a- or ß-Transfusion Dependent Thalassemia. Transfusion dependent is defined as 6 to 20 RBC units transfused and a =6-week transfusion-free period during the 24-week period before randomization. Thalassemia beta-Thalassemia alpha- Thalassemia Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases
Conditions
Interventions
Study AG348-C-018 is a Phase 3, double-blind, randomized, placebo-controlled,nmulticenter study evaluating the efficacy and safety of mitapivat versus placebo in adult subjects with a- or ß-TDT follow
Subjects will receive 100 mg twice-daily mitapivat for oral administration. Subjects will be randomly assigned in a 2
1 ratio to receive study drug (mitapivat or placebo, respectively)
Treatment
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. =18 years of age at the time of providing informed consent. 2. Documented diagnosis of thalassemia (ß-thalassemia with or without a-globin gene mutations, HbE/ß-thalassemia, or a-thalassemia/HbH disease) based on DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, DNA analysis can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test, results from the comprehensive a- and ß-globin genotyping performed by the study central laboratory can be used. 3. Transfusion dependent, defined as 6 to 20 RBC units transfused and a =6-week transfusion-free period during the 24-week period before randomization. 4. If taking hydroxyurea, the hydroxyurea dose must be stable for =16 weeks before randomization. 5. Women of childbearing potential (WOCBP) and men with partners who are 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, 1 of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can be an acceptable barrier method. 6. Written informed consent before any study-related procedures are conducted and willingto comply with all study procedures for the duration of the study.
Exclusion criteria
Exclusion criteria: 1. Pregnant or breastfeeding. 2. Documented history of homozygous or heterozygous HbS or HbC. 3. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. 4. Currently receiving treatment with luspatercept; the last dose must have been administered =36 weeks before administration of the first dose of study drug. 5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered =36 weeks before administration of the first dose of study drug. 6. 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 consent. 7. History of active and/or uncontrolled cardiac or pulmonary disease =6 months before providing informed consent, 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. Heart rate–corrected QT interval using Fridericia’s method =450 milliseconds, except for right or left bundle branch block d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated 8. Hepatobiliary disorders, including but not limited to: a. Liver disease with histopathological evidence 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 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN (unless due to hepatic iron deposition) 9. Estimated glomerular filtration rate 440 mg/dL (5 mmol/L). 11. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. 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. 12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen. 13. Positive test for HIV-1 Ab or HIV-2 Ab. 14. History of major surgery (including splenectomy) =6 months before providing informed consent and/or a major surgical procedure planned during the study. 15. Current enrollment or past participation (=12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational treatment, whichever is longer) in any other clinical study involving an investigational treatment or device. 16. Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been stopped for =5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for =4 weeks or a tim
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: Effect of mitapivat versus placebo on transfusion burden ;Timepoints: any consecutive 12-week period through Week 48 compared with baseline;Measure: Transfusion reduction response (TRR), defined as a =50% reduction in transfused red blood cell (RBC) units with a reduction of =2 units of transfused RBCs | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: To compare the durability of the effect of mitapivat versus placebo on transfusion burden;Timepoints: Week 13 through Week 48 compared with baseline;Measure: • =33% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR3) • =50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with baseline (TRR2) • =50% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR4) | — |
Contacts
Public ContactAziz Zoghbi
Director of Country Oversight and Manageme nt MENA, Gulf and Africa
Outcome results
None listed