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The goal of this study is to evaluate how much quercetin or isoquercetin is absorbed after a single dose and evaluate for pharmacokinetic inhibition of protein disulfide isomerase. Pharmacodynamic studies will also be performed in an additional cohort of 10 patients with evidence of antiphospholipid antibodies
To compare the absorption and activity of quercetin or isoquercetin with or without ascorbic acid in healthy adults. Oral chews containing quercetin (500mg) or isoquercetin(500 mg total) with or without ascorbic acid will be given. Pharmacokinetic parameters (AUC, Cmax, Tmax, elimination half-life) will be determined over 24 hours (8 time points). Pharmacodynamic inhibition of protein disulfide isomerase activity will also be assessed.
In addition to healthy subjects, a cohort of 10 individuals with antiphospholipid antibodies will participate. These participants will receive isoquercetin 1000 mg and have pharmacodynamics studies performed at time 0 and 4 hours.
All study drugs will be provided by Quercegen Pharma.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Quercetin | Experimental | Single dose of quercetin with or without ascorbic acid |
|
| Isoquercetin | Active Comparator | Single dose of isoquercetin with or without ascorbic acid |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| isoquercetin or quercetin | Drug | Single dose PK/PD study |
|
| Measure | Description | Time Frame |
|---|---|---|
| AUC | AUC 0-24 hours of measured plasma quercetin aglycone for Arms A1, B1, A2, B2, C Collected at timepoints: baseline and 1, 2, 4, 6, 8, and 24 hours after dose. PK and PDI samples were not measured for Arm D (anti-phospholipid antibody cohort) | 24 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Reductase Activity of PDI Using Dieosin Glutathione Disulfide | Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide) | 2 hours. Not measured in D |
| Platelet-induced Thrombin Generation (U/mL) |
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Inclusion Criteria
Subject is willing to participate and provide informed consent
Subject is considered reliable and capable of adhering to the protocol per the judgment of the Investigator
Subjects in group D must exhibit good organ reserves (within prior 4 weeks) defined as:
Minimum age 18 years old
Body mass index (BMI) between 18 and 35 kg/m2
For cohort D (antiphospholipid antibodies) a. Subjects in group D must have at least one positive antiphospholipid antibody within the last 8 weeks and/or previous confirmed antibodies (2 or more occasions at least 12 weeks apart) : i. Positive lupus anticoagulant ii. anticardiolipin antibody IgM or IgG (>40U GPL) iii. anti-β2 Glycoprotein1 antibody titer (>35 units)
Exclusion Criteria
Pregnant. If female of child-bearing age, negative urinary pregnancy test prior to dosing of quercetin or isoquercetin
No history of malabsorptive gastrointestinal disorder
Currently taking aspirin, NSAIDS, warfarin, low-molecular weight heparin or other anticoagulants (such as direct thrombin inhibitors or factor X inhibitors)
a. Note: Study subjects taking aspirin or NSAIDS, if treating physician concurs, are permitted to enroll if plan to hold for aspirin 10 days or NSAIDS 24 hours prior to dosing of quercetin/isoquercetin
Prescribed niacin for hyperlipidemia
Known HIV
History of sensitivity or intolerance to flavonoids, niacin or ascorbic acid
May not have uncontrolled intercurrent illness including, but not limited to ongoing or active infection, hepatitis, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey Zwicker, MD | Beth Israel Deaconess Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28097231 | Derived | Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight. 2017 Jan 12;2(1):e89373. doi: 10.1172/jci.insight.89373. |
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Contact PI
3 years
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| ID | Title | Description |
|---|---|---|
| FG000 | Quercetin 500mg (ARM A1) | Single dose PK/PD analyses of quercetin 500 mg |
| FG001 | Isoquercetin 500mg (ARM B1) | Single dose PK/PD of isoquercetin 500 mg |
| FG002 | Quercetin 500 mg + Ascorbic Acid (ARM A2) | Single dose quercetin with 500 mg + ascorbic acid pk/pd analyses |
| FG003 | Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Single dose isoquercetin 500 mg + ascorbic acid pk/pd analyses |
| FG004 | Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | Single dose isoquercetin + 1000 mg ascorbic acid |
| FG005 | Antiphospholipid Antibody Cohort (ARM D) | Single dose isoquercetin 1000 mg + 1000 mg ascorbic acid in patients with antiphospholipid antibodies |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Measure Analysis Population Description: Antiphospholipid Antibody (ARM D): 2 withdrew consent without any data collected
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| ID | Title | Description |
|---|---|---|
| BG000 | Quercetin 500 mg (ARM A1) | Single dose of quercetin PK/PD analysis |
| BG001 | Isoquercetin 500 mg (ARM B1) | Single dose of isoquercetin PK/PD analysis |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Antiphospholipid Antibody (ARM D): 2 withdrew consent without data collected |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | AUC | AUC 0-24 hours of measured plasma quercetin aglycone for Arms A1, B1, A2, B2, C Collected at timepoints: baseline and 1, 2, 4, 6, 8, and 24 hours after dose. PK and PDI samples were not measured for Arm D (anti-phospholipid antibody cohort) | Posted | Mean | Standard Deviation | uM hr/L | 24 hours |
|
Assessed during visit 1, up to 24 hours
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Quercetin 500 mg (ARM A1) | Toxicity over 24 hours following single dose | 0 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey Zwicker, Division of Thrombosis and Haemostasis, Division of Hematology and Oncology | Beth Israel Deaconess Medical Center, Harvard Medical School | 617-667-9299 | jzwicker@bidmc.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 26, 2016 | Apr 6, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C016527 | isoquercitrin |
| D011794 | Quercetin |
| ID | Term |
|---|---|
| D044948 | Flavonols |
| D005419 | Flavonoids |
| D002867 | Chromones |
| D001578 | Benzopyrans |
| D011714 |
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Thrombin induced thrombin generation measured in patient plasma |
| 4 hours |
| BG002 | Quercetin 500 mg + Ascorbic Acid (ARM A2) | Single dose of quercetin + ascorbic acid PK/PD analysis |
| BG003 | Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Single dose of isqouercetin +ascorbic acid PK/PD analysis |
| BG004 | Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | single dose isoquercetin + ascorbic acid PK/PD analyses |
| BG005 | Antiphospholipid Antibody (ARM D) | single dose isoquercetin +ascorbic acid in patients with antiphospholipid antibodies |
| BG006 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Sex: Female, Male | Antiphospholipid Antibody (ARM D): 2 withdrew consent without data collected | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Antiphospholipid Antibody (ARM D): 2 withdrew consent without data collected | Count of Participants | Participants |
|
| Race (NIH/OMB) | Antiphospholipid Antibody (ARM D): 2 withdrew consent without data collected | Count of Participants | Participants |
|
Single dose, measurement of plasma quercetin aglycone |
| OG003 | Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Single dose, measurement of plasma quercetin aglycone |
| OG004 | Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | Single dose, measurement of plasma quercetin aglycone |
|
|
| Secondary | Reductase Activity of PDI Using Dieosin Glutathione Disulfide | Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide) | 2 hours after oral ingestion | Posted | Mean | Standard Deviation | Percent inhibition | 2 hours. Not measured in D |
|
|
|
| Secondary | Platelet-induced Thrombin Generation (U/mL) | Thrombin induced thrombin generation measured in patient plasma | 4 hours after single dose only measured in Arm C and Arm D | Posted | Mean | Standard Deviation | U/mL | 4 hours |
|
|
|
| 5 |
| 0 |
| 5 |
| 0 |
| 5 |
| EG001 | Isoquercetin 500 mg (ARM B1) | Toxicity over 24 hours following single dose | 0 | 5 | 0 | 5 | 0 | 5 |
| EG002 | Quercetin 500 mg + Ascorbic Acid (ARM A2) | Toxicity over 24 hours following single dose of combined quercetin and ascorbic acid | 0 | 5 | 0 | 5 | 0 | 5 |
| EG003 | Isoquercetin 500 mg + Ascorbic Acid (ARM B2) | Toxicity over 24 hours following single dose of combined isoquercetin and ascorbic acid | 0 | 5 | 0 | 5 | 0 | 5 |
| EG004 | Isoquercetin 1000 mg + Ascorbic Acid (ARM C) | Toxicity over 24 hours following single dose of isoquercetin | 0 | 10 | 0 | 10 | 0 | 10 |
| EG005 | Antiphospholipid Antibody (ARM D) | Toxicity over 24 hours following single dose of isoquercetin | 0 | 6 | 0 | 6 | 0 | 6 |
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| Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |