NCT05175105进行中（未招募）3 期
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Mitapivat in Pediatric Subjects With Pyruvate Kinase Deficiency Who Are Not Regularly Transfused, Followed by a 5-Year Open-label Extension Period
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
- 30
- 试验地点
- 30
- 主要终点
- Percentage of Participants Achieving a Hemoglobin (Hb) Response
研究概览
简要总结
Study ACTIVATE-Kids (AG348-C-023) will evaluate the efficacy and safety of orally administered mitapivat as compared with placebo in pediatric participants with pyruvate kinase deficiency (PKD) who are not regularly receiving blood transfusions. Participants will be randomized 2:1 to receive either mitapivat or matching placebo. Randomization will be stratified by age (1 to < 6 years, 6 to < 12 years, 12 to < 18 years). Participants will be dosed by age and weight during a double-blind period consisting of an 8-week dose titration period followed by a 12-week fixed-dose period. Participants who complete the double-blind period will be eligible to receive mitapivat for up to 5 years in the open-label extension (OLE) 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
- 1 Year 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent from the participant, or the participant's legally authorized representative, parent(s), or legal guardian, and the participant's assent, where applicable (informed consent/assent) must be obtained before any study-related procedures are conducted, and participants must be willing to comply with all study procedures for the duration of the study;
- •Aged 1 to <18 years. Participants between 12 and 24 months of age must weigh a minimum of 7 kilograms (kg);
- •Clinical laboratory confirmation of pyruvate kinase deficiency (PKD), defined as documented presence of at least 2 mutant alleles in the pyruvate kinase L/R (PKLR) gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory;
- •No more than 5 red blood cell (RBC) transfusions in the 52-week period before providing informed consent/assent and no RBC transfusions ≤12 weeks before administration of the first dose of study drug;
- •Hemoglobin concentration ≤10 grams per deciliter (g/dL) for participants 12 to <18 years of age or ≤9 g/dL for participants 1 to <12 years of age during the screening period. Hb concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the screening period;
- •Receiving folic acid supplementation as part of routine clinical care for at least 21 days before administration of the first dose of study drug, to be continued during study participation;
- •Female participants who have attained menarche and/or breast development in Tanner Stage 2 must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle, or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of informed consent/assent, throughout the study, and for 28 days after the last dose of study drug (including the time required to dose taper). The second form of contraception can include an acceptable barrier method.
排除标准
- •Pregnant or breastfeeding;
- •Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory;
- •History of malignancy;
- •History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent;
- •Hepatobiliary disorders including, but not limited to:
- •Liver disease with histopathological evidence of cirrhosis or severe fibrosis;
- •Clinically symptomatic cholelithiasis or cholecystitis (participants with prior cholecystectomy are eligible);
- •History of drug-induced cholestatic hepatitis;
- •Aspartate aminotransferase >2.5×upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition);
- •Renal dysfunction as defined by an estimated glomerular filtration rate <60 milliliters per minute (mL/min)/1.73 m^2;
- •Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
- •Active uncontrolled infection requiring systemic antimicrobial therapy;
- •Participants with known active hepatitis B or hepatitis C virus infection;
- •Participants with known human immunodeficiency virus (HIV) infection;
- •History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or planning on undergoing a major surgical procedure during the screening or double-blind period;
- •Current enrollment or past participation (within 90 days before the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device;
- •Prior exposure to gene therapy, or bone marrow or stem cell transplantation;
- •Currently receiving hematopoietic stimulating agents; the last dose must have been administered at least 28 days or a time frame equivalent to 5 half-lives (whichever is longer) before randomization;
- •Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization;
- •Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization;
- •Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Food, Drug, and Cosmetics blue dye number 2 (FD&C Blue #2)], Opadry® II White [hypromellose, titanium dioxide, lactose monohydrate, and triacetin], and magnesium stearate);
- •Any medical, hematologic, 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 included 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).
- •Receiving a pyruvate kinase activator that has not been stopped for ≥52 weeks before providing informed consent/assent.
研究组 & 干预措施
Mitapivat (OLE period)
Experimental
Participants who have completed the double-blind period will be eligible to receive mitapivat for up to 5 years in the OLE period. Participants entering the OLE period will first receive blinded mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment before being transitioned to only receive active, open-label drug (mitapivat).
干预措施: Mitapivat-matching placebo (Drug)
Placebo
Placebo Comparator
Double-Blind Period: Participants will receive mitapivat-matching placebo orally for 8 weeks in the dose titration period and for 12 weeks in the fixed-dose period.
干预措施: Mitapivat-matching placebo (Drug)
Mitapivat
Experimental
Double-Blind Period: Participants will receive mitapivat orally, at doses based on age and weight, for 8 weeks in the dose titration period and for 12 weeks in the fixed-dose period.
干预措施: Mitapivat (Drug)
Mitapivat (OLE period)
Experimental
Participants who have completed the double-blind period will be eligible to receive mitapivat for up to 5 years in the OLE period. Participants entering the OLE period will first receive blinded mitapivat and placebo for 8 weeks to maintain the double-blind treatment assignment before being transitioned to only receive active, open-label drug (mitapivat).
干预措施: Mitapivat (Drug)
结局指标
主要结局
Percentage of Participants Achieving a Hemoglobin (Hb) Response
时间窗: Baseline up to Week 20
Hb response is defined as a ≥1.5 grams per deciliter (g/dL) (0.93 millimoles per liter \[mmol/L\]) increase in Hb concentration from baseline that is sustained at 2 or more scheduled assessments at Weeks 12, 16, and 20 during the double-blind period. The individual participant's baseline Hb concentration is defined as the average of all available Hb concentrations collected for that participant during the screening period up to the first dose of study drug.
次要结局
- Change From Baseline in Serum Ferritin Concentration(Baseline up to Week 280)
- Change From Baseline in the Size of Ovarian Cysts in Female Participants(Baseline up to Week 286)
- Change From Baseline in Bone Mineral Density (BMD) Z-score(Baseline up to Week 286)
- Change From Baseline in Free Testosterone Concentration in Participants ≥7 Years of Age or Tanner Stage ≥2 (Whichever Occurs First)(Baseline up to Week 286)
- Average Change From Baseline in Hb Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Estradiol Concentration(Baseline up to Week 286)
- Change From Baseline in Total Testosterone Concentration(Baseline up to Week 286)
- Change From Baseline in Transferrin/Transferrin Saturation(Baseline up to Week 280)
- Change From Baseline in Sexual Maturity Rating with Tanner Stage(Baseline up to Week 286)
- Change From Baseline in Weight-for-age Z-score(Baseline up to Week 286)
- Change From Baseline in Body Mass Index (BMI)-for-age Z-score(Baseline up to Week 286)
- Maximal Change in Hb Concentration From Baseline During the Double-blind Period(Baseline up to Week 20)
- Change From Baseline in Estrone Concentration(Baseline up to Week 286)
- Average Change From Baseline in Lactose Dehydrogenase (LDH) Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Haptoglobin Concentration at Week 16(Baseline, Week 16)
- Change from Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale(Baseline up to Week 280)
- Change From Baseline in Luteinizing Hormone Concentration in Participants ≥6 Years of Age(Baseline up to Week 286)
- Number of Female Participants With Development of Ovarian Cysts(Baseline up to Week 286)
- Change From Baseline in Height-for-age Z-score(Baseline up to Week 286)
- Change From Baseline in Serum Iron Concentration(Baseline up to Week 280)
- Change From Baseline in Total Iron-binding Capacity(Baseline up to Week 280)
- Change from Baseline in PedsQL Generic Core Scale (GCS)(Baseline up to Week 280)
- Population PK Model Parameter Estimate: Area Under the Concentration-time Curve (AUC) Derived From Plasma Concentrations of Mitapivat(Weeks 2, 8, 12, and 16)
- Average Change From Baseline in Indirect Bilirubin Concentration at Weeks 12, 16, and 20(Baseline, Weeks 12, 16, and 20)
- Change From Baseline in Reticulocytes(Baseline up to Week 286)
- Concentration at Steady State (Css) of Mitapivat(Week 16: 6 and 8 hours postdose)
- Trough Concentration (Ctrough) of Mitapivat(Week 8: ≤30 minutes predose; Week 12: ≤30 minutes predose)
- Population Pharmacokinetic (PK) Model Parameter Estimate: Maximum Plasma Concentration (Cmax) of Mitapivat(Weeks 2, 8, 12, and 16)
研究者
研究点 (30)
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