A Phase 3 Study of Danicopan (ALXN2040) as Add-on Therapy to a C5 Inhibitor (Eculizumab or Ravulizumab) in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Have Clinically Evident Extravascular Hemolysis (EVH)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Change From Baseline in Hgb at Week 12
研究概览
简要总结
The main objective of this study is to evaluate the efficacy of danicopan as add-on therapy to a complement component 5 (C5) inhibitor (eculizumab or ravulizumab) in participants with PNH who have clinically evident EVH.
详细描述
This is a multiple-region, randomized, double-blind, placebo controlled, multiple-dose, study in participants with PNH who have clinically evident EVH on a C5 inhibitor (eculizumab or ravulizumab).
Participants will be randomized to receive danicopan or placebo, in a 2:1 ratio for 12 weeks (Treatment Period 1) in addition to their C5 inhibitor (eculizumab or ravulizumab) therapy. At Week 12, participants randomized to receive placebo will be switched to danicopan in addition to their C5 inhibitor for an additional 12 weeks (Treatment Period 2) and participants randomized to danicopan will continue on danicopan for an additional 12 weeks, while remaining on their ongoing C5 inhibitor therapy.
At the end of the 2 treatment periods (Week 24), participants may enter a Long-Term Extension (LTE) Period and continue to receive danicopan in addition to their C5 inhibitor therapy. The Long-Term Extension period will consist of a first year of LTE(Year1) and a second year of optional LTE(Year2).All patients will complete 72 weeks of LTE(Year 1) assessments. After Week 72 (at the end of the first year of LTE), patients have the choice to complete participation in this study or continue to the optional second year (Year2) of LTE.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of PNH
- •Clinically Evident EVH defined by:
- •Anemia (Hgb ≤9.5 gram/deciliter) with absolute reticulocyte count ≥120 x 10^9/liter
- •Receiving an approved C5 inhibitor for at least 6 months prior to Day 1
- •Platelet count ≥30,000/microliters (µL)
- •Absolute neutrophil counts ≥500/μL
- •Documentation of/or willingness to receive vaccinations for N. meningiditis and prophylactic antibiotics as required
排除标准
- •History of a major organ transplant or hematopoietic stem cell transplantation (HSCT)
- •Participants with known aplastic anemia or other bone marrow failure that requires HSCT or other therapies including anti-thymocyte globulin and/or immunosuppressants
- •Known or suspected complement deficiency
- •Laboratory abnormalities at screening, including:
- •Alanine aminotransferase >2 x ULN (>3 x ULN in case of patients with documented liver iron overload defined by serum ferratin values
- •500 ng/ML)
- •Direct bilirubin >2 x ULN (unless due to EVH or documented Gilbert's Syndrome)
- •Current evidence of biliary cholestasis
- •Estimated glomerular filtration rate of <30 milliliters/minute/1.73 meter squared and/or are on dialysis
- •Evidence of human immunodeficiency virus, hepatitis B, or active hepatitis C infection at screening
研究组 & 干预措施
Danicopan + C5 Inhibitor
Participants will receive danicopan, in addition to their C5 inhibitor therapy, for 24 weeks (12 weeks in Treatment Period 1, followed by 12 weeks in Treatment Period 2).
干预措施: Danicopan (Drug)
Danicopan + C5 Inhibitor
Participants will receive danicopan, in addition to their C5 inhibitor therapy, for 24 weeks (12 weeks in Treatment Period 1, followed by 12 weeks in Treatment Period 2).
干预措施: C5 Inhibitor (Drug)
Placebo + C5 Inhibitor
Participants will receive placebo, in addition to their C5 inhibitor therapy, for 12 weeks during Treatment Period 1. At Week 12, participants randomized to receive placebo will be switched to danicopan for an additional 12 weeks (Treatment Period 2).
干预措施: Placebo (Drug)
Placebo + C5 Inhibitor
Participants will receive placebo, in addition to their C5 inhibitor therapy, for 12 weeks during Treatment Period 1. At Week 12, participants randomized to receive placebo will be switched to danicopan for an additional 12 weeks (Treatment Period 2).
干预措施: C5 Inhibitor (Drug)
结局指标
主要结局
Change From Baseline in Hgb at Week 12
时间窗: Baseline, Week 12
Baseline was defined as the lowest Hgb value observed between and including Screening and Day 1. The least square (LS) mean and standard error (SE) were produced using mixed-effect model for repeated measures (MMRM). Hgb values collected within 4 weeks after transfusion were not included in the MMRM.
次要结局
- Change From Baseline in Lactate Dehydrogenase at Week 12(Baseline, Week 12)
- Percentage of Participants With Hgb Normalization at Week 12(Week 12)
- Percentage of Participants With Hgb Increase of ≥2 Grams/Deciliter (g/dL) (≥20 g/L) From Baseline in the Absence of Transfusion at Week 12(Week 12)
- Percentage of Participants With Transfusion Avoidance Through Week 12(Week 12)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score at Week 12(Baseline, Week 12)
- Change From Baseline in Absolute Reticulocyte Count at Week 12(Baseline, Week 12)
- Change in the Number of Red Blood Cell (RBC) Units Transfused From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment(24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment)
- Change in Number of Transfusion Instances From 24 Weeks Prior to Initiation of Treatment to Post 24 Weeks of Treatment(24 weeks prior to initiation of treatment to 24 weeks post initiation of treatment)
- Percentage of Participants With Transfusion Avoidance Through Week 24(24 weeks)
- Change in the Number of RBC Units Transfused From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment(12 weeks prior to initiation of treatment to 12 weeks post initiation of treatment)
- Change in Number of Transfusion Instances From 12 Weeks Prior to Initiation of Treatment to Post 12 Weeks of Treatment(12 weeks prior to initiation of treatment to post 12 weeks of treatment (24 weeks))
- Change From Baseline FACIT Fatigue Scores at Week 24(Baseline, Week 24)
- Percentage of Participants With Hgb Stabilization During Last 12 Weeks of Treatment in Participants Receiving 24 Weeks of Danicopan(Week 12 to Week 24)
- Percentage of Participants With Hgb Increase of ≥2 g/dL (≥ 20 g/L) From Baseline in the Absence of Transfusion at Week 24(Week 24)
- Change From Baseline in Total and Direct Bilirubin at Week 12(Baseline, Week 12)
- Change From Baseline in Paroxysmal Nocturnal Hemoglobinuria (PNH) RBC Clone Size at Week 12(Baseline, Week 12)
- Change From Baseline in Complement Component 3 Fragment Deposition (C3d PNH Type 3 Cells) on PNH RBCs at Week 12(Baseline, Week 12)
- Percentage of Participants With Hgb Normalization at Week 24(Week 24)