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
Overview
- Phase
- Phase 1
- Intervention
- Mitapivat
- Conditions
- Sickle Cell Disease
- Sponsor
- National Heart, Lung, and Blood Institute (NHLBI)
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Primary outcome measure: Long-term safety and tolerability of mitapivat in subjects with stable sickle cell disease
- Status
- Active, not recruiting
- Last Updated
- 11 days ago
Overview
Brief Summary
Background:
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.
Objective:
To test the long-term tolerability and safety of mitapivat (or AG-348) in people with SCD.
Eligibility:
Adults age 18-70 with SCD who took part in and benefited from NIH study #19H0097.
Design:
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.
Detailed Description
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 years. Objectives: Primary Objective: \- To assess the long-term safety and tolerability of mitapivat in subjects with stable sickle cell disease. Secondary Objectives: * 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 subjects. * 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 long-term. Tertiary/Exploratory Objectives: \- To assess the feasibility and usability of digital health technology in a drug trial for patients with SCD. Endpoints: Primary Endpoints: \- Frequency and severity of AEs and changes in clinical and laboratory parameters over 8 years of therapy with mitapivat. Secondary Endpoints: * Change from baseline in pharmacokinetic and pharmacodynamic measures over time. * Hemoglobin (Hb) response and changes in hemolytic markers at 24 and 48 weeks on mitapivat. * Sustained Hb response from weeks 12-48. * Change from baseline in functional and cardiopulmonary status at 24 and 48 weeks on mitapivat. * 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. Tertiary/Exploratory Endpoints: \- Usability of SCD Warrior digital Microhealth application (app) by providers and participants through simple feedback tools at each protocol visit reviewing ease of use and patient satisfaction.
Investigators
Eligibility Criteria
Inclusion Criteria
- •INCLUSION CRITERIA:
- •Subjects completing Study 19H0097 will first be screened for eligibility. Eligibility criteria are identical with the exception of criteria 5.1.4, 5.2.2, and 5.2.3.p. If any of the 15 subjects completing the 19H0097 study are unable to participate in or complete the current extension study (defined as completing 24 weeks of treatment with study drug to allow for assessment of the primary endpoint), then additional new subjects naive to mitapivat treatment may be enrolled to replace them.
- •Subjects will enroll onto the study and undergo screening. Subjects who do not meet any of the following criteria during screening will not receive the study intervention but will be counted toward study accrual. Screen failures may be rescreened at a later time.
- •In order to be eligible to participate in this study, an individual must meet all of the following criteria:
- •1.1 Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
- •1.2 Age between 18-70 years
- •1.3 Unequivocal diagnosis of HbSS confirmed by hemoglobin electrophoresis performed on patients at least 90 days after a blood transfusion if previously transfused, or DNA genotyping
- •1.4 No transfusion in the 12 weeks prior to signing consent, or absence of Hb A on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
- •1.5 Have adequate organ function, as defined by:
- •Serum aspartate aminotransferase (AST) \<=2.5 x Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis) and alanine aminotransferase (ALT) \<=2.5 x ULN.
Exclusion Criteria
- •2.1 Documented pyruvate kinase deficiency
- •2.2 Screening hemoglobin level of \>= 11 g/dL
- •2.3 Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
- •Poorly controlled hypertension (defined as systolic blood pressure \[BP\] \>150 mmHg or diastolic BP \>90 mmHg) refractory to medical management.
- •History of recent (within 24 weeks prior to signing consent) decompensated congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
- •Cardiac dysrhythmias judged as clinically significant by the Investigator.
- •Heart-rate corrected QT interval-Fredericia's method (QTcF) \>480 msec with the exception of subjects with right or left bundle branch block.
- •Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved.
- •History of drug-induced cholestatic hepatitis.
- •Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (e.g., clinically significant impaired left ventricular ejection fraction), hepatic (e.g., fibrosis, cirrhosis), or pancreatic (e.g., diabetes) dysfunction.
Arms & Interventions
1
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 laboratory and clinical endpoints at pre-specified intervals during the study period.
Intervention: Mitapivat
Outcomes
Primary Outcomes
Primary outcome measure: Long-term safety and tolerability of mitapivat in subjects with stable sickle cell disease
Time Frame: 48 weeks
Frequency and severity of AEs and changes in clinical and laboratory parameters over 48 weeks of maintenance therapy with mitapivat.
Secondary Outcomes
- To evaluate the pharmacokinetic(24 and 48 weeks)
- To evaluate the pharmacokinetic(24 and 48 weeks)
- 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.(24 and 48 weeks)
- To monitor SCD-related safety endpoints in SCD subjects maintained on mitapivat long-term.(24 and 48 weeks)