EUCTR2017-003803-22-ES进行中（未招募）1 期
An Open-Label Study to Evaluate the Efficacy and Safety of AG-348 in Regularly Transfused Adult Subjects With Pyruvate Kinase (PK) Deficiency
适应症
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 20
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
入选标准
- •1. Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
- •2. Be male or female, aged 18 years and older.
- •3. Have documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 is a missense mutation, as determined per the genotyping performed by the study central genotyping laboratory.
- •4. Have a history of a minimum of 6 transfusion episodes in the 52-week period prior to date of informed consent as documented in the transfusion history of the subject.
- •5. Have complete records of transfusion history, defined as having the following available for the 52 weeks prior to the date of informed consent: (1) all the transfusion dates, (2) the number of blood units transfused for all the transfusions, and (3) Hb levels within 1 week prior to transfusion for at least 80% of the transfusions.
- •6. Received at least 0.8 mg of oral folic acid daily for at least 21 days prior to the first dose of study drug, to be continued daily during study participation.
- •7. Have adequate organ function, as defined by:
- •a. Serum AST =2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and ALT =2.5 × ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition)
- •b. Normal or elevated levels of serum bilirubin. In subjects with serum bilirubin >ULN, the elevation must be attributed to hemolysis with or without Gilbert’s syndrome and must not be associated with hepatocellular or biliary disease.
- •c. Serum creatinine =1.25 × ULN. If serum creatinine is >1.25 × ULN, then 24-hour measured or calculated (Cockcroft-Gault) glomerular filtration rate (GFR) must be =60 mL/min.
- •d. Absolute neutrophil count (ANC) =1.0 × 109/L
- •e. Platelet count =100 × 109/L
- •f. Activated partial thromboplastin time (aPTT) and international normalized ratio (INR) =1.25 × ULN, unless the subject is receiving therapeutic anticoagulants
- •8. For women of reproductive potential— defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (ie, who have not menstruated at all for at least the preceding 12 months and have an elevated follicle-stimulating hormone (FSH) level indicative of menopause at screening):
- •a. Have a negative serum pregnancy test during Screening.
- •b. For women of reproductive potential as well as fertile men and their partners who are women of reproductive potential:
- •- Be abstinent as part of their usual life style, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 30 days (both men and women) following the last dose of AG-348. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier method (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization.
- •9. Be willing to comply with all study procedures, in particular the Individual TT (calculated based on 52 weeks of transfusion history), for the duration of the stu
排除标准
- •1. Be homozygous for the R479H mutation or have 2 non-missense mutations in the PKLR gene, as determined per the genotyping performed by the study central genotyping laboratory.
- •2. Have a significant medical condition that confers an unacceptable risk to participate in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
- •a. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mm Hg or diastolic BP >90 mm Hg) refractory to medical management.
- •b. History of recent (within 6 months prior to providing informed consent) congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
- •c. Cardiac dysrhythmias judged as clinically significant by the Investigator.
- •d. Heart-rate corrected QT interval-Fridericia’s method (QTcF) >450 msec with the exception of subjects with right or left bundle branch block.
- •e. Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.
- •f. History of drug-induced cholestatic hepatitis.
- •g. Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (eg, clinically significant impaired left ventricular ejection fraction), hepatic (eg, fibrosis, cirrhosis), or pancreatic (eg, diabetes) dysfunction.
- •h. Have a diagnosis of any other congenital or acquired blood disorder, or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy.
- •i. Positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCVAb, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be re-screened after receiving appropriate hepatitis C treatment.
- •j. Positive test for human immunodeficiency virus (HIV)-1 or -2 Ab.
- •k. Active infection requiring the use of parenteral antimicrobial agents or =Grade 3 in severity (per NCI CTCAE) within 2 months prior to first dose of study drug.
- •l. Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary.
- •m. History of any primary malignancy, with the exception of: curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
- •n. Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise.
- •o. Current or recent history of psychiatric disorder that, in the opinion of the Investigator or the Medical Monitor, could compromise the ability of the subject to cooperate with study visits and procedures.
- •3. Have a h
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