A Study to Investigate the Effect of Mitapivat on Transfusion Burden in Subjects With Sickle Cell Disease (SCD)

Inclusion Criteria: * Age ≥12 years. * Documented diagnosis of SCD (hemoglobin SS (HbSS), combined heterozygosity for hemoglobins S and C (HbSC), sickle cell hemoglobin (HbS)/β0-thalassemia, HbS/β+-thalassemia, or other sickle cell syndrome variants). * No more than 10 SCPCs in the 12 months before providing informed assent/consent. * At least 1 transfusion of packed RBCs in the 12 months before informed assent/consent. * Hb ≥5.5 and ≤10.5 g/dL. Hb concentration must be based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period. * Additional signs or symptoms of hemolysis, as evidenced by any laboratory assessment during the Screening Period with * Hb \<8 g/dL, or * Absolute reticulocyte count \> upper limit of normal (ULN), or * Indirect bilirubin \>ULN, or * LDH \>ULN * If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days prior to randomization. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent. * Women of childbearing potential (WOCBP) and pediatric 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 a highly effective method of contraception from the time of providing informed assent/consent, throughout the study, and for 28 days after the last dose of study drug; if the highly effective method of contraception is hormonal contraception, then an acceptable barrier method must also be used. * Written informed assent/consent (for subjects under 18 years of age, or prior to the age at which a subject is considered legally an adult per local regulations, parental permission and child assent will be obtained) 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. Exclusion Criteria: * Pregnant, breastfeeding, or parturient. * Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or vaso-occlusive crisis (VOC) is permitted. Additionally, a subject who requires episodic transfusion(s) may not have received a transfusion(s) within 60 days before providing informed assent/consent or during the Screening Period. * Hospitalized for an SCPC and/or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or outpatient clinic visit. A visit to an emergency room that does not result in an in-patient admission does not meet the definition of hospitalization. * Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of voxelotor, crizanlizumab, and L-glutamine must have been administered at least 90 days before randomization. * History of any malignancy except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment ≤5 years before providing informed assent/consent. * History of active and uncontrolled cardiac or pulmonary disease within 6 months before randomization, including but not limited to: * New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia. * Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism. * Heart rate-corrected QT interval using Fridericia's method of ≥470 milliseconds for female subjects and ≥450 milliseconds for male subjects, except for right or left bundle branch block. * Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis \>50%. * Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated. * Hepatobiliary disorders including but not limited to: * Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis. * Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible). * History of drug-induced cholestatic hepatitis. * Aspartate aminotransferase (AST) \>2.5× ULN (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) \>2.5× ULN (unless due to hepatic iron deposition). * Renal dysfunction as defined by an estimated glomerular filtration rate \<30 milliliters per minute (mL/min)/1.73-meter square (m\^2) by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. * Active uncontrolled infection requiring systemic antimicrobial therapy. * Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg). * Positive test for human immunodeficiency virus (HIV)-1 antibody or HIV-2 antibody. * History of major surgery (including splenectomy) ≤16 weeks before providing informed assent/consent and/or planning on undergoing a major surgical procedure during the study. * Current enrollment or past participation (within 90 days before randomization 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. * Past enrollment in a clinical study involving mitapivat. * Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. * Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before randomization. * Receiving products that are strong inhibitors of Cytochrome3A4/5 (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 Cytochrome3A4 (CYP3A4) that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), prior to 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 ≥10 weeks before randomization. * Known allergy to mitapivat or tablet excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, magnesium stearate, and the Opadry Blue II film-coat \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD\&C Blue #2\]). * Any medical, hematological, psychological, or behavioral condition(s), including alcohol use disorder, 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 unable to receive RBC transfusions (eg, due to presence of allo-antibodies, lack of blood availability). * Subjects deprived of liberty by court or administrative decision (eg, persons accommodated in an institution by order of an authority or court). * Subjects undergoing psychiatric care without their consent. * Subjects admitted to a health or social establishment for purposes other than research. * Adult Subjects subject to a legal protection measure (guardian, curatorship, legal protection). * Subjects unable to express their consent. * Receiving herbal or dietary supplements that have not been stable in dose and preparation for ≥8 weeks prior to randomization.