genetic red blood cell enzyme disorder hemolytic anemia
Conditions
Interventions
The study is happening in two parts.
In the Core part of the study, some patients will receive the new medicine,
mitapivat, and some patients will receive placebo, for 32 weeks (Double-Blind
period
Sponsors
Agios Pharmaceuticals, Inc.
Eligibility
Age
No minimum to 17 Years
Inclusion criteria
Inclusion criteria: 1. Written informed consent from the subject, or the subject*s legally authorized representative, parent(s), or legal guardian, and the subject*s assent, where applicable (informed consent/assent) 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. 2. Aged 1 to
Exclusion criteria
Exclusion criteria: 1. Pregnant or breastfeeding 2. Homozygous for the R479H mutation or have 2 nonmissense mutations, without the presence of another missense mutation, in the PKLR gene as determined per the genotyping performed by the study central genotyping laboratory 3. History of malignancy 4. History of active and/or uncontrolled cardiac or pulmonary disease or clinically relevant QT prolongation within 6 months before providing informed consent/assent 5. 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×ULN (unless due to hepatic iron deposition) 6. Renal dysfunction as defined by an estimated glomerular filtration rate 440 mg/dL (5 mmol/L) 8. Active uncontrolled infection requiring systemic antimicrobial therapy 9. Subjects with known active hepatitis B or hepatitis C who subsequently test positive for hepatitis B antigen or hepatitis C virus antibody with signs of active hepatitis B or hepatitis C virus infection 10. Subjects with known HIV infection 11. History of major surgery (including splenectomy) =5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for >=28 days or a time frame equivalent to 5 half-lives (whichever is longer), before randomization 16. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization 17. Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2], Opadry® II White [hypromellose, titanium dioxide, lactose monohydrate, and triacetin], and magnesium stearate) 18. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Transfusion reduction response (TRR), defined as achievement of a >=33% reduction in the total red blood cell (RBC) transfusion volume from Week 9 through Week 32 of the Double-blind Period normalized by weight and actual study drug duration compared with the historical transfusion volume standardized by weight and to 24 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| • Transfusion-free response, defined as achievement of 0 transfusions administered from Week 9 through Week 32 of the Double-blind Period • Change in the number of transfusion episodes from Week 9 through Week 32 of the Double-blind Period compared with the historical number of transfusion episodes standardized to 24 weeks • Percentage change in weight-normalized and study treatment duration- normalized total transfusion volume from Week 9 through Week 32 of the Doubleblind Period compared with the historical transfusion volume standardized by weight and to 24 weeks • Normal hemoglobin (Hb) response, defined as achievement of Hb concentrations in the normal range at least once, 8 weeks or more after a transfusion during Week 9 through Week 32 of the Double-blind Period • Changes in safety assessments including measurement of sex hormones, sexual maturity rating with Tanner stage, development and the assessment of ovarian cysts (female subjects only) • Changes over time in height-for-age z-score, weightfor-age z-score, and body mass index-for-age z-score • Changes over time in bone mineral density z-score • Change from baseline in markers of iron metabolism and indicators of iron overload (serum iron, serum ferritin, total iron-binding capacity, transferrin/transferrin saturation) • Change from baseline in quality of life assessments: Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale and PedsQL Generic Core Scale • Pharmacokinetic parameters including, but not limited to, Cmax (maximum concentration), AUC (area under the concentration-time curve), Css (concentration at steady state), and Ctrough (trough concentration) | — |
Countries
Netherlands
Outcome results
None listed