drug)
VSA012 dose E
干预措施: VSA012 (Drug)
结局指标
主要结局
Number of Participants with Treatment-Emergent Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
时间窗: up to Day 540
preliminary efficacy
时间窗: up to Day 540
Percentage change from baseline in lactate dehydrogenase (LDH) by visit Change from baseline in hemoglobin (Hb) level by visit
Number of Participants with Treatment-Emergent Adverse Events (AEs) and/or Serious Adverse Events (SAEs)
时间窗: up to Day 196
preliminary efficacy
时间窗: up to Day 196
Percentage change from baseline in lactate dehydrogenase (LDH) by visit Change from baseline in hemoglobin (Hb) level by visit
次要结局
- PD of VSA012:Change from baseline in PNH clones, including number of PNH clones in erythrocytes, number of PNH clones in granulocytes, and number of PNH clones in monocytes(up to Day 540)
- Pharmacodynamic (PD) profile of VSA012:Change from baseline in complement factor B (CFB) and complement bypass pathway (CAP) activities(up to Day 540)
- Pharmacokinetics (PK) of VSA012 (First dose): Maximum Observed Plasma Concentration (Cmax)(Up to 48 hours post-dose)
- PK of VSA012(First dose): Time to Maximum Observed Plasma Concentration (Tmax)(Up to 48 hours post-dose)
- PK of VSA012(First dose)：Area under the concentration-time curve during the dosing interval (AUC 0-tau)(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：Trough concentration (C min)(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：Accumulation ratio of C max(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：AUC 0-tau(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：T max(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：C max (RacC max)(Up to 48 hours post-dose)
- PK of VSA012 (Multiple dose)：Accumulation ratio of AUC 0-tau (RacAUC 0-tau)(Up to 48 hours post-dose)
- Pharmacodynamic (PD) profile of VSA012:Change from baseline in complement factor B (CFB) and complement bypass pathway (CAP) activities(up to Day 196)
- PD of VSA012:Change from baseline in PNH clones, including number of PNH clones in erythrocytes, number of PNH clones in granulocytes, and number of PNH clones in monocytes(up to Day 196)