Quercetin PK/PD Study in Healthy Adults and Patients With Hypercoagulable States

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01722669
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 91
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: isoquercetin or quercetin	Early Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Pharmacokinetic and Pharmacodynamic Study of Oral Quercetin and Isoquercetin in Healthy Adults and Patients With Hypercoagulable States.
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Dec 1, 2019
• Actual Study Completion Date: Dec 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Quercetin Single dose of quercetin with or without ascorbic acid	Drug: isoquercetin or quercetin; Single dose PK/PD study
Active Comparator: Isoquercetin Single dose of isoquercetin with or without ascorbic acid	Drug: isoquercetin or quercetin; Single dose PK/PD study

Outcome Measures

Primary Outcome Measures

1. AUC [24 hours]

   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)

Secondary Outcome Measures

1. Reductase Activity of PDI Using Dieosin Glutathione Disulfide [2 hours. Not measured in D]

   Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide)

2. Platelet-induced Thrombin Generation (U/mL) [4 hours]

   Thrombin induced thrombin generation measured in patient plasma

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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:

1. Estimated GFR >35 (formula),

2. Platelet count >65 K/uL,

3. Hemoglobin >10.5 grams/dL

4. Total bilirubin <2.0 mg/dL

• 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)

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center

Investigators

• Principal Investigator: Jeffrey Zwicker, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 26, 2016

More Information

Publications

None provided.

• Responsible Party: Jeff Zwicker, Associate Professor, Harvard Medical School, Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT01722669
• Other Study ID Numbers: 2012P000022
• First Posted: Nov 7, 2012
• Last Update Posted: Oct 12, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jeff Zwicker, Associate Professor, Harvard Medical School, Beth Israel Deaconess Medical Center: quercetin; isoquercetin; pharmacokinetic; pharmacodynamic
• Additional relevant MeSH terms: Thrombophilia; Quercetin

Study Results

Participant Flow

Arm/Group Title	Quercetin 500mg (ARM A1)	Isoquercetin 500mg (ARM B1)	Quercetin 500 mg + Ascorbic Acid (ARM A2)	Isoquercetin 500 mg + Ascorbic Acid (ARM B2)	Isoquercetin 1000 mg + Ascorbic Acid (ARM C)	Antiphospholipid Antibody Cohort (ARM D)
Arm/Group Description	Single dose PK/PD analyses of quercetin 500 mg	Single dose PK/PD of isoquercetin 500 mg	Single dose quercetin with 500 mg + ascorbic acid pk/pd analyses	Single dose isoquercetin 500 mg + ascorbic acid pk/pd analyses	Single dose isoquercetin + 1000 mg ascorbic acid	Single dose isoquercetin 1000 mg + 1000 mg ascorbic acid in patients with antiphospholipid antibodies
Period Title: Overall Study
STARTED	5	5	5	5	10	8
COMPLETED	5	5	5	5	10	6
NOT COMPLETED	0	0	0	0	0	2

Baseline Characteristics

Arm/Group Title	Quercetin 500 mg (ARM A1)	Isoquercetin 500 mg (ARM B1)	Quercetin 500 mg + Ascorbic Acid (ARM A2)	Isoquercetin 500 mg + Ascorbic Acid (ARM B2)	Isoquercetin 1000 mg + Ascorbic Acid (ARM C)	Antiphospholipid Antibody (ARM D)	Total
Arm/Group Description	Single dose of quercetin PK/PD analysis	Single dose of isoquercetin PK/PD analysis	Single dose of quercetin + ascorbic acid PK/PD analysis	Single dose of isqouercetin +ascorbic acid PK/PD analysis	single dose isoquercetin + ascorbic acid PK/PD analyses	single dose isoquercetin +ascorbic acid in patients with antiphospholipid antibodies	Total of all reporting groups
Overall Participants	5	5	5	5	10	6	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	5 100%	5 100%	5 100%	5 100%	10 100%	4 66.7%	34 94.4%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	2 33.3%	2 5.6%
Sex: Female, Male (Count of Participants)
Female	2 40%	3 60%	2 40%	3 60%	5 50%	5 83.3%	20 55.6%
Male	3 60%	2 40%	3 60%	2 40%	5 50%	1 16.7%	16 44.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	2 20%	0 0%	2 5.6%
Not Hispanic or Latino	2 40%	1 20%	2 40%	1 20%	5 50%	6 100%	17 47.2%
Unknown or Not Reported	3 60%	4 80%	3 60%	4 80%	3 30%	0 0%	17 47.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 20%	1 20%	1 20%	1 20%	1 10%	0 0%	5 13.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 20%	0 0%	1 20%	0 0%	0 0%	1 16.7%	3 8.3%
White	2 40%	2 40%	2 40%	2 40%	5 50%	5 83.3%	18 50%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 20%	2 40%	1 20%	2 40%	4 40%	0 0%	10 27.8%

Outcome Measures

1. Primary Outcome

Title	AUC
Description	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)
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quercetin 500 mg (ARM A1)	Isoquercetin 500 mg (ARM B1)	Quercetin 500 mg + Ascorbic Acid (ARM A2)	Isoquercetin 500 mg + Ascorbic Acid (ARM B2)	Isoquercetin 1000 mg + Ascorbic Acid (ARM C)
Arm/Group Description	Single dose, measurement of plasma quercetin aglycone	Single dose, measurement of plasma quercetin aglycone	Single dose, measurement of plasma quercetin aglycone	Single dose, measurement of plasma quercetin aglycone	Single dose, measurement of plasma quercetin aglycone
Measure Participants	5	5	5	5	10
Mean (Standard Deviation) [uM hr/L]	4.78 (1.67)	15.00 (8.94)	5.41 (2.13)	16.34 (10.08)	40.3 (17.11)

2. Secondary Outcome

Title	Reductase Activity of PDI Using Dieosin Glutathione Disulfide
Description	Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide)
Time Frame	2 hours. Not measured in D

Outcome Measure Data

Analysis Population Description

2 hours after oral ingestion

Arm/Group Title	Quercetin 500 mg (ARM A1)	Isoquercetin 500 mg (ARM B1)	Quercetin 500 mg + Ascorbic Acid (ARM A2)	Isoquercetin 500 mg + Ascorbic Acid (ARM B2)	Isoquercetin 1000 mg + Ascorbic Acid (ARM C)
Arm/Group Description	PDI activity measured by DiESSG assay at 0 and 2 hours	PDI activity measured by DiESSG assay at 0 and 2 hours	PDI activity measured by DiESSG assay at 0 and 2 hours	PDI activity measured by DiESSG assay at 0 and 2 hours	PDI activity measured by DiESSG assay at 0 and 2 hours
Measure Participants	5	5	5	5	10
Mean (Standard Deviation) [Percent inhibition]	31.9 (24.14)	63.2 (25.3)	16 (31.8)	8.3 (15.03)	38 (35)

3. Secondary Outcome

Title	Platelet-induced Thrombin Generation (U/mL)
Description	Thrombin induced thrombin generation measured in patient plasma
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

4 hours after single dose only measured in Arm C and Arm D

Arm/Group Title	Isoquercetin 1000 mg + Ascorbic Acid (ARM C)	Antiphospholipid Antibody (ARM D)
Arm/Group Description	Thrombin induced thrombin generation measured before and after isoquercetin + Ascorbic acid at time 0 and 4 hours	Thrombin induced thrombin generation measured at time 0 and 4 hours following isoquercetin 1000 mg
Measure Participants	10	6
Mean (Standard Deviation) [U/mL]	0.30 (.28)	1.40 (2.14)

Adverse Events

Time Frame	Assessed during visit 1, up to 24 hours
Arm/Group Title	Quercetin 500 mg (ARM A1)		Isoquercetin 500 mg (ARM B1)		Quercetin 500 mg + Ascorbic Acid (ARM A2)		Isoquercetin 500 mg + Ascorbic Acid (ARM B2)		Isoquercetin 1000 mg + Ascorbic Acid (ARM C)		Antiphospholipid Antibody (ARM D)
Arm/Group Description	Toxicity over 24 hours following single dose		Toxicity over 24 hours following single dose		Toxicity over 24 hours following single dose of combined quercetin and ascorbic acid		Toxicity over 24 hours following single dose of combined isoquercetin and ascorbic acid		Toxicity over 24 hours following single dose of isoquercetin		Toxicity over 24 hours following single dose of isoquercetin
All Cause Mortality
	Quercetin 500 mg (ARM A1)		Isoquercetin 500 mg (ARM B1)		Quercetin 500 mg + Ascorbic Acid (ARM A2)		Isoquercetin 500 mg + Ascorbic Acid (ARM B2)		Isoquercetin 1000 mg + Ascorbic Acid (ARM C)		Antiphospholipid Antibody (ARM D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/10 (0%)		0/6 (0%)
Serious Adverse Events
	Quercetin 500 mg (ARM A1)		Isoquercetin 500 mg (ARM B1)		Quercetin 500 mg + Ascorbic Acid (ARM A2)		Isoquercetin 500 mg + Ascorbic Acid (ARM B2)		Isoquercetin 1000 mg + Ascorbic Acid (ARM C)		Antiphospholipid Antibody (ARM D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/10 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Quercetin 500 mg (ARM A1)		Isoquercetin 500 mg (ARM B1)		Quercetin 500 mg + Ascorbic Acid (ARM A2)		Isoquercetin 500 mg + Ascorbic Acid (ARM B2)		Isoquercetin 1000 mg + Ascorbic Acid (ARM C)		Antiphospholipid Antibody (ARM D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/5 (0%)		0/5 (0%)		0/10 (0%)		0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.