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| ID | Type | Description | Link |
|---|---|---|---|
| U54AT008909 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Center for Complementary and Integrative Health (NCCIH) | NIH |
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Supplements containing goldenseal, a perennial herb native to North America, have consistently ranked among the top 20 highest selling natural products throughout the last decade. Goldenseal products are marketed as licensed natural health products in Canada and as dietary supplements in the United States. Natural products made from dried roots of the goldenseal plant are purported to have therapeutic value and are used to self-treat a range of medical complications, including the common cold, allergic rhinitis, and digestive disorders, such as diarrhea and constipation. Based on a previous clinical study, goldenseal have been shown to precipitate pharmacokinetic interactions with metformin in healthy volunteers. This follow-up study aims to evaluate the goldenseal-metformin interaction in type 2 diabetic patients. Results from this proposed clinical study will (1) characterize the pharmacokinetic interaction between the botanical dietary supplement goldenseal and anti-diabetic drug metformin, (2) provide evidence-based recommendations to mitigate drug interaction risks, and (3) contribute to the development of a comprehensive strategy for effectively assessing other potential natural-product drug interactions.
Many patient groups, including those afflicted with cardiovascular disease, cancer, HIV/AIDS, hepatitis C, and diabetes, often supplement their prescribed pharmacotherapeutic regimens with herbal and other natural products, raising concern for adverse interactions. Unlike for drug-drug interactions, rigorous, harmonized guidelines for assessing the risk of natural product-drug interactions do not exist. The NCCIH-funded Center of Excellence for Natural Product Drug Interaction (NaPDI) Research was established in September 2015. The mission of the NaPDI Center is to provide leadership in the identification, evaluation, and dissemination of potential clinically meaningful pharmacokinetic natural product-drug interactions. Goldenseal is one of four high priority natural products selected by the NaPDI Center for further evaluation for drug interaction potential.
A recent clinical study completed by researchers at the NaPDI center showed that a well-characterized, adulterant- and contaminant-free goldenseal product administered to 16 healthy volunteers (3 g daily by mouth for 6 consecutive days) resulted in a significant decrease (23%) in metformin systemic exposure [area under the plasma concentration-time curve (AUC)] with no change in half-life or renal clearance. Based on these clinical observations, along with complementary in vitro data, the current working hypothesis is that goldenseal interacts with intestinal organic cation transporter 1 to alter metformin disposition. These observations may have clinical implications for diabetic patients, as metformin is the first-line treatment and most prescribed anti-diabetic medication for type 2 diabetes. The objective of this study is to assess the potential for goldenseal to alter the pharmacokinetics and clinical effects of standard metformin treatment in well-controlled adult type 2 diabetic patients.
Transporter inhibition represents an understudied mechanism of natural product-drug interactions. The proposed clinical study will be the first of its kind to evaluate whether such pharmacokinetic interactions can potentially affect clinical outcomes. The knowledge gained from these efforts will ultimately build upon a systematic framework for effectively studying other transporter-mediated natural product-drug interactions.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study Arm 1: Baseline | Experimental | An anticipated twenty type 2 diabetic subjects (10 males, 10 females) will be administered a single dose of midazolam (0.5 mg) intravenously via a peripherally inserted catheter in conjunction with their daily oral administration of metformin. Plasma and urine will be collected from 0-24 hours post-midazolam administration. Participants will take their metformin as prescribed for the entirety of the study with no interruption in pharmacotherapy. |
|
| Study Arm 2: Acute Goldenseal Exposure | Experimental | For Arm 2, the same 20 subjects will be administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam (as described in Arm 1). Plasma and urine will be collected in a manner identical to that in Arm 1. With respect to midazolam administration, a washout period of 7 days will separate Arm 2 from Arm 1. |
|
| Study Arm 3: Chronic Goldenseal Exposure | Experimental | For Arm 3, the same 20 subjects will be administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants will be administered the goldenseal three times daily, as well as the single dose of midazolam (as described in Arm 1). Plasma and urine will be collected in a manner identical to that in Arm 1. A designated washout period for midazolam will not be necessary to separate Arm 3 from Arm 2 since there will be 27 days of goldenseal administration prior to the midazolam administration. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam Hcl 1Mg/Ml Inj | Drug | 0.5 mL of an intravenous solution (1 mg/mL) will be administered. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Metformin AUC | Area under the plasma concentration time curve of metformin | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
| Metformin Cmax | maximum concentration of metformin | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
| Measure | Description | Time Frame |
|---|---|---|
| Metformin Half-Life | half-life of metformin | 0-24h |
| Metformin Renal Clearance | renal clearance of metformin | 0-24h |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington State University College of Pharmacy and Pharmaceutical Sciences | Spokane | Washington | 99202 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33174626 | Background | Nguyen JT, Tian DD, Tanna RS, Hadi DL, Bansal S, Calamia JC, Arian CM, Shireman LM, Molnar B, Horvath M, Kellogg JJ, Layton ME, White JR, Cech NB, Boyce RD, Unadkat JD, Thummel KE, Paine MF. Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail. Clin Pharmacol Ther. 2021 May;109(5):1342-1352. doi: 10.1002/cpt.2107. Epub 2020 Dec 23. | |
| 28495567 | Background |
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A washout period of ≥7 days between each arm was implemented in the study design.
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| ID | Title | Description |
|---|---|---|
| FG000 | Midazolam Alone - Washout - Midazolam + Acute Goldenseal - Washout - Midazolam + Chronic Goldenseal | Twenty-two adults (12 males, 10 females) with type 2 diabetes participated in this three-arm, crossover study to assess a pharmacokinetic natural product-drug interaction. In arm 1 (midazolam alone), participants were administered a single dose of midazolam (0.5 mg) intravenously via a peripherally inserted catheter; at this time, participants were instructed to co-administer their entire daily dose of metformin orally. For Arm 2 (midazolam + acute goldenseal exposure), the same 22 participants were administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam and metformin. For Arm 3 (chronic goldenseal exposure), participants self-administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants were administered the goldenseal three times daily, as well as the single dose of midazolam and metformin. Plasma and urine were collected from 0-24 hours post-midazolam administration for all 3 arms of the study. A washout period of 7 days separated each arm to ensure appropriate washout of midazolam. Participants continued their routine administration of metformin as prescribed throughout the duration of the study without interruption in pharmacotherapy. Midazolam HCl 1mg/mL inj: 0.5 mL of intravenous solution Goldenseal (Hydrastis canadensis) 550 mg capsules: dried root powder in vegetable capsules (Solaray; Lot #1020199) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Midazolam Alone - Washout - Midazolam + Acute Goldenseal - Washout - Midazolam + Chronic Goldenseal | Twenty-two adults (12 males, 10 females) with type 2 diabetes participated in this three-arm, crossover study to assess a pharmacokinetic natural product-drug interaction. In arm 1 (midazolam alone), participants were administered a single dose of midazolam (0.5 mg) intravenously via a peripherally inserted catheter; at this time, participants were instructed to co-administer their entire daily dose of metformin orally. For Arm 2 (midazolam + acute goldenseal exposure), the same 22 participants were administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam and metformin. For Arm 3 (chronic goldenseal exposure), participants self-administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants were administered the goldenseal three times daily, as well as the single dose of midazolam and metformin. Plasma and urine were collected from 0-24 hours post-midazolam administration for all 3 arms of the study. A washout period of 7 days separated each arm to ensure appropriate washout of midazolam. Participants continued their routine administration of metformin as prescribed throughout the duration of the study without interruption in pharmacotherapy. Midazolam HCl 1mg/mL inj: 0.5 mL of intravenous solution Goldenseal (Hydrastis canadensis) 550 mg capsules: dried root powder in vegetable capsules (Solaray; Lot #1020199) |
| 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, Categorical | Count of Participants |
| 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 | Metformin AUC | Area under the plasma concentration time curve of metformin | All 22 participants completed the 3 arms of the study (baseline, acute goldenseal exposure, and chronic goldenseal exposure). | Posted | Geometric Mean | 90% Confidence Interval | mcg*hr/mL | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
|
All participants were monitored up to whenever they completed the final arm of the study, which was on average ~2 months.
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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 | Study Arm 1: Baseline | Twenty-two type 2 diabetic subjects (12 men, 10 women) were administered a single dose of midazolam (0.5 mg) intravenously via a peripherally inserted catheter in conjunction with their daily oral administration of metformin. Plasma and urine were collected from 0-24 hours post-midazolam administration. Participants self-administered their metformin as prescribed throughout the entirety of the study without interruption in pharmacotherapy. Midazolam HCl 1 mg/mL inj: 0.5 mL of an intravenous solution was administered. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| presyncope | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mary Paine | Washington State University | 5093587759 | mary.paine@wsu.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 | May 9, 2023 | May 29, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008874 | Midazolam |
| ID | Term |
|---|---|
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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|
| Goldenseal (Hydrastis canadensis) | Dietary Supplement | Goldenseal (Solaray; Lot #1020199) is supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules will be administered with 240 mL of water. |
|
| Midazolam AUC | area under the concentration vs. time curve of midazolam | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
| Liang X, Giacomini KM. Transporters Involved in Metformin Pharmacokinetics and Treatment Response. J Pharm Sci. 2017 Sep;106(9):2245-2250. doi: 10.1016/j.xphs.2017.04.078. Epub 2017 May 8. |
| 39943692 | Derived | Nguyen JT, Arian CM, Tanna RS, Cherel MG, Layton ME, White JR, Thummel KE, Paine MF. The Pharmacokinetic Interaction Between Metformin and the Natural Product Goldenseal Is Metformin Dose-Dependent: A Three-Arm Crossover Study in Adults With Type 2 Diabetes. Clin Transl Sci. 2025 Feb;18(2):e70120. doi: 10.1111/cts.70120. |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| OG001 | Study Arm 2: Acute Goldenseal Exposure | For Arm 2, the same 22 subjects were administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam and metformin. Plasma and urine were collected in a manner identical to that in Arm 1. With respect to midazolam administration, a washout period of 7 days separated Arm 2 from Arm 1. Midazolam HCl 1 mg/mL inj: 0.5 mL of an intravenous solution was administered. Goldenseal (Hydrastis canadensis): goldenseal (Solaray; Lot #1020199) was supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules were administered with 240 mL of water. |
| OG002 | Study Arm 3: Chronic Goldenseal Exposure | For Arm 3, the same 22 subjects self-administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants were administered the goldenseal three times daily, as well as the single dose of midazolam and metformin. Plasma and urine were collected in a manner identical to that in Arm 1 and 2. A designated washout period for midazolam was not necessary to separate Arm 3 since there will be 27 days of goldenseal administration prior to the midazolam administration. Midazolam HCl 1mg/mL inj: 0.5 mL of an intravenous solution was administered. Goldenseal (Hydrastis canadensis): Goldenseal (Solaray; Lot #1020199) was supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules were administered with 240 mL of water. |
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| Primary | Metformin Cmax | maximum concentration of metformin | Posted | Geometric Mean | 90% Confidence Interval | nM | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
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| Secondary | Metformin Half-Life | half-life of metformin | Posted | Geometric Mean | 90% Confidence Interval | hours | 0-24h |
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| Secondary | Metformin Renal Clearance | renal clearance of metformin | Posted | Geometric Mean | 90% Confidence Interval | mL / min | 0-24h |
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| Secondary | Midazolam AUC | area under the concentration vs. time curve of midazolam | Posted | Geometric Mean | 90% Confidence Interval | mcg*hr/mL | Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration. |
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| 0 |
| 22 |
| 0 |
| 22 |
| 9 |
| 22 |
| EG001 | Study Arm 2: Acute Goldenseal Exposure | For Arm 2, the same 22 subjects were administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam and metformin. Plasma and urine were collected in a manner identical to that in Arm 1. With respect to midazolam administration, a washout period of 7 days separated Arm 2 from Arm 1. Midazolam HCl 1 mg/mL inj: 0.5 mL of an intravenous solution was administered. Goldenseal (Hydrastis canadensis): goldenseal (Solaray; Lot #1020199) was supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules were administered with 240 mL of water. | 0 | 22 | 0 | 22 | 4 | 22 |
| EG002 | Study Arm 3: Chronic Goldenseal Exposure | For Arm 3, the same 22 subjects self-administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants were administered the goldenseal three times daily, as well as the single dose of midazolam and metformin. Plasma and urine were collected in a manner identical to that in Arm 1 and 2. A designated washout period for midazolam was not necessary to separate Arm 3 since there will be 27 days of goldenseal administration prior to the midazolam administration. Midazolam HCl 1mg/mL inj: 0.5 mL of an intravenous solution was administered. Goldenseal (Hydrastis canadensis): Goldenseal (Solaray; Lot #1020199) was supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules were administered with 240 mL of water. | 0 | 22 | 0 | 22 | 2 | 22 |
| emesis | Nervous system disorders | Non-systematic Assessment |
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| D004700 | Endocrine System Diseases |
| D006571 | Heterocyclic Compounds |