Sickle Cell Disease (SCD) / Patients with SCD endure chronic hemolytic anemia and acute and recurrent clinical events that vary in frequency and severity, the most common being VOCs (vaso-occlusions). The use of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The current treatment options are not universally effective or globally available, tend to address only a single component of the di
Conditions
Interventions
Study AG348-C-020 is a Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease. In the phase 2
In the Phase 2 portion of the study, eligible subjects will be randomized 1:1:1 to receive 50 mg BID mitapivat, 100 mg BID mitapivat, or matched placebo. In the Phase 3 portion of the study, eligible
Treatment
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Age
16 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Age =16 years; subjects age 16 or 17 years must be documented Tanner Stage 5. 2. Documented diagnosis of SCD (HbSS, HbSC, HbS/ß0-thalassemia, HbS/ß+-thalassemia, or other sickle cell syndrome variants). 3. At least 2 SCPCs and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent. 4. Hemoglobin =5.5 and =10.5 g/dL. 5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days prior to randomization. 6. 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, one of which must be considered highly effective, from the time of providing informed assent/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 include an acceptable barrier method. 7. Written informed assent/consent (for subjects under 18 years of age, 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
Exclusion criteria: 1. Pregnant or breastfeeding. 2. Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. Additionally, subjects may not have received a transfusion within 60 days before providing informed assent/consent or during the Screening Period. 3. Hospitalized for an SCPC or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. 4. Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before randomization. 5. 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. 6. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed assent/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 of =470 milliseconds forfemale subjects and =450 milliseconds for male subjects, 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 heart failure, and oxygen indicated. 7. Hepatobiliary disorders including but not limited to: a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis. b. Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible). c. History of drug-induced cholestatic hepatitis. 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). 8. Renal dysfunction as defined by an estimated glomerular filtration rate 440 mg/dL (5 mmol/L). 10. Active uncontrolled infection requiring systemic antimicrobial therapy. 11. Positive test for hepatitis C virus antibody with evidence of active hepatitis C virus infection, or positive test for hepatitis B surface antigen. 12. Positive test for HIV-1 antibody or HIV-2 antibody. 13. 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. 14. 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. 15. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. 16. Currently receiving treatmen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: Phase 2: To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on Anemia in subjects with sickle cell disease (SCD);Timepoints: Week 12;Measure: Hemoglobin (Hb) response, defined as a =1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline;Name: Phase 2: To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on Safety;Timepoints: Up to Week 12;Measure: Type, severity, and relationship to study drug of adverse events (AEs) and serious (SAEs);Name: Phase 3: To determine the effect of mitapivat versus placebo on Anemia in subjects with sickle cell disease (SCD);Timepoints: Week 52;Measure: Hemoglobin (Hb) response, defined as a =1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline;Name: Phase 3: To determine the effect of mitapivat versus placebo on Sickle cell pain crises (SCPCs) in subjects with SCD;Timepoints: Up to Week 52;Measure: Annualized rate of SCPCs | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Anemia;Timepoints: Baseline, Week 10 up to Week 12;Measure: Average change from baseline in Hb concentration from Week 10 through Week 12;Name: Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Markers of hemolysis and erythropoiesis;Timepoints: Baseline, Week 10 up to Week 12 ;Measure: Average change from baseline in markers of hemolysis, including indirect bilirubin and lactate dehydrogenase (LDH), from Week 10 through Week 12. Average change from baseline in markers of erythropoiesis, including absolute reticulocyte count, percent reticulocyte, and erythropoietin, from Week 10 through Week 12;Name: Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Patient-reported fatigue;Timepoints: Baseline, Week 10 up to Week 12;Measure: Average change from baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) score from Week 10 through Week 12;Name: Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Sickle cell pain crises (SCPCs);Timepoints: Up to Week 12;Measure: Annualized rate of SCPCs;Name: Phase 2: To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat;Timepoints: Day 1 up to Week 8;Measure: Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG);Name: Phase 2: To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat;Timepoints: Day 1 up to Week 8;Measure: Mitapivat Concentration Over Time/Mitapivat Area Under the Concentration/Mitapivat Maximum (Peak) Concentration ;Name: Phase 3: To evaluate the effect of mitapivat versus placebo on Anemia in subjects with SCD;Timepoints: Baseline, Week 24 up to Week 52 ;Measure: Change from baseline in average Hb concentration from Week 24 through Week 52;Name: Phase 3: To evaluate the effect | — |
Countries
United States of America
Contacts
Public ContactAziz Zoghbi
Director of Country Oversight and Manageme nt MENA, Gulf and Africa
Outcome results
None listed