Study Description:
Subjects actively enrolled protocol AG348-C-020 (NIH protocol IRB001565-H), an industry-sponsored phase 2/3 study investigating the efficacy of mitapivat in treating sickle cell disease (SCD), will be invited to participate in this protocol simultaneously to further investigate the mechanistic effects of mitapivat. Subjects will be asked for a blood sample at study visits and undergo near infrared spectroscopy (NIRS) testing to investigate the mechanisms of action of mitapivat in subjects with SCD.
Objectives:
To evaluate the mechanisms of action of mitapivat in subjects with SCD.
Endpoints:
PRIMARY ENDPOINT DURING BLINDED PERIOD:
The percentage change in the oxygen affinity measure p50 (defined as the partial pressure of oxygen at which Hb is 50% saturated with oxygen) between baseline and the average value at 12, 24 and 52 weeks. This change will be compared between the placebo and mitapivat arms.
PRIMARY ENDPOINTS DURING OPEN LABEL EXTENSION (OLE):
* Evaluate the effect of mitapivat by comparing inter-patient and intra-patient changes between year one and year two.
* Evaluate the effects of long term use of mitapivat in patients who were randomized onto mitapivat during the first year of the study.
* Evaluate the intra-patient changes for patients who were randomized onto the placebo during the first year of the study and transition to mitapivat during year two.
SECONDARY ENDPOINTS DURING BLINDED PERIOD:
* The p50 changes will also be assessed at the individual time points of 12, 24, and 52 weeks.
* Percentage of sickled cells and time to 50% sickling (t50) under normal and hypoxic ex vivo conditions at regular time intervals on mitapivat and percentage change from baseline to the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms.
* Percentage change in intracellular reactive oxidative species (ROS) in red blood cells (RBCs) using a ROS sensitive fluorescent probe and mass spectrometry- based proteomics of RBC lysates between baseline and the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms.
* The percentage change in phosphatidylserine (PS) externalization using annexin V labeling (marker of red cell survival) by flow cytometry between baseline and the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms.
* Percentage change in muscle physiology, tissue oxygenation and blood flow using NIRS methodologies between baseline the individual time points at 12, 24, and 52 weeks. This change will be compared between the placebo and mitapivat arms.
* RBC deformability and sickling using osmotic and oxygen gradient ektacytometry
TERTIARY/EXPLORATORY ENDPOINTS DURING BLINDED PERIOD:
* Evaluate effect of mitapivat on RBC metabolomics and proteomics between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms.
* Measurement of glycated Hb S level as a surrogate measure for red cell half-life between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms.
* Evaluate effect of mitapivat on RBC band 3 tyrosine phosphorylation between baseline and various follow-up periods.
This change will be compared between the placebo and mitapivat arms.
* Correlation between potential exploratory biomarkers and clinical laboratory parameters.
* Evaluate change in cerebral hemodynamic measurements through magnetic resonance imaging (MRI) for cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen consumption from baseline, at 12 and 52 weeks. This change will be compared between the placebo and mitapivat arms.
