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

  • STATUS
    Recruiting
  • End date
    Oct 28, 2022
  • participants needed
    60
  • sponsor
    National Heart, Lung, and Blood Institute (NHLBI)
Updated on 15 May 2022
hydroxyurea
blood transfusion
electrophoresis
thalassemia
vaso-occlusive crisis

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 may have a peripheral arterial tonometry (Endo-Pat) test to check the function of their blood vessels. For this, a thimble-shaped cup is placed on their finger and a blood pressure cuff is placed on their arm.

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 will take folic acid once a day.

Participants will have an end-of-study visit. They will discuss any side effects and repeat some of the screening tests. They may have an Endo-Pat test.

About a month after the last study 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 blood tests.

Participation will last from 8 to 12 weeks.

Description

Sickle Cell Disease (SCD) is an inherited monogenic hemoglobin disorder caused by a mutation in the gene encoding the beta globin subunit of adult hemoglobin (HbA) resulting in a substitution of valine for glutamic acid at position 6 and thus producing hemoglobin S (HbS). When deoxygenated, HbS polymerizes, rendering the red cell rigid, viscous, and abnormally adherent to the capillary endothelium. This impedes blood flow in the microcirculation, causing ischemia and microinfarcts that lead to painful crises, cerebrovascular stroke, renal impairment, retinopathy and other end-organ damage. The current scientific literature currently recognizes the contribution of an acquired hypercoagulable state in SCD to vascular pathobiology, chronic organ dysfunction, and mortality.

Similar to cancer, sickle cell disease is associated with an acquired hypercoagulable state and exhibits a high prevalence of incident and recurrent venous thromboembolism (VTE). Elevated levels of the procoagulant protein tissue factor and its activator, protein disulfide isomerase in humans with SCD suggest a causal role for thrombogenesis. In cancer patients, pharmacological inhibition of plasma PDI with Isoquercetin (IQ) led to a reduction in VTE biomarkers and VTE recurrence. These findings provide support to test the hypothesis that Isoquercetin in sickle cell disease would diminish thrombo-inflammatory VTE biomarkers and attenuate the associated hypercoagulable state.

Details
Condition VTE
Treatment Placebo, Isoquercetin
Clinical Study IdentifierNCT04514510
SponsorNational Heart, Lung, and Blood Institute (NHLBI)
Last Modified on15 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Age 18-70 years old
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
Be willing to comply with all study procedures for the duration of the study
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
Have provided signed written informed consent prior to performing any study procedure
including screening procedures

Exclusion Criteria

SCD with a recent VOC (<60 days from D0 of study)
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
SCD with a recent VTE (within 90 days of diagnosis of either DVT, PE or both)
in the analysis for statistical purposes
following
SCD with history of recent blood transfusion (<60 days from D0 of study) or exchange
transfusion (<90 days from D0 of study)
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
Have a prior bone marrow or stem cell transplant
INCLUSION OF VULNNERABLE PARTICIPANTS
History of recent (within 3 months prior to signing informed consent) congestive
in the study
Vulnerable subjects will not be included in this study
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
Diabetes mellitus judged to be under poor control by the Investigator evidenced
by a single fasting sugar value >250 gm/dl or requiring >3 antidiabetic agents
including insulin (all insulins are considered 1 agent); use of insulin per se is
not exclusionary
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
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