Safety and Pharmacokinetics of an Extract of Naringenin

Study Overview
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Brief Summary
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This study evaluates the safety of administering single ascending doses (150, 300, 600, and 900 mg) of a citrus extract of the flavonoid narigenin, and assesses the blood concentrations of naringenin following oral administration of the extract.

Detailed Description
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Naringenin is a component of food with therapeutic potential to improve glucose metabolism. In order to explore the mechanisms by which naringenin may increase energy expenditure and improve glucose metabolism in humans, it is of vital importance that the safety, tolerability, and bioavailability of naringenin are evaluated, when administered to humans. This study tests the safety of four doses of a citrus extract of naringenin and measures serum concentrations of naringenin at the 150 mg and 600 mg doses over a period of 24 hours, and at the 300 and 900 mg doses at four hours after subjects have been given the respective doses of naringenin.

Official Title
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Clinical Safety and Pharmacokinetic Evaluation of Naringenin: Single Dose Escalation Randomized Double Blind Controlled Trial

Conditions
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Safety Issues, Pharmacokinetics

Intervention / Treatment
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* Dietary Supplement: Naringenin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years) Body mass index between 20 and 35 kg/m2 Must have fasting blood sugar <126 mg/dL) Must be willing to refrain from consuming citrus fruits and tomato in any form, for 36 hours prior to each test day. Exclusion Criteria: Report citrus allergies. Report a history of cardiovascular disease, diabetes, or cancer Have evidence of hepatic disease or dysfunction Are currently pregnant or breastfeeding Are women of childbearing potential who will not use an effective method of birth control Chronically use of medications except over the counter medications that have been stopped 72 hours prior to the study visit Report clinically significant GI malabsorption syndromes Have clinically significant abnormal laboratory markers Anticipate surgery during the study period. Report history of substance abuse or alcoholism or significant psychiatric disorder that would interfere with the ability to complete the study. Have donated blood during the month prior to study entry or plan to do so during the study. Have participated in other studies using an investigational drug during the preceding three months. Are current smokers or have smoked within the previous three months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study consists of two cohorts of nine subjects each. In the first cohort subjects will receive the 150 mg dose and proceed to the 300 mg dose only if the 150 mg dose is deemed safe. The study is a double blind randomized controlled crossover trial, therefore, subjects could receive a placebo at the first or second visit. Similarly in the second cohort, 600 mg and 900 mg doses will be evaluated.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 150 mg dose<br>Blood will be drawn at at 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours to measure serum naringenin concentrations in response to a single 150 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin. | Dietary Supplement: Naringenin<br>* An extract of Citrus Sinensis containing naringenin and its precursor naringin<br>|
| Experimental: 300 mg dose<br>Blood will be drawn at at 0, and 4 hours to measure serum naringenin concentrations in response to a single 300 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin. | Dietary Supplement: Naringenin<br>* An extract of Citrus Sinensis containing naringenin and its precursor naringin<br>|
| Experimental: 600 mg dose<br>Blood will be drawn at at 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours to measure serum naringenin concentrations in response to a single 600 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin. | Dietary Supplement: Naringenin<br>* An extract of Citrus Sinensis containing naringenin and its precursor naringin<br>|
| Experimental: 900 mg dose<br>Blood will be drawn at at 0, and 4 hours to measure serum naringenin concentrations in response to a single 900 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin. | Dietary Supplement: Naringenin<br>* An extract of Citrus Sinensis containing naringenin and its precursor naringin<br>|
| Placebo Comparator: Placebo<br>Subjects in the first cohort will receive 150 mg and 300 mg ascending doses of naringenin and subjects in the second cohort will receive 600 mg and 900 mg ascending doses of naringenin. Each cohort will also have a placebo group. | Other: Placebo<br>* Cellulose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | All adverse events will be recorded following the first administration of the study product or placebo. The study physician in consultation with the coordinator will review and determine whether a subject can be administered the next ascending dose. The cohorts will be run in series. There will be an interval of up to four weeks between the two cohorts. During this time an interim analysis will be conducted and a safety summary of adverse events for Cohort 1 will be compiled and reviewed by the investigators. Dose safety will be investigated by compiling by treatment (e.g. 150 mg dose, 300 mg dose, placebo) a list of adverse events. The frequency of these events will be counted and compared with the placebo group. | Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The area under the serum concentration versus time curve will be determined. | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | 
| Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The maximal serum concentration will be determined. | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | 
| Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The time to peak serum naringenin concentration will be determined. | 24 hours | 
| Measurement of Half Life of Naringenin at 150 and 600 mg Doses | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The half life of naringenin will be determined. | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | 
| Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The apparent oral clearance of naringenin will be determined. | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | 
| Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses | Blood will be drawn at 0 hours and 4 hours following ingestion of the 300 and 900mg doses of naringenin and serum naringenin concentrations will be measured. | 0 and 4 hours |