inherited hemoglobin disorder Sickle Cell Disease
Conditions
Interventions
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, eligibl
however, study subjects, Investigators,
clinical study center personnel, and the Sponsor will continue to remain
blinded to the randomized treatment assignment during the previous Double-blind
Peri
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
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 (see Appendix 3) 2. Documented diagnosis of SCD (HbSS, HbSC [combined heterozygosity for hemoglobins S and C], HbS/β0-thalassemia, HbS/β+-thalassemia, or other sickle cell syndrome variants) 3. At least 2 SCPCs (defined in Section 8.5.2.1) and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent. 4. Hemoglobin >=5.5 and =7 days) collected during the Screening Period. 5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days prior to randomization. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent.
Exclusion criteria
Exclusion criteria: 1. Pregnant, breastfeeding or parturient 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 and/or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or out patient clinic visit. A visit to an emergency room that does not result in an in-patient admission does not meet the definition of hospitalization. 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 voxelotor, crizanlizumab, and L-glutamine 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 =470 milliseconds for female 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 2: • Hemoglobin (Hb) response, defined as a >=1.0 g/dL increase in average Hb concentration from Week 10through Week 12 compared with baseline • Type, severity, and relationship to study drug of adverse events (AEs) and serious (SAEs) Phase 3: • Hemoglobin (Hb) response, defined as a >=1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline • Annualized rate of SCPCs (as defined in Section 8.5.2.1) | — |
Secondary
| Measure | Time frame |
|---|---|
| Phase 2: • Average change from baseline in Hb concentration from Week 10 through Week 12 • 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 percent reticulocyte, and erythropoietin, from Week 10 through Week 12 • Average change from baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) score from Week 10 through Week 12 • Annualized rate of SCPCs (as defined in Section 8.5.2.1) • Exposure response (or pharmacokinetic/pharmacodynamic) relationship between relevant pharmacokinetic parameters and endpoints that are indicators of clinical activity and safety • Change in mitapivat concentration over time and derived mitapivat pharmacokinetic parameters (including area under the concentration × time curve and maximum [peak] concentration) Phase 3: • Average Change from baseline in average Hb concentration from Week 24 through Week 52 • Average Change from baseline in average indirect bilirubin from Week 24 through Week 52 • Average Change from baseline in average percent reticulocyte from Week 24 through Week 52 • Average Change from baseline in average Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) scores from Week 24 through Week 52 • Annualized frequency of hospitalizations for SCPC • Average Change from baseline in average LDH concentration from Week 24 through Week 52 • Average Change from baseline in average absolute reticulocytes and erythropoietin from Week 24 through Week 52. • Improvement on the Patient Global Impression of Severity (PGIS) of fatigue by at least 1 category at Weeks 24, 28, 40, and 52 compared to baseline, or remain stable if none or mild fatigue at baseline • Improvement on the Patient Global Impression of Change (PGIC) of fatigue at Weeks 24, 28, 40, and 52, or "no change" | — |
Countries
Netherlands
Outcome results
None listed