NCT04770779进行中（未招募）3 期
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE-T)
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 258
- 试验地点
- 111
- 主要终点
- Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
研究概览
简要总结
The primary objective of this study was to compare the effect of mitapivat versus placebo on transfusion burden in participants with α- or β-transfusion-dependent thalassemia.
详细描述
The mitapivat group included 171 participants. The placebo group included 87 participants.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Greater than or equal to (≥)18 years of age at the time of providing informed consent;
- •Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;
- •Considered transfusion-dependent, defined as 6 to 20 red blood cells (RBC) units transfused and ≤6-week transfusion-free period during the 24-week period before randomization;
- •If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
- •Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
- •Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.
排除标准
- •Pregnant, breastfeeding, or parturient;
- •Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
- •Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
- •Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
- •Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
- •History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
- •History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
- •Hepatobiliary disorders;
- •Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 meter (m)^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
- •Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
- •Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
- •Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
- •Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
- •History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
- •Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
- •Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
- •Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization;
- •Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD&C) Blue #2]);
- •Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:
- •Participants who are institutionalized by regulatory or court order
- •Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
研究组 & 干预措施
Placebo
Placebo Comparator
Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the DB period followed by mitapivat 100 mg, orally, BID for up to 5 years in the OLE period.
干预措施: Mitapivat (Drug)
Mitapivat
Experimental
Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in the double-blind (DB) period and for up to 5 years in the open label extension (OLE) period.
干预措施: Mitapivat (Drug)
Placebo
Placebo Comparator
Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the DB period followed by mitapivat 100 mg, orally, BID for up to 5 years in the OLE period.
干预措施: Placebo Matching Mitapivat (Drug)
结局指标
主要结局
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
时间窗: Double-blind Period: Baseline through Week 48
TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders.
次要结局
- Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat(Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36)
- Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat(Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36)
- Double-blind Period: Change From Baseline in Serum Ferritin Levels(Double-blind Period: Baseline through Week 48)
- Double-blind Period: Change From Baseline in Total Iron Binding Capacity(Double-blind Period: Baseline through Week 48)
- Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels(Double-blind Period: Baseline through Week 48)
- Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3(Double-blind Period: From first dose of study drug up to week 48)
- Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3(Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years))
- Double-blind Period: Plasma Concentrations of Mitapivat(Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36)
- Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat(Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36)
- Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat(Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36)
- Double-blind Period: Percentage of Participants Who Achieved TRR2(Double-blind period: Baseline through Week 48)
- Double-blind Period: Percentage of Participants Who Achieved TRR3(Double-blind period: Baseline up to Week 13 through Week 48)
- Double-blind Period: Percentage of Participants Who Achieved TRR4(Double-blind period: Baseline up to Week 13 through Week 48)
- Double-blind Period: Percent Change From Baseline in Transfused RBC Units(Double-blind Period: Baseline, Week 13 through Week 48)
- Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence(Double-blind Period: Baseline through Week 48)
- Double-blind Period: Change From Baseline in Iron Levels(Double-blind Period: Baseline through Week 48)
- Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat(Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36)
- Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)(Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36)
- Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)(Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36)
研究者
研究点 (111)
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