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

Sponsor

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Overall Status

Enrolling by invitation

CT.gov ID

NCT05675436

Collaborator

(none)

Enrollment

Location

56.6

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 000997.

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia Sickle Cell Thalassemia Sickle Cell Pain Hbss Hbsc Sickle Beta Thalassemia Sickle Beta Zero Thalassemia Sickle Cell Syndrome Variant

Detailed Description

Study Description:

Subjects actively enrolled protocol AG348-C-020 (NIH protocol #000997), 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 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 12 weeks. This change will be compared between the placebo and mitapivat arms.

SECONDARY ENDPOINTS:

The p50 changes will also be assessed at other time intervals besides 12 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 change from baseline to various follow-up periods. This change will be compared between the placebo and mitapivat arms.
Change in intracellular reactive oxidative species (ROS) in RBCs using a ROS sensitive fluorescent probe and mass spectrometrybased proteomics of RBC lysates between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms.
Phosphatidylserine (PS) externalization using annexin V labeling (marker of red cell survival) by flow cytometry between baseline andvarious follow-up periods. This change will be compared between the placebo and mitapivat arms.
Assessment of muscle physiology, tissue oxygenation and blood flow using NIRS methodologies between baseline and various follow-up periods. This change will be compared between the placebo and mitapivat arms.

TERTIARY/EXPLORATORY ENDPOINTS:

Assessment of mitochondrial retention in circulating erythrocytes through measurement of nuclear and mitochondrial cell-free DNA levels, as well as RBC 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 metabolomics 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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

20 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Anticipated Study Start Date :

Feb 6, 2023

Anticipated Primary Completion Date :

Sep 13, 2023

Anticipated Study Completion Date :

Oct 27, 2027

Arms and Interventions

Arm	Intervention/Treatment
1 i. Phase 2: Mitapivat 50 mg BID
2 ii. Phase 2: Mitapivat 100 mg BID
3 iii. Phase 2: Mitapivat Placebo
4 iv. Phase 2: Mitapivat Open-Label Extension Period
5 v. Phase 3: Mitapivat 50 mg BID
6 vi. Phase 3: Mitapivat 100 mg BID
7 vii. Phase 3: Mitapivat Open-Label Extension Period

Outcome Measures

Primary Outcome Measures

The change in the oxygen affinity measure p50 (defined as the partial pressure of oxygen at which Hb is 50% saturated with oxygen) between baseline [12 weeks]
This change will be compared between the placebo and mitapivat arms.

Secondary Outcome Measures

Change in intracellular reactive oxidative species (ROS) in RBCs using a ROS sensitive fluorescent probe and mass spectrometry-based proteomics of RBC lysates between baseline and various follow-up periods. [various time periods]
This change will be compared between the placebo and mitapivat 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 change from baseline to various follow-up periods [follow up time periods]
This change will be compared between the placebo and mitapivat arms.
Assessment of muscle physiology, tissue oxygenation and blood flow using near infrared spectroscopy (NIRS) methodologies between baseline and various follow-up periods [follow up time periods]
Assessment of muscle physiology, tissue oxygenation and blood flow using near infrared spectroscopy (NIRS) methodologies between baseline and various follow-up periods
The p50 changes will also be assessed at other time intervals besides [various time periods]
This change will be compared between the placebo and mitapivat arms.
Phosphatidylserine (PS) externalization using annexin V labeling (marker of red cell survival) by flow cytometry between baseline and various follow-up periods [follow up time periods]
Phosphatidylserine (PS) externalization using annexin V labeling (marker of red cell survival) by flow cytometry between baseline and various follow-up periods