Investigating the Mechanistic Effects of Mitapivat in Subjects With Sickle Cell Disease

Observational Study Investigating the Mechanistic Effects of Mitapivat in Subjects With Sickle Cell Disease

Background:

Sickle cell disease (SCD) is an inherited blood disorder. The disease affects the ability of red blood cells to carry oxygen; this in turn can injure organs including the heart, lungs, and kidneys. SCD can lead to serious illness and death. Treatments such as bone marrow transplants and gene therapies can cure SCD, but they are not widely available. Current drug treatments for SCD are not always effective. This natural history study will examine how a study drug (mitapivat) affects red blood cells in people with SCD.

Objective:

To learn how mitapivat affects red blood cells in people with SCD.

Eligibility:

People with SCD who are enrolled in the parent study, NIH protocol IRB001565-H.

Design:

Procedures for this study will be done during visits already scheduled for the parent study.

Participants will have additional blood drawn during study visits. The additional amount will be about 3.5 teaspoons.

Participants will undergo a test called near infrared spectroscopy (NIRS) up to 9 times. Probes will be placed on their skin. A blood pressure cuff will be placed on their arm. The cuff will be filled with air for up to 5 minutes and then released. Participants may be asked to breathe at a certain rate or to hold their breath during these measurements. NIRS measures oxygen levels, blood flow, and the makeup of skin and muscle.

Researchers will draw additional information for this study from participants medical records.

Study Overview

• Status: Enrolling by invitation
• Conditions: Sickle Cell Anemia; Sickle Beta Thalassemia; Sickle Cell Thalassemia; Sickle Beta Zero Thalassemia; Sickle Cell Pain; Hbss; Hbsc; Sickle Cell Syndrome Variant

Detailed Description

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 specified time points before and after starting on mitapivat and to 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:

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.

SECONDARY ENDPOINTS:

• The p50 changes will also be assessed at the individual time points of 12, 24, and 52 weeks and compared between arms.
• 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, 52, and 59 weeks. This change will be compared between the placebo and mitapivat arms.

TERTIARY/EXPLORATORY ENDPOINTS:

• 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 weeks, 52, and 59 weeks. This change will be compared between the placebo and mitapivat arms.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

primary clinical

Description

• INCLUSION CRITERIA:

All subjects enrolled at NIH meeting eligibility for the parent study (AG348-C-020) are eligible for this study.

EXCLUSION CRITERIA:

Subjects that did not meet eligibility criteria to the parent protocol (AG348-C-020) will not be eligible to enroll for this study.

Subjects will be screened for implanted metal objects or devices that may be incompatible with MRI (i.e. cerebral aneurysm clip, cochlear implant, pacemaker, etc.) These subjects will be eligible to proceed with study enrollment, but will not undergo the optional MRI study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
1; i. Phase 3: Mitapivat 50 mg BID
2; ii. Phase 3: Mitapivat 100 mg BID
3; iii. Phase 3: Mitapivat Open-Label Extension Period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	This change will be compared between the placebo and mitapivat arms.	12, 24 and 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	This change will be compared between the placebo and mitapivat arms.	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	This change will be compared between the placebo and mitapivat arms.	12, 24, and 52 weeks
The p50 changes will also be assessed at the individual time points	This change will be compared between the placebo and mitapivat arms.	12, 24, and 52 weeks
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	This change will be compared between the placebo and mitapivat arms.	12, 24, and 52 weeks
Percentage change in muscle physiology, tissue oxygenation and blood flow using NIRS methodologies between baseline the individual time points	This change will be compared between the placebo and mitapivat arms.	12, 24, 52, and 59 weeks

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Swee Lay Thein, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): April 23, 2024
• Primary Completion (Estimated): October 27, 2027
• Study Completion (Estimated): October 27, 2027

Study Registration Dates

• First Submitted: January 6, 2023
• First Submitted That Met QC Criteria: January 6, 2023
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Estimated): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 2, 2024

More Information

Terms related to this study

• Keywords: Natural History; Hemoglobin; Sickle Cell Anemia; Sickle Cell Pain Crisis; Sickle Cell Treatment; Sickle Cell Therapy
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: 10001061; 001061-H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .Undecided: It is not yet known if there will be a plan to make IPD available

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No