Isoquercetin in Sickle Cell Anemia

Phase 2

Withdrawn

• Conditions: Sickle Cell-Beta0-Thalassemia; Sickle Cell Disease
• Interventions: Drug: Isoquercetin

• Registration Number: NCT04474626
• Lead Sponsor: Jeffrey Zwicker, MD

Brief Summary

This research study is being done to assess the safety and effectiveness of isoquercetin to reduce levels of soluble P-Selectin in patients with sickle cell disease. Isoquercetin is a naturally occurring flavonoid-or vitamin. You will find quercetin and isoquercetin in fruits and vegetables.

The names of the study drug involved in this study are/is:

- Isoquercetin

Detailed Description

This is a single-arm phase 2 study in adults with Sickle Cell Disease (SCD) to assess the effect of oral isoquercetin on biomarkers of endothelial and platelet activation, inflammation and ongoing blood coagulation.

* The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

* The names of the study drug involved in this study are/is: Isoquercetin

* Participants will receive study treatment for 1 year and will be followed for 30 days after the last dose.

* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

* The U.S. Food and Drug Administration (FDA) has not approved isoquercetin as a treatment for any disease.

Study Timeline

• Study First Submitted: 2020-07-06
• Study First Submitted QC: 2020-07-13
• Study First Posted: 2020-07-17
• Study Start: 2020-12
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-07
• Last Update Posted: 2021-01-11
• Primary Completion: 2022-12-31
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Eligible subjects require an established diagnosis of sickle cell disease/homozygous hemoglobin S (SCD-SS) or sickle cell disease hemoglobin β0-thalassemia (SCD-Sβ0-thal).

• Patients on other therapy including hydroxyurea will be included.

• Age 18-50 years.

• Participants must have preserved organ and marrow function as defined below:

  • leukocytes ≥2,000/mcL
  • platelets ≥75,000/mcL
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
  • Estimated creatinine clearance ≥45 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

• Subjects with no evidence of worsening over the last 4 weeks (e.g. any acute complication of SCD including but not limited to VOC, acute chest syndrome and stroke, that required unscheduled medical attention or intervention) as determined by the investigator will be included.

• Patients on anticoagulation therapy will be excluded.

• The effects of isoquercetin on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of isoquercetin administration.

• Ability to understand and the willingness to sign a written informed consent document

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Exclusion Criteria

• Please ensure exclusion criteria are clearly worded to describe participants who will not be eligible.
• Participants may not be concurrently receiving any other study agents.
• Subjects with no evidence of worsening over the last 1 month (e.g. any acute complication of SCD including but not limited to VOC, acute chest syndrome and stroke, that required unscheduled medical attention or intervention) as determined by the investigator will be included.
• Familial bleeding diathesis.
• Known diagnosis of disseminated intravascular coagulation.
• Currently receiving anticoagulant therapy.
• Currently using daily use of aspirin (>81mg daily), Clopidogrel (Plavix), cilostazol (Pletal), aspirin-dipyridamole (Aggrenox) (within 10 days)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to isoquercetin.
• Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness/social situations that would limit study compliance.
• Pregnant women are excluded from this study because isoquercetin is a PDI inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with isoquercetin, breastfeeding should be discontinued if the mother is treated with isoquercetin. These potential risks may also apply to other agents used in this study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ISOQUERCETIN	Isoquercetin	The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits - ISOQUERCETIN: Oral Study Drug, 1 time per day, per predetermined dosed per 28 treatment cycle. This will continue for up to 337 days.

Primary Outcome Measures

Name	Time	Method
Change in sP Selectin levels with isoquercetin	baseline to 28 Days	Comparisons between baseline and follow-up measurements (i.e. change in sP-Selectin), will be performed using a two-tailed, paired t-test analyses.

Secondary Outcome Measures

Name	Time	Method
Platelet dependent thrombin generation (coagulation)	baseline to 1 year	Laboratory values at baseline and subsequent monthly follow-up time points will be modeled using linear mixed effects regression with an autoregressive covariance structure.
sE-selectin (adhesion)-Biomarker	baseline to 1 year	Laboratory values at baseline and subsequent monthly follow-up time points will be modeled using linear mixed effects regression with an autoregressive covariance structure.
Number of Participants With Treatment-Related Adverse Events	start of study treatment up to 13 months	Sickle cell events such as SCPC, uncomplicated pain crisis, hospitalizations, emergency room visits, transfusions, acute chest syndrome and transfusion support will be summarized as annualized numbers. Statistical comparisons will be made for each patient relative to the number from the previous year using a Wilcoxon rank-sum test.
C-reactive protein CRP	baseline to 1 year	Laboratory values at baseline and subsequent monthly follow-up time points will be modeled using linear mixed effects regression with an autoregressive covariance structure.