Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease

NCT04514510 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 20013720-H-0137
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Sickle cell disease (SCD) is an inherited hemoglobin disorder. People with SCD have an increased chance for getting blood clots. Researchers want to see if a dietary supplement called isoquercetin can decrease levels of inflammation and blood clotting in people with SCD. Objective: To see how isoquercetin works in people with SCD. Eligibility: Adults age 18-70 years old who have SCD and are in a steady-state (have not experienced a pain crisis in the last 60 days and, if taking hydroxyurea, have not had a dose change in the past 90 days). Design: Participants will be screened with a physical exam, medical history, medicine review, and blood tests. Participants will be put in 1 of 2 treatment groups. They will take 4 capsules of isoquercetin or placebo all at once, by mouth, every day for 4 weeks. They will get a pill dispenser and keep a medicine diary. Participants may have an optional near infrared spectroscopy (NIRS) test to measure how treatment affects blood flow. In this test, probes will be placed on the skin to measure tissue oxygen level and blood flow. A blood pressure cuff placed on the arm will be filled with air briefly to restrict the blood flow in the arm (for up to 5 minutes) and then released. Participants may also be asked to breathe at a certain rate or hold their breath for as long as they can during measurements. Participants will take folic acid once a day. Participants will have an end-of-study drug visit. They will discuss any side effects and repeat some of the screening tests. They may have an additional optional NIRS test. About a month after the end of study drug visit, participants will be contacted by phone to see if they have any side effects. Those who do may have a follow-up visit. At this visit, they may have additional blood tests performed. Participation will last from 8 to 12 weeks.

Conditions

Sickle Cell Disease

Keywords

Venous thrombosis; Protein disulfide isomerase; Thrombo-inflammation; HbS polymerization; P-selectin

Outcome Measures

Primary Outcomes (1)

• Mean Change in the Plasma Soluble P-selectin Level

  Mean change in plasma soluble P-selectin level comparing the baseline versus IQ or placebo.

  Baseline and Day 28

Secondary Outcomes (9)

• Mean Change in Plasma Protein Disulfide Isomerase Activity

  Baseline and 28 days

• Median Change of Tissue Factor Vesicle Number

  Baseline and Day 28

• Mean Change in Tissue Factor Vesicle Procoagulant Activity

  Baseline and Day 28

• Mean Change in D-Dimer

  Baseline and Day 28

• Mean Change in Vascular Cell Adhesion Molecule

  Baseline and Day 28

Study Arms (2)

Participants with Sickle Cell Disease Receiving Isoquercetin

EXPERIMENTAL

Isoquercetin 1000 mg, once daily by mouth for 28 days in participants with Sickle Cell Disease.

Drug: Isoquercetin

Participants with Sickle Cell Disease Receiving Placebo

PLACEBO COMPARATOR

Placebo once daily, by mouth for 28 days in participants with Sickle Cell Disease.

Drug: Placebo

Interventions

Isoquercetin DRUG

Isoquercetin (quercetin-3-O-beta-D-glucoside, also referred to as isoquercitrin) is a naturally occurring monoglucoside of the most studied and widely consumed bioflavonoid, quercetin. Isoquercetin given at 1000 mg, once daily by mouth for 28 days.

Also known as: isoquercitrin

Participants with Sickle Cell Disease Receiving Isoquercetin

Placebo DRUG

Silicified microcrystalline cellulose NF, Ascorbic acid, Nicotinic acid, Mg stearate, Silica and Colloidal Anhydrous Ph. Eur./Colloidal Silicon dioxide USP/NF. Placebo give at 1000 mg, once daily by mouth for 28 days.

Participants with Sickle Cell Disease Receiving Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For enrollment onto the active phase of the study (IQ supplement vs placebo), subjects must meet all of the following criteria during the screening period (visit #1) which can last from 0-28 days prior to start of study intervention:
• Unequivocal diagnosis of sickle cell anemia (Hemoglobin SS or Hemoglobin SC or Beta Thalassemia Major or Beta Thalassemia Minor) confirmed by hemoglobin electrophoresis performed on patients at least 90 days after a blood transfusion if previously transfused, or DNA genotyping.
• Age 18-70 years old
• Steady state SCD (no acute vaso-occlusive crisis within 60 days of D0 of the study) and if on HU therapy, on an optimized dose for at least 30 days. For those newly initiated on HU therapy, the dose should be unchanged for at least 90 days.
• Be willing to comply with all study procedures for the duration of the study.
• Have provided signed written informed consent prior to performing any study procedure, including screening procedures.

You may not qualify if:

• Subjects who meet any of the following criteria during screening will not receive the study intervention and will be counted toward study accrual. Screen failures will not be included in the analysis for statistical purposes:
• SCD with a recent VOC (\<60 days from D0 of study).
• SCD with history of recent blood transfusion (\<60 days from D0 of study) or exchange transfusion (\<90 days from D0 of study).
• SCD with a recent VTE (within 90 days of diagnosis of either DVT, PE or both).
• Any patient receiving crizanlizumab therapy for SCD or that has received crizanlizumab within the past 30 days of D0 of study.
• 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:
• History of recent (within 3 months prior to signing informed consent) congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke.
• Active infection requiring the use of parenteral antimicrobial agents or Grade greater than or equal to 3 in severity (per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) within 2 months prior to the first dose of study drug.
• Active viral infection as evidenced by testing positive for hepatitis B surface antigen or hepatitis C virus (HCV) antibody (Ab) with signs of active hepatitis B or C virus infection. If the subject is positive for HCV Ab, a reverse transcriptase-polymerase chain reaction test will be conducted. Subjects with hepatitis C may be rescreened after receiving appropriate hepatitis C treatment.
• Testing positive for human immunodeficiency virus (HIV) 1 or 2 Ab with evidence for ongoing active infection (i.e., CD4 count \<400/microL and viral load \>100,000 copies/mL) on antiretroviral therapy.
• Active acute inflammatory disorders rheumatoid arthritis or systemic lupus erythematosus on disease modifying therapy.
• History of any primary malignancy, with the exception of curatively treated nonmelanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years.
• Any injury or medical condition that, in the judgement of the Investigator would prevent the subject from participating in the study.
• Have a prior bone marrow or stem cell transplant.
• Vulnerable subjects will not be included in this study.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead
• Quercis Pharma AG: collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Lizarralde-Iragorri MA, Parachalil Gopalan B, Merriweather B, Brooks J, Hill M, Lovins D, Pierre-Charles R, Cullinane A, Dulau-Florea A, Lee DY, Villasmil R, Jeffries N, Shet AS. Isoquercetin for thromboinflammation in sickle cell disease: a randomized double-blind placebo-controlled trial. Blood Adv. 2024 Jan 9;8(1):172-182. doi: 10.1182/bloodadvances.2023011542.

  PMID: 38157227 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Anemia, Sickle Cell; Venous Thrombosis

Interventions

isoquercitrin

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Arun Shet, MD, PhD
• Organization: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH)

arun.shet@nih.gov

301.827.6808

Study Officials

• Arun S Shet, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2020
• First Posted: August 17, 2020
• Study Start: November 2, 2020
• Primary Completion: June 13, 2022
• Study Completion: July 7, 2022
• Last Updated: January 2, 2024
• Results First Posted: June 27, 2023

Record last verified: 2023-11

Locations

US (1)