A study to investigate the efficacy, pharmacokinetics, and safety of mitapivat in pediatric subjects with α- or β-transfusion-dependent thalassemia

Prior treatment

• Active infection requiring systemic antimicrobial therapy at the time of providing informed consent/assent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before randomization.
• History of major surgery (including splenectomy) ≤6 months before providing informed consent/assent and/or a major surgical procedure planned during the study.
• Current enrollment or past participation (within ≤12 weeks or a timeframe equivalent to 5 half-lives of the investigational study drug before administration of the first dose of 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 CYP3A4/5 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.
• 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: • Subjects who are institutionalized by regulatory or court order • Subjects 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)
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation, including any prior exposure to myeloablative chemotherapy.
• 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.

Other illness

• Subjects with known active hepatitis B or hepatitis C virus infection.
• Subjects with known HIV infection.
• Documented history of homozygous or heterozygous HbS or HbC.
• Any conditions other than thalassemia expected to affect sexual maturation.

Lab values

• Nonfasting triglycerides >215 mg/dL (5 mmol/L).
• Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry filmcoat [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2]).
• 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: a. Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary) c. History of drug-induced cholestatic hepatitis d. Aspartate aminotransferase >2.5×ULN (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5×ULN (unless due to hepatic iron deposition)

Age

• History of malignancy (active or treated) ≤5 years before providing informed consent/assent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ.

Other

• Pregnant or breastfeeding.
• Renal dysfunction as defined by an estimated glomerular filtration rate <60 mL/min/1.73 m2

• Written informed consent/assent from the subject (or their legally authorized representative, parent(s), or legal guardian) must be obtained before any study-related procedures are conducted, and subjects must be willing to comply with all study procedures for the duration of the study.
• Aged 1 to <18 years and weighing at least 7 kg at the time of providing informed consent/assent.
• Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on Hb electrophoresis, Hb high-performance liquid chromatography, and/or DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, the test(s) can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test(s), results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
• Transfusion dependent, defined as 6 to 20 transfusion episodes (also referred to as “transfusion events”) and a ≤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.
• Female subjects who have attained menarche 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. The second form of contraception can include an acceptable barrier method.