A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

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追踪信息

首次提交日期 ^ICMJE

September 10, 2018

首次发布日期e ^ICMJE

October 2, 2018

最后更新发布日期

October 2, 2018

预计研究开始日期 ^ICMJE

November 2018

预计主要完成日期

December 2021 (主要结果测量的最终数据收集日期)

目前主要观察指标 ^ICMJE

Percentage of Participants Achieving a Hemoglobin Response (HR)[ Time Frame: Up to 12 weeks ]

HR is defined as a ≥1.0 gram per deciliter (g/dL) increase in Hb concentration from baseline at 1 or more assessments between Week 4 and Week 12 (inclusive). A participant's baseline Hb concentration is defined as the average of all the participant's available Hb concentrations during the 42-day screening period up to the first dose of study drug.

原始主要观察测量 ^ICMJE

与当前相同

目前的二级观察 ^ICMJE

Mean Change from Baseline in Hb Concentrations from Week 12 to Week 24[ Time Frame: Baseline, Week 12 to Week 24 ]
Percentage of Participants Achieving a Sustained Hb Response (sHR)[ Time Frame: Week 12 to Week 24 ]
sHR is defined as a ≥1.0 g/dL increase in Hb concentration at 2 or more evaluable Hb assessments out of the 4 scheduled assessments between the Week 12 Visit and Week 24 Visit
Change from Baseline in Hb Concentration over an Additional 2 Years in the Extension Period[ Time Frame: Baseline up to approximately 2.5 years ]
Time to Achieve HR[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Reticulocyte Count[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Bilirubin[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Lactate Dehydrogenase (LDH)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Haptoglobin[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Nucleated Red Blood Cells (NRBCs)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Erythropoietin (EPO)[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Soluble Transferrin Receptor[ Time Frame: Up to approximately 2.5 years ]
Change from Baseline in Iron[ Time Frame: Up to Week 120 ]
Change from Baseline in Serum Ferritin[ Time Frame: Up to Week 120 ]
Change from Baseline in Total Iron-binding Capacity (TIBC)[ Time Frame: Up to Week 120 ]
Change from Baseline in Transferrin Saturation[ Time Frame: Up to Week 120 ]
Change from Baseline in Hepcidin[ Time Frame: Up to Week 120 ]
Change from Baseline in C-reactive Protein[ Time Frame: Up to Week 120 ]
Drug Concentrations over Time for AG-348[ Time Frame: Pre-dose at Weeks 1, 2, 3, 4, 6, 8, 16, 20, and 24 ]
Change from Baseline in Adenosine Triphosphate (ATP) Concentrations[ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
Change from Baseline in 2,3-DPG Concentrations[ Time Frame: Pre-dose on Day 1 and at Weeks 6, 8, 12, and 24 ]
Change from Baseline in Red Blood Cell (RBC)-specific Form of Pyruvate Kinase (PKR) Activity[ Time Frame: Pre-dose and at 2 hours post-dose on Day 1; pre-dose at Week 12 ]
Change from Baseline in PKR Protein Levels[ Time Frame: Pre-dose on Day 1 and at Weeks 12 and 24 ]
Change from Baseline in PKR Flux Assay Results[ Time Frame: Pre-dose on Day 1 and at Week 12 ]
Percentage of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Significant Interest (AESIs), and AEs Leading to Study Drug Dose Reduction, Study Drug Interruption, and Study Drug Discontinuation[ Time Frame: Up to approximately 2.5 years ]

描述性信息

简略标题 ^ICMJE

A Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Participants With Non-transfusion-dependent Thalassemia

正式标题 ^ICMJE

A Phase 2, Open-label, Multicenter Study to Determine the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of AG-348 in Adult Subjects With Non-transfusion-dependent Thalassemia

简要概况

Study AG348-C-010 is a multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-dependent thalassemia (NTDT). This study will include a 24-week core period followed by a 2-year extension period for eligible participants. Approximately 17 participants with NTDT will be enrolled. The initial dose of AG-348 will be 50 milligrams (mg) twice daily (BID) with one potential dose-level increase to 100 mg BID, at the Week 6 visit based on the participant's safety and hemoglobin (Hb) concentrations.

详细说明

研究类型 ^ICMJE

Interventional

研究阶段

Phase 2

研究设计 ^ICMJE

分配:
干预模型: Single Group Assignment
干预模型描述:
盲法: Interventional
盲法描述:
主要目的: Treatment

适用条件 ^ICMJE

干预项目 ^ICMJE

Drug: AG-348
Core period: Participants will receive an initial AG-348 dose of 50 mg BID, oral tablets, and may undergo one potential dose-level increase to 100 mg BID, based on an evaluation of the participant's safety profile and Hb concentrations. Extension Period: Participants who achieve a Hb response with no safety issues will continue receiving treatment with AG-348 for up to 2 years at the same dose they were receiving at the Week 24 Visit.

研究工具

Experimental: AG-348
Core period: Participants will receive AG-348 for up to 24 weeks. Depending on the safety observations and hemoglobin (Hb) concentrations, they may undergo one potential dose-level increase from 50 to 100 mg BID. Extension Period: Eligible participants will continue to receive AG-348 for up to 2 years at the same dose they were receiving at the Week 24 visit.

招募信息

招募状态 ^ICMJE

Not yet recruiting

预计入组 ^ICMJE

原始预计入组 ^ICMJE

与当前相同

预计研究完成日期

December 2021

预计主要完成日期

December 2021 (主要结果测量的最终数据收集日期)

合格标准 ^ICMJE

Inclusion Criteria: - Informed consent; - Be aged 18 years or older; - Known medical history of thalassemia, including β-thalassemia intermedia, Hb E β-thalassemia, α-thalassemia (Hb H disease), or β-thalassemia with mutations of 1 or more α genes; - Documented clinical laboratory confirmation of thalassemia by Hb electrophoresis/high-performance liquid chromatography (HPLC) or deoxyribonucleic acid (DNA) analysis, either from medical records or during the screening period; - Hb concentration ≤9.0 grams per deciliter (g/dL), regardless of sex, based on an average of at least 2 Hb measurements (separated by a minimum of 7 days) during the screening period; - Considered non-transfusion-dependent, defined as having no more than 5 units of red blood cells (RBCs) transfused during the 24-week period up to the first day of study drug and no RBC transfusions in the 8 weeks prior to the first day of study drug; - Have adequate organ function; - For women of reproductive potential: negative serum pregnancy test during the screening period and a negative serum or urine pregnancy test on Day 1; - For women of reproductive potential as well as men with partners who are women of reproductive potential: abstinent as part of their usual lifestyle, or agreement to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of giving informed consent, during the study, and for 28 days (both men and women) following the last dose of study drug; - Willingness to comply with all study procedures for the duration of the study; Exclusion Criteria: - Known history of diagnosis of Hb S or Hb C forms of thalassemia; - Significant medical condition that confers an unacceptable risk to participating in the study, and/or could confound the interpretation of the study data; - Splenectomy scheduled during the study treatment period or having undergone splenectomy within 12 months prior to signing informed consent; - Currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo; - Exposure to any investigational drug, device, or procedure within 3 months prior to the first day of study drug; - Prior exposure to sotatercept (ACE-011), luspatercept (ACE-536), ruxolitinib, or gene therapy; - Prior bone marrow or stem cell transplant; - Currently pregnant or breastfeeding; - History of major surgery within 6 months of signing informed consent; - Are currently receiving medications that are strong inhibitors of cytochrome P450 (CYP)3A4, strong inducers of CYP3A4, strong inhibitors of P-glycoprotein (P-gp), or digoxin (a P-gp sensitive substrate medication) that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first day of study drug; - Currently receiving chronic anticoagulant therapy, unless started and on a stable dose for at least 28 days prior to first day of study drug; - Currently receiving anabolic steroids, including testosterone preparations, if initiated ≤28 days prior to the first day of study drug; - Currently receiving hematopoietic stimulating agents (e.g., erythropoietins, granulocyte colony stimulating factors, thrombopoietins), if initiated ≤8 weeks prior to the first day of study drug; - History of allergy to sulfonamides if characterized by acute hemolytic anemia, drug-induced liver injury, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson syndrome, cholestatic hepatitis, or other serious clinical manifestations; - History of allergy to AG-348 or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol).

性别

参与研究的性别:

All

年龄

最小年龄：18 Years ，最大年龄：N/A

接受健康的志愿者

没有

可入组国家 ^ICMJE

Canada|United Kingdom|United States

管理信息

数据检测委员会

研究涉及美国FDA监管的产品

研究美国FDA监管的药品: Yes
研究涉及美国FDA监管的设备产品: No

IPD 共享声明

计划分享 IPD:

责任方

，

研究赞助商 ^ICMJE

Agios Pharmaceuticals, Inc.

合作者 ^ICMJE

研究员 ^ICMJE

Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.

PRS 账户

验证日期

September 2018

^ICMJE 国际医学期刊编辑委员会和世界卫生组织 ICTRP 要求的元素

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