An Adaptive, Randomized, Placebo-controlled, Double-blind, Multi-center Study of Oral Etavopivat, a Pyruvate Kinase Activator in Patients With Sickle Cell Disease (HIBISCUS)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 450
- 试验地点
- 271
- 主要终点
- Hemoglobin response rate
研究概览
简要总结
This clinical trial is a Phase 2/3 study that will evaluate the efficacy and safety of etavopivat and test how well etavopivat works compared to placebo to improve the amount of hemoglobin in the blood and to reduce the number of vaso-occlusive crises (times when the blood vessels become blocked and cause pain).
详细描述
Etavopivat is designed to activate PKR and thereby modulate RBC metabolism by impacting two critical pathways in RBCs. The etavopivat clinical development program will investigate whether decreasing 2,3-DPG may help oxygen bind to hemoglobin (i.e. increasing oxygen affinity), and thereby increase ATP and impact RBC function. This study is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study of patients age 12 to 65 years (inclusive), with sickle cell disease. There is one planned interim analyses in this study design. Initially, patients will be randomized at 1:1:1 to one of two dose levels of etavopivat or placebo. At the first interim analysis, one of the two etavopivat dose levels will be selected for the Phase 3 portion of the study, in which patients will be randomized at 1:1 to the selected etavopivat dose or placebo. Efficacy on hemoglobin will be evaluated at conclusion of the double-blind treatment period. Following completion of 52 weeks of double-blind treatment, patients may enter a 112-week etavopivat open-label extension period.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Provision of consent
- •Patient has a confirmed diagnosis of sickle cell disease
- •At least 2 episodes of vaso-occlusive crises in the past 12 months
- •Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL (≥ 55 and ≤ 105 g/L) during screening
- •Patients taking hydroxyurea, must demonstrate a stable dose for at least 90 days prior to start of study treatment
- •Patients on crizanlizumab or L-glutamine treatment at the time of consent must be on a stable dose for ≥ 12 months and must be ≥ 80% compliant with the planned regimen at the time of consent and meet the VOC eligibility criteria
- •Female patients of childbearing potential must use highly effective methods of contraception, male patients are willing to use barrier methods of contraception
排除标准
- •More than 15 vaso-occlusive crises within the past 12 months
- •Female who is breastfeeding or pregnant
- •Hepatic dysfunction characterized by:
- •Alanine aminotransferase (ALT) > 4.0 × upper limit of normal (ULN)
- •Direct bilirubin > 3.0 × ULN
- •Known HIV positivity
- •Active hepatitis B or hepatitis C infection
- •Severe renal dysfunction or on chronic dialysis
- •History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:
- •Unstable angina pectoris or myocardial infarction or elective coronary intervention
- •Congestive heart failure requiring hospitalization
- •Uncontrolled clinically significant arrhythmias
- •Symptomatic pulmonary hypertension
- •History of overt clinical stroke within previous 2 years or any history of an intracranial hemorrhage
- •History of deep venous thrombosis requiring systemic anti-coagulation therapy for ≥ 6 weeks, occurring within 6 months prior to Day 1 of study treatment.
- •Prior/Concomitant Therapy
- •Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion)
- •Receiving or use of concomitant medications that are strong inducers of CYP3A4/5 within 2 weeks of starting study treatment or anticipated need for such agents during the study
- •Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study
- •Use of an experimental selectin antagonist (eg, monoclonal antibody or small molecule) within 28 days of starting study treatment or anticipated need for such agents during the study
- •Use of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study
- •Receipt of prior cellular-based therapy (eg, hematopoietic cell transplant, gene modification therapy)
研究组 & 干预措施
Double blind placebo
Double blind placebo
干预措施: Placebo Tablets (Drug)
Double blind etavopivat High Dose
Double blind etavopivat High Dose
干预措施: Etavopivat Tablets High dose (Drug)
Double blind etavopivat Low Dose
Double blind etavopivat Low Dose
干预措施: Etavopivat Tablets Low dose (Drug)
Open label etavopivat
Open label etavopivat
干预措施: Etavopivat Tablets (Drug)
结局指标
主要结局
Hemoglobin response rate
时间窗: 24 Weeks
Hemoglobin response rate at Week 24 (increase of \> 1 g/dL \[\> 10 g/L\] from baseline) during the blinded treatment period
Annualized vaso-occlusive crisis
时间窗: 52 Weeks
Annualized vaso-occlusive crisis rate during the 52-week blinded treatment period based on adjudicated vaso-occlusive crisis review
次要结局
- Hemoglobin(52 Weeks)
- Absolute reticulocyte count(24 Weeks)
- Indirect bilirubin(24 Weeks)
- Lactate dehydrogenase(24 Weeks)
- Vaso-occlusive crisis(52 Weeks)
- Fatigue(52 Weeks)