A study of mitapivat in sickle cell disease

Phase 1

Conditions: Sickle cell disease
MedDRA version: 21.0Level: PTClassification code: 10040644Term: Sickle cell disease Class: 100000004850
Therapeutic area: Diseases [C] - Hemic and Lymphatic Diseases [C15]

Registration Number: CTIS2024-515569-32-00

Lead Sponsor: Julius Clinical International B.V.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 10

Inclusion Criteria

Male or female with documented homozygous sickle cell anemia (HbSS) or HbS/beta(0 or +)-thalassemia. Documentation of genotype may be based on documented history of laboratory testing or must be confirmed by laboratory testing during screening (thin layer isoelectric focusing or high performance liquid chromatography (HPLC) with confirmation by deoxyribonucleic acid (DNA) testing if necessary)., Patients with increased albumin to creatinine ratio are prioritized above patients with a normal albumin to creatinine ratio. Both are eligible., For women of reproductive potential, have a negative urine and serum pregnancy test during the Screening Period (D-50 to D-1). Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 12 months prior to signing informed consent)., For (fertile men of) women of reproductive potential, agree to use double anticonception during the trial period plus 90 days (for male subjects) or 28 days (for female subjects) after the last dose of AG-348., Documented history of VOCs, and number of days admitted in hospital for acute sickle cell related complications during 24 months before inclusion., SCD with at least one of the following conditions: I.at least 1 (but no more than 10) VOC in the past 12 months prior to the first day of study treatment; II.any sickle cell related hospital admission in the past 12 months prior to the first day of study treatment; III.any history of sickle cell related complications (such as osteonecrosis, osteoporosis, nephropathy, retinopathy, leg ulcer, acute chest syndrome, acute hemolytic crisis); IV.presence of any clinical biomarkers associated with increased mortality in SCD prior to the first day of study treatment (NT-proBNP >160 pg/mL, LDH/HbCO ratio >1,200, tricuspid regurgitant jet velocity =2.5 m/s)., Age =16 years, inclusive; subjects age 16 or 17 years must be documented Tanner Stage 5., Hemoglobin (Hb) =6.9 mmol/L (approx. 11.1 g/dL) and >2.5 mmol/L (approx. 4.0 g/dL)) during screening., For subjects taking hydroxyurea (HU), the dose of HU (mg/kg) must have been stable for at least 3 months prior to the first day of study treatment., Subjects must start or continue taking at least the equivalent of daily 0.7 mg oral folic acid for the duration of the study., Have adequate organ function, as defined by: a. Serum aspartate aminotransferase (AST) =2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) =2.5 × ULN. 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 choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease. Elevated bilirubin attributed to hemolysis with or without Gilbert’s syndrome is not exclusionary. c. Serum creatinine =1.25 × ULN. If serum creatinine is >1.25 × ULN, then glomerular filtration rate, estimated by 24-hour measured or calculated (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) creatinine clearance, must be =60 mL/min/1,73 m2. d. Absolute neutrophil count =1.0 × 109/L during screening. e. Platelet count =100 × 109/L during screening.

Exclusion Criteria

More than 10 VOCs within the past 12 months., Have a prior bone marrow or stem cell transplant., Are currently pregnant or breastfeeding, or planning to become pregnant during the course of the study., Have a history of major surgery within 6 months prior to signing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context., Are currently receiving medications that are strong inhibitors of CYP3A4 or strong inducers of CYP3A4 that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment., Are currently receiving hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment., Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) or history of acute allergic reaction to drugs characterized by acute hemolytic anemia, druginduced liver injury, anaphylaxis, rash of erythema multiforme type or StevensJohnson syndrome, cholestatic hepatitis, or other serious clinical manifestations., For men and women of reproductive potential: unwillingness to use double anticonception during the trial period., Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior the first day of study treatment. Subjects who may get hospitalized during the Screening Period are allowed to be rescreened 14 days after discharge., Have a point of sickling (PoS) =24.6 mmHg as quantified by the Oxygenscan during screening to exclude subjects with no clinical relevant detectable sickling., Subjects age 16 or 17 years who are documented Tanner stage 1-4., Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic or preventive transfusion), defined as more than 4 transfusion episodes in the 12-month period up to the first day of study treatment, and/or have received a transfusion within the past 3 months prior to the first day of study treatment., Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound interpretation of the study data. Such significant medical conditions include, but are not limited to: a) Poorly controlled hypertension (defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg) refractory to medical management. b) Any history of congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; or recent (< 6 months prior to signing informed consent) deep venous thrombosis, or pulmonary or arterial embolism. c) Cardiac dysrhythmias judged as clinically significant by the Investigator. d) Heart-rate corrected QT interval (QTc) by Fridericia's method >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 (e