Evaluation of the Safety,Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
Sickle cell disease (SCD) is a disorder that causes episodes of acute pain and progressive
organ damage. Ways to manage SCD have evolved slowly. Treatments do not always work.
Researchers want to see if a drug called mitapivat can help people with SCD.
To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD.
Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097.
Participants will be screened with a medical history and physical exam. They will give a
blood sample. They will have an electrocardiogram to test heart function.
Participants will repeat some of the screening tests during the study.
Participants will complete 6-minute walk tests to measure mobility and function. They will
have transthoracic echocardiograms to measure heart and lung function. They will have
dual-energy X-ray absorptiometry scans to measure bone health. They will complete online
questionnaires that measure their overall health and well-being.
Participants will take the study drug in the form of a tablet twice a day.
Participants will keep a study diary. They will record any symptoms they may have.
Participation will last for about 54 weeks. After 48 weeks, participants can either keep
taking the study drug for 48 more weeks or be tapered off of the study drug to complete the
study. Those who are on the study for 1 year will have 10 study visits. Those who are on the
study for 2 years will have 14 study visits.
Study Description: The objective of this extension study is to evaluate the safety and
tolerability of mitapivat (AG-348) as long-term maintenance therapy for subjects with sickle
cell disease (SCD) who have completed the Phase I dose escalation study of mitapivat
(NCT04000165, protocol 19H0097). Subjects will be treated with a maintenance dose of
mitapivat previously assessed for safety and tolerability in the Phase I study for an initial
48 weeks and undergo safety monitoring, evaluation of pharmacokinetics and pharmacodynamics,
and assessment of secondary clinical endpoints at regular intervals over the study period.
Exploratory endpoints will allow for investigation of the mechanisms by which mitapivat may
modulate red cell metabolism and survival and lead to clinical benefits in SCD. Subjects
benefiting from the study drug will have the option to continue therapy for an additional 5
Primary Objective: To assess the long-term safety and tolerability of mitapivat in subjects
with stable sickle cell disease.
To evaluate the pharmacokinetic/pharmacodynamic profile of long-term dosing of
mitapivat, as well as its mechanisms of action on the glycolytic pathway in SCD
To evaluate hemoglobin (Hb) response, changes in hemolytic markers, functional status,
cardiopulmonary function, and health-related quality of life in SCD subjects maintained
on mitapivat long-term.
To monitor SCD-related safety endpoints in SCD subjects maintained on mitapivat
Primary Endpoints: Frequency and severity of AEs and changes in clinical and laboratory
parameters over 6 years of therapy with mitapivat.
Change from baseline in pharmacokinetic and pharmacodynamic measures over time.
Hemoglobin (Hb) response and changes in hemolytic markers at 24 and 48 weeks on
Sustained Hb response from weeks 12-48.
Change from baseline in functional and cardiopulmonary status at 24 and 48 weeks on
Change from baseline in quality of life at 24 and 48 weeks on mitapivat.
Frequency of acute vaso-occlusive clinical events at 24 and 48 weeks on mitapivat.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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