Clinical Evaluation of the Pharmacokinetic Goldenseal-Metformin Interaction in Diabetic Patients

NCT05081583 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: 18889-002U54AT008909
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Interaction, Adverse Herb-Drug; Diabetes Mellitus, Type 2

Keywords

pharmacokinetics; natural product-drug interactions; transporters

Outcome Measures

Primary Outcomes (2)

• 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.

Secondary Outcomes (3)

• Metformin Half-Life

  0-24h

• Metformin Renal Clearance

  0-24h

• Midazolam AUC

  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.

Study Arms (3)

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.

Drug: Midazolam Hcl 1Mg/Ml Inj

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.

Drug: Midazolam Hcl 1Mg/Ml Inj; Dietary Supplement: Goldenseal (Hydrastis canadensis)

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.

Drug: Midazolam Hcl 1Mg/Ml Inj; Dietary Supplement: Goldenseal (Hydrastis canadensis)

Interventions

Midazolam Hcl 1Mg/Ml Inj DRUG

0.5 mL of an intravenous solution (1 mg/mL) will be administered.

Also known as: Versed

Study Arm 1: Baseline; Study Arm 2: Acute Goldenseal Exposure; Study Arm 3: Chronic Goldenseal Exposure

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.

Study Arm 2: Acute Goldenseal Exposure; Study Arm 3: Chronic Goldenseal Exposure

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• are 18-65 years old and healthy
• have been medically diagnosed with Type 2 diabetes and currently taking metformin (1- 2 g daily), but otherwise healthy as determined by the study physician
• have an HbA1c \< 8% as determined by laboratory analysis on initial screening
• are not taking any medications, dietary/herbal supplements, or citrus juices that can interfere with your ability to eliminate the study drugs and goldenseal from your body
• are willing to stop consuming alcohol, caffeinated beverages or other caffeine- containing products the evening before and the morning of the first day of each study arm
• are female and are willing to use an acceptable method of birth control that does not include oral birth control pills or patches (such as abstinence, copper IUD, condom)
• can provide written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for the subject to comply with the requirements of the study

You may not qualify if:

• have an HbA1c ≥ 8%
• have other chronic illnesses other than type 2 diabetes (e.g., type 1 diabetes, kidney disease, hepatic disease, uncontrolled hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS)
• have a hematologic (blood) disorder
• have a history of drug or alcohol abuse
• have any major psychiatric illness
• are pregnant or breastfeeding
• have a history of intolerance or allergy to midazolam or goldenseal products
• are taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products) known to alter the pharmacokinetics of either study drug or goldenseal constituents

Sponsors & Collaborators

• Washington State University: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

Washington State University College of Pharmacy and Pharmaceutical Sciences

Spokane, Washington, 99202, United States

Location

Related Publications (3)

• 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.

  PMID: 33174626 BACKGROUND

• 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.

  PMID: 28495567 BACKGROUND

• 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.

  PMID: 39943692 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Midazolam

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Mary Paine
• Organization: Washington State University

mary.paine@wsu.edu

5093587759

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 4, 2021
• First Posted: October 18, 2021
• Study Start: September 16, 2021
• Primary Completion: January 16, 2023
• Study Completion: August 31, 2023
• Last Updated: December 19, 2024
• Results First Posted: December 19, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)