The Effect of Mitapivat on Cerebral Perfusion and Oxygen Metabolism in Sickle Cell Disease

Prior treatment

• History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent, including but not limited to the following: • Unstable angina pectoris or myocardial infarction or elective coronary intervention. • Congestive heart failure requiring hospitalization. • Uncontrolled clinically significant arrhythmias.
• Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
• Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device).
• Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 90 days before participation.
• Patients receiving with voxelotor or inhibitors of CYP3A4
• Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior participation.

Other illness

• Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy: • Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. • Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive.
• History of malignancy within the past 2 years prior to participation requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy).
• Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent.
• Patients with history of overt stroke
• Patients allergic to mitapivat or sulphonamide-based drugs

Lab values

• Hepatic dysfunction characterized by alanine aminotransferase (ALT) >2.5 × ULN

Other

• No informed consent has been given.
• Severe renal dysfunction (estimated glomerular filtration rate <30mL/min).
• Receipt of erythropoietin or other hematopoietic growth factors within 28 days of signing ICF or anticipated need for such agents during the study.
• Contra-indication for MRI or acetazolamide
• Female who is breast feeding or pregnant

• Documented SCD genotype (HbSS, HbSβ0-thalassemia) which may be based on history of laboratory testing or must be confirmed by laboratory testing during screening
• Age 18 and above
• Hemoglobin (Hb) ≤10.5 g/dL.
• For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 90 days prior to participation and with no anticipated need for dose adjustments
• Female participants of childbearing potential should agree to be abstinent as part of their usual lifestyle or use a highly effective method of contraception. Furthermore, due to the potential for mitapivat to reduce the effectiveness of hormonal contraceptives, women using hormonal contraception must also use an acceptable barrier method while enrolled in the study and for at least 28 days after their last dose. Women using non-hormonal methods of contraception as a highly effective method do not need to use an additional barrier method.
• Participant has provided documented informed consent or assent (the informed consent form [ICF] must be reviewed and signed by each participant; the participant’s legal representative or legal guardian, and the participant’s assent must be obtained).