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临床试验/NCT02476916
NCT02476916已完成2 期

A Phase 2, Open Label, Randomized, Dose Ranging, Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Study of AG-348 in Adult Patients With Pyruvate Kinase Deficiency

Agios Pharmaceuticals, Inc.25 个研究点 分布在 6 个国家目标入组 52 人开始时间: 2015年6月26日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
2 期
状态
已完成
入组人数
52
试验地点
25
主要终点
Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Study AG348-C-003 is a multicenter study designed to evaluate the safety and efficacy of different dose levels of AG-348 (mitapivat) in participants with PK deficiency.

详细描述

This is a Phase 2, open label, two arm, multicenter, randomized, dose-ranging study during which adult participants with PK deficiency will receive multiple doses of AG-348 for up to 24 weeks (Core Period); eligible participants may enter an Extension Period to receive AG-348 for up to 8 additional years. Data will be reviewed on a regular basis and study design, dose and schedule will be adapted based on these reviews. The study will evaluate the safety and tolerability of multiple doses of AG-348, pharmacokinetic and pharmacodynamic (PD) profile of AG-348 and early indicators of clinical efficacy.

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
None

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

  • •Informed consent
  • •Male or female, aged 18 years and older
  • •Known medical history of PK deficiency
  • •PK deficiency confirmed by enzymatic assay at Screening
  • •Genotypic characterization of PKR gene at Screening
  • •Genotypic characterization of uridine-5'-diphosphate-glucuronyltransferase-A1 (UGTA1) gene to document underlying Gilbert's disease (Gilbert's disease patients are eligible)
  • •Males Hb ≤ 12.0 g/dL, females Hb ≤ 11 g/dL
  • •Transfusion independent, defined as no more than 3 units of red blood cells (RBC) transfused in 12 months prior to the first day of study dosing and no transfusions within 4 months of first day of study dosing
  • •Splenectomized patients must have had the procedure at least 6 months prior to Screening and must be up-to-date in recommended vaccinations
  • •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • •Must be taking at least 1 mg folic acid daily in the 21 days prior to screening
  • •Adequate organ function defined by liver function, kidney function, platelet count and coagulation assessments
  • •Agreement to use approved contraceptive measures
  • •Women must not be breastfeeding
  • •For entry into the Extension Period, patients must meet criteria # 15-16:
  • •Must have completed 24 weeks of treatment during the Core Period and tolerated AG-348
  • •The treating Investigator agrees that there is a potential for clinical benefit to continued treatment and recommends participation in the Extension Period and the Medical Monitor approves

排除标准

  • •Hb ˃ 12.0 g/dL if male, Hb ˃11.0 g/dL if female
  • •Additional diagnosis of other congenital or acquired blood disorder
  • •Iron overload sufficiently severe to result in cardiac, hepatic or pancreatic insufficiency
  • •Bone marrow or stem cell transplant
  • •Clinically symptomatic cholelithiasis or cholecystitis
  • •Currently enrolled in any other investigational trial. Participation in the PK Deficiency Natural History Study (NCT02053480) is permitted
  • •Exposure to any investigational drug, device or procedure within 28 days prior to screening or during trial participation
  • •Concurrent medical condition such as poorly controlled hypertension, heart failure, active infection, frequent post-splenectomy sepsis, Hepatitis B or C, Human Immunodeficiency Virus type 1 (HIV1) or Human Immunodeficiency Virus type 2 (HIV2) infection, poorly controlled diabetes mellitus, history of primary malignancy with the exception of curatively treated nonmelanomatous skin cancer, cervical cancer of breast cancer in situ
  • •Major surgery in the last 6 months
  • •Psychiatric disorder that could compromise the ability of the patient to cooperate with the study
  • •Serum bilirubin higher to the upper limit of normal attributable to factors other than hemolysis or Gilbert's Syndrome
  • •Use of restricted products known to strongly inhibit cytochrome P450 (CYP) 3A4 metabolism within 5 days prior to Prior Day 1 dosing, or to strongly induce cytochrome P450 3A4 (CYP3A4) metabolism within 28 days prior to Day 1 dosing, or to strongly inhibit P-glycoprotein transporter within 5 days prior to Day 1 dosing, or digoxin within 5 days prior to Day 1 dosing.
  • •Heart-rate corrected QT interval - Fridericia's method (QTcF) interval ˃ 450 ms in male, QTcF > 470 ms in female, with the exception of patients with a left Bundle Branch Block
  • •Cardiac arrhythmias that are clinically significant or treated with drugs that are substrates of CYP3A4
  • •Allergy to sulfonamides if characterized by acute hemolytic anemia, anaphylaxis, rash of erythema multiforme type or Stevens-Johnson Syndrome
  • •Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to participate in the study
  • •Patients will not be permitted to enter the Extension Period if: The patient experienced AEs during the Core Period that are considered by the treating Investigator or the Sponsor's designated Medical Monitor to pose a significant safety risk to the patient if treatment were to be extended

研究组 & 干预措施

AG-348 300 mg BID

Experimental

Participants with PK deficiency will receive AG-348, 300 mg, as initial dose, BID for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent AEs and Hb levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 300 mg, BID, up to 102 months.

干预措施: AG-348 (Drug)

AG-348 50 mg BID

Experimental

Participants with Pyruvate Kinase (PK) deficiency will receive AG-348, 50 milligrams (mg), as initial dose, twice daily (BID) for 24 weeks (Core Period). Participants will be assigned to initial doses, however, over the course of the Core Period they will be treated across a range of doses due to treatment emergent adverse events (AEs) and hemoglobin (Hb) levels exceeding mid-point of sex-adjusted ranges. At the Week 24 visit, Core Period participants who have safely tolerated AG-348 and demonstrating clinical activity in response to AG-348 will be rolled over to the Extension Period. During the extension period, participants will continue to receive AG-348 50 mg, BID, for up to 102 months.

干预措施: AG-348 (Drug)

结局指标

主要结局

Percentage of Participants Experiencing at Least One Adverse Event (AEs) in the Core Period

时间窗: Up to Week 24

An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered study drug-related.

次要结局

  • Change From Baseline in Reticulocyte Count Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Carbon Monoxide Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Hematocrit Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Hemoglobin (Hb) Value at Week 24(Baseline and Week 24)
  • Change From Baseline in Reticulocyte Count at Week 24(Baseline and Week 24)
  • Change From Baseline in Hb Value Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Hematocrit at Week 24(Baseline and Week 24)
  • Change From Baseline in Carbon Monoxide at Week 24(Baseline and Week 24)
  • Percentage of Participants Experiencing at Least One AE Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Haptoglobin at Week 24(Baseline and Week 24)
  • Change From Baseline in Haptoglobin Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in EPO Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Transferrin Saturation Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Indirect Bilirubin Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Ferritin Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Total Bilirubin at Week 24(Baseline and Week 24)
  • Change From Baseline in Indirect Bilirubin at Week 24(Baseline and Week 24)
  • Change From Baseline in Ferritin at Week 24(Baseline and Week 24)
  • Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24(Baseline and Week 24)
  • Change From Baseline in LDH Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Total Bilirubin Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Change From Baseline in Hepcidin at Week 24(Baseline and Week 24)
  • Change From Baseline in Hepcidin Over the Duration of the Extension Period(Up to approximately 8.5 years)
  • Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for 2,3 - Diphosphoglycerate (2,3-DPG)(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Change From Baseline in Erythropoietin (EPO) at Week 24(Baseline and Week 24)
  • Change From Baseline in Transferrin Saturation at Week 24(Baseline and Week 24)
  • Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP)(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Area Under the Concentration-time Curve From Time Zero to the Last Non-zero Concentration (AUC0-t) for AG-348 and Its Metabolite AGI-8702(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Maximum Plasma Concentration (Cmax) for AG-348 and Its Metabolite AGI-8702(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Time to Reach Peak Plasma Concentration (Tmax) for AG-348 and Its Metabolite AGI-8702(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1 and pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Apparent Clearance at Steady-State (Clss/F) for AG-348 and Its Metabolite AGI-8702(pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • Percentage of Participants Experiencing at Least One AE up to Month 102(Up to Month 102)
  • Change From Baseline Hb Value up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Hematocrit up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Reticulocyte Count up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Haptoglobin up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Carboxyhemoglobin (COHb) at Week 24(Baseline and Week 24)
  • Change From Baseline in COHb up to Month 30(Baseline, Months 12, 18, 24, and 30)
  • Change From Baseline in LDH up to Month 30(Baseline, Months 12, 18, 24, and 30)
  • Change From Baseline in Total Bilirubin up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Indirect Bilirubin up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in (EPO) up to Month 30(Baseline, Months 12, 18, 24, and 30)
  • Change From Baseline in Hepcidin up to Month 30(Baseline, Months 12, 18, 24, and 30)
  • Change From Baseline in Ferritin up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Change From Baseline in Transferrin Saturation up to Month 102(Baseline, Months 12, 36, 60, 84, and 102)
  • Maximum Change From Baseline Response Value Over 12 Hours Post-dose (BRmax) for Adenosine Triphosphate (ATP)(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1)
  • Maximum Change From Baseline Response Value Over 8 Hours Post-dose at Steady State (BRmax ss) for ATP(pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)
  • BRmax for 2,3 - Diphosphoglycerate (2,3-DPG)(pre-dose, 0.5, 1, 2, 4, 8, 12 hours post-dose Day 1)
  • BRmax ss for 2,3-DPG(pre-dose, 0.5, 1, 2, 4, 8 hours post-dose Day 15)

研究者

申办方类型
Industry
责任方
Sponsor

研究点 (25)

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