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| Name | Class |
|---|---|
| Louisiana Clinical and Translational Science Center | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 150 mg dose | Experimental | 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. |
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| 300 mg dose | Experimental | 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. |
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| 600 mg dose | Experimental | 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. |
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| 900 mg dose | Experimental | 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. |
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| Placebo |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Naringenin | Dietary Supplement | An extract of Citrus Sinensis containing naringenin and its precursor naringin |
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| 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. |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Candida Rebello | Pennington Biomedical Research Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pennington Biomedical Research Center | Baton Rouge | Louisiana | 70808 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27146015 | Background | Mulvihill EE, Burke AC, Huff MW. Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis. Annu Rev Nutr. 2016 Jul 17;36:275-99. doi: 10.1146/annurev-nutr-071715-050718. Epub 2016 May 4. |
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Of the 38 participants screened, 10 participants did not meet the study criteria, 7 had schedule conflicts and declined to participate, and 3 were screened before the study was determined to have met the recruiting goal. 18 participants were randomized.
38 subjects were screened for eligibility between May 25, 2018 and September 12, 2018.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1: NAR150, Placebo, NAR300 | Cohort 1 Sequence 1: NAR150 first, then Placebo, then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| FG001 | Cohort 1: NAR150, NAR300, Placebo, | Cohort 1 Sequence 2: NAR150 first, then NAR300 and then Placebo. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| FG002 | Cohort 1: Placebo, NAR150, NAR300 | Cohort 1 Sequence 3: Placebo first, then NAR150, and then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| FG003 | Cohort 2. NAR600, Placebo, NAR900 | Cohort 2 Sequence 1: NAR600, then Placebo, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| FG004 | Cohort 2: NAR600, NAR900, Placebo | Cohort 2 Sequence 2: NAR600, then NAR900, and then Placebo. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| FG005 | Cohort 2: Placebo, NAR600, NAR900 | Cohort 2 Sequence 3: Placebo, NAR600, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1/Visit 1 |
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| Washout Period ( At Least 1 Week) |
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| Intervention 2/Visit 2 |
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| Washout Period (At Least 1 Week) |
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| Intervention 3/Visit 3 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1: NAR150, Placebo, NAR300 | Cohort 1 Sequence 1: NAR150 first, then Placebo, then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | 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. | Subjects who completed the study | Posted | Count of Participants | Participants | Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week. |
|
Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week.
The study team employed open-ended and non-leading verbal questioning of the subject as the preferred method to inquire about adverse event occurrence. For example, appropriate questions included: "How are you feeling?", "Have you had any (other) medical problems since your last visit/contact?" The study staff established a diagnosis of the event based on signs, symptoms, and/or other clinical information. Subjects were asked about adverse events at each visit to the clinic for testing.
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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 | 150 mg Dose | 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 28% naringenin |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vomiting | Gastrointestinal disorders | Standard terminology | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Candida Rebello | Pennington Biomedical Research Center | 225-763-3159 | Candida.Rebello@pbrc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | May 7, 2018 | Dec 2, 2019 | ICF_000.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 30, 2018 | Jan 2, 2020 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| C005273 | naringenin |
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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.
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Except for the pharmacist who will prepare and dispense the capsules, all study staff and the investigators will be blinded to the randomization.
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. |
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| Placebo | Other | Cellulose |
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| 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 |
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| BG001 | Cohort 1: NAR150, NAR300, Placebo | Cohort 1 Sequence 2: NAR150 first, then NAR300 and then Placebo. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| BG002 | Cohort 1: Placebo, NAR150, NAR300 | Cohort 1 Sequence 3: Placebo first, then NAR150, and then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| BG003 | Cohort 2. NAR600, Placebo, NAR900 | Cohort 2 Sequence 1: NAR600, then Placebo, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| BG004 | Cohort 2: NAR600, NAR900, Placebo | Cohort 2 Sequence 2: NAR600, then NAR900, and then Placebo. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| BG005 | Cohort 2: Placebo, NAR600, NAR900 | Cohort 2 Sequence 3: Placebo, NAR600, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. |
| BG006 | Total | Total of all reporting groups |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Serum Naringenin Concentrations | Mean | Standard Deviation | uM |
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| OG000 |
| 150 mg Dose |
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 28% naringenin |
| OG001 | 300 mg Dose | 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 28% naringenin |
| OG002 | 600 mg Dose | 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 28% naringenin |
| OG003 | 900 mg Dose | 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 28% naringenin. |
| OG004 | Placebo | 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. |
|
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| Secondary | 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. | Subjects who completed the study | Posted | Least Squares Mean | Standard Error | (ug/mL) x hour | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours |
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| Secondary | 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. | Posted | Mean | Standard Error | ug/mL | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours |
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| Secondary | 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. | Subjects who completed the study | Posted | Least Squares Mean | Standard Error | hour | 24 hours |
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| Secondary | 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. | Subjects who completed the study. The half-life uses all the pooled data to calculate an estimate of the slope (k) to determine the half-life estimate. We did not calculate the slope of each individual subject. | Posted | Number | hour | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours |
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| Secondary | 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. | Subjects who completed the study | Posted | Least Squares Mean | Standard Error | L/hour | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours |
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| Secondary | 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. | Subjects who participated in the study | Posted | Least Squares Mean | Standard Error | uM | 0 and 4 hours |
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| 0 |
| 9 |
| 0 |
| 9 |
| 3 |
| 9 |
| EG001 | 300 mg Dose | 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 28% naringenin | 0 | 9 | 0 | 9 | 3 | 9 |
| EG002 | 600 mg Dose | 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 28% naringenin | 0 | 9 | 0 | 9 | 2 | 9 |
| EG003 | 900 mg Dose | 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 28% naringenin. | 0 | 9 | 0 | 9 | 1 | 9 |
| EG004 | Placebo | 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. | 0 | 18 | 0 | 18 | 4 | 18 |
| Diarrhea | Gastrointestinal disorders | Standard terminology | Systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | Standard terminology | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Standard terminology | Systematic Assessment |
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| Itching | Skin and subcutaneous tissue disorders | Standard terminology | Systematic Assessment |
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| Acne | Skin and subcutaneous tissue disorders | Standard terminology | Systematic Assessment |
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| Cyst on Foot | Skin and subcutaneous tissue disorders | Standard terminology | Systematic Assessment |
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| Headache | Nervous system disorders | Standard terminology | Systematic Assessment |
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| Drowsiness | Nervous system disorders | Standard terminology | Systematic Assessment |
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| Joint pain | Musculoskeletal and connective tissue disorders | Standard terminology | Systematic Assessment |
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| Sinus congestion | Respiratory, thoracic and mediastinal disorders | Standard terminology | Systematic Assessment |
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| Visual Disturbance | Eye disorders | Standard terminology | Systematic Assessment |
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