A Clinical Study of Mitapivat in Patients with Sickle Cell Disease and Kidney Disease

Laborértékek

• Hepatobiliary disorders including but not limited to: a. Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis at any time b. Clinically symptomatic cholelithiasis or cholecystitis within 60 days before study drug administration (subjects with prior cholecystectomy are eligible) c. History of drug-induced cholestatic hepatitis within 90 days before study drug administration d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5× the ULN (unless due to hepatic iron deposition) within 60 days before study drug administration 10. Renal dysfunction as defined by an eGFR <45 mL/min/1.73 m² by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (National Kidney Foundation, 2021b) at Screening. 11. History of renal disease due to another disorder (eg, diabetes, hypertension, primary focal segmental glomerulosclerosis, autoimmune) unrelated to SCD at any time. 12. Evidence of acute kidney injury (in the opinion of the Investigator) within 4 weeks before informed consent/assent or during Screening Period. 13. Currently undergoing renal replacement therapy (ie, hemodialysis, peritoneal dialysis, hemofiltration, kidney transplantation). 14. History of kidney transplant at any time. 15. Nonfasting triglycerides >440 mg/dL (5 mmol/L) at Screening. 16. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mm Hg or diastolic BP >90 mm Hg) refractory to medical management. Please refer to Protocol, Section 5.2. for detailed list of Exclusion Criteria.

Életkor

• Currently receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. 2. Have received an RBC transfusion within 60 days before providing informed consent/assent or during the Screening Period. 3. Hospitalized within 14 days before providing informed consent/assent or during the Screening Period either for an SCPC (defined in Section 8.2.1) or other vaso-occlusive event. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an ER or outpatient clinic visit. A visit to an ER that does not result in an in-patient admission does not meet the definition of hospitalization. 4. More than10 SCPCs (defined in Section 8.2.1) in the 52 weeks before providing informed consent/assent. 5. History of stroke or meeting criteria for primary stroke prophylaxis (history of 2 transcranial Doppler [TCD] measurements ≥200 cm/s by nonimaging TCD or ≥185 cm/s by imaging TCD) at any time. 6. Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), except for hydroxyurea. The last dose of such therapies must have been administered at least 90 days before Study Day 1. 7. 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. 8. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before Study Day 1, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% d. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated

• Aged ≥16 years at the time of providing informed consent/assent (except in France where subjects must be aged ≥18 years at the time of providing informed consent). a. Females must be post-menarche. 2. Documented diagnosis of SCD (HbSS or HbS/β0-thalassemia). 3. Hemoglobin concentration ≥5.5 and ≤10.5 g/dL during the Screening Period. If more than one measurement is collected during the Screening Period, the average must be ≥5.5 and ≤10.5 g/dL. 4. If taking hydroxyurea, the dose of hydroxyurea must have been stable for at least 90 days before Study Day 1 with no planned dose adjustment during the study and no sign of hematologic toxicity. a. Discontinuation of hydroxyurea requires a 90-day washout before providing informed consent/assent. 5. Two urine ACR results collected during the Screening Period, both of which must be ≥100 and <2000 mg/g. One ACR result can be from an untimed urine sample collected as part of a clinic visit. The other ACR result must be from a urine sample that is the first (or second) morning void on another day. 6. One ACR result >100 mg/g within 24 weeks before providing informed consent/assent. 7. If taking ACE inhibitor or ARB therapy, must have been on stable dose for at least 90 days before providing informed consent/assent with no planned dose adjustment during the study. 8. Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing 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 (see Appendix 1). 9. Written informed consent/assent (for subjects aged <18 years, or younger than 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.