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

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ClinicalTrials.gov Identifier: NCT04514510
Recruitment Status : Recruiting
First Posted : August 17, 2020
Last Update Posted : October 18, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

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 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.


Condition or disease Intervention/treatment Phase
VTE Drug: Isoquercetin Drug: Placebo Phase 2

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: Effects of Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease
Actual Study Start Date : November 2, 2020
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : October 28, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ISO
Subjects with sickle cell disease; Isoquercetin 1000mg once daily 28 days.
Drug: Isoquercetin
Isoquercetin (quercetin-3-O-D-glucoside, also referred to as isoquercitrin) is a naturally occurring monoglucoside of the most studied and widely consumed bioflavonoid, quercetin.

Placebo Comparator: Placebo
Subjects with sickle cell disease; placebo once daily fr 28 days.
Drug: Placebo
Silicified microcrystalline cellulose NF, Ascorbic acid, Nicotinic acid, Mg stearate, Silica and Colloidal Anhydrous Ph. Eur./Colloidal Silicon dioxide USP/NF




Primary Outcome Measures :
  1. The primary outcome will be the change in the plasma soluble P-selectin level comparing the baseline to IQ response [ Time Frame: 28 days ]
    The primary outcome will be the change in plasma soluble P-selectin level comparing the baseline versus IQ or placebo.


Secondary Outcome Measures :
  1. plasma protein disulfide isomerase activity [ Time Frame: 28 days ]
    Compare baseline and end of study plasma protein disulfide isomerase activity

  2. tissue factor positive extracellular vesicle number [ Time Frame: 28 days ]
    Compare baseline and end of study plasma tissue factor positive extracellular vesicle number

  3. procoagulant activity [ Time Frame: 28 days ]
    Compare baseline and end of study plasma tissue factor procoagulant activity

  4. inflammation and coagulation parameters [ Time Frame: 28 days ]
    Compare baseline and end of study inflammation and coagulation parameters

  5. biomarkers of vascular function and atherothrombosis [ Time Frame: 28 days ]
    Compare baseline and end of study contemporary biomarkers of vascular function and atherothrombosis

  6. safety/tolerability and adherence to oral IQ [ Time Frame: 28 days ]
    Assess safety/tolerability and adherence to oral IQ



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 46 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • 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 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.

EXCLUSION CRITERIA:

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:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. Active acute inflammatory disorders rheumatoid arthritis or systemic lupus erythematosus on disease modifying therapy.
    6. 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.
    7. 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.
    8. 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.

INCLUSION OF VULNNERABLE PARTICIPANTS:

Vulnerable subjects will not be included in this study.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04514510


Contacts
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Contact: Brenda F Merriweather, R.N. (301) 529-7440 brenda.merriweather@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Arun S Shet, M.D. National Heart, Lung, and Blood Institute (NHLBI)
Additional Information:
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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT04514510    
Other Study ID Numbers: 200137
20-H-0137
First Posted: August 17, 2020    Key Record Dates
Last Update Posted: October 18, 2021
Last Verified: October 14, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
VTE
protein disulfide isomerase
thrombo-inflammatory pathobiology
HbS polymerizes
P-selectin
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn