Interaction, Adverse Herb-DrugEarly Phase 1NCT05081583

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

A Early Phase 1 study testing Midazolam Hcl 1Mg/Ml Inj and Goldenseal (Hydrastis canadensis) in people with Interaction, Adverse Herb-Drug and Diabetes Mellitus, Type 2, run by Washington State University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Interaction, Adverse Herb-Drug, Diabetes Mellitus, Type 2
What is being tested?: Midazolam Hcl 1Mg/Ml Inj and Goldenseal (Hydrastis canadensis)
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 22 participants
Where: 1 siteUnited States
Study dates: 16 Sep 2021to 31 Aug 2023
Phase: Early Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

United States1 site

Washington State University College of Pharmacy and Pharmaceutical Sciences
Spokane, Washington, 99202

Other trials in United States

About this study

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.

Read the detailed description

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.

Conditions: Interaction, Adverse Herb-Drug, Diabetes Mellitus, Type 2
Being tested: Midazolam Hcl 1Mg/Ml Inj, Goldenseal (Hydrastis canadensis)
Keywords: pharmacokinetics, natural product-drug interactions, transporters
Medical subject headings: Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Midazolam Hcl 1Mg/Ml InjDrug
Also called Versed
0.5 mL of an intravenous solution (1 mg/mL) will be administered.
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 groups in NCT05081583
Study group	Role	What they receive
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. Receives: 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. Receives: 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. Receives: Drug: Midazolam Hcl 1Mg/Ml Inj; Dietary Supplement: Goldenseal (Hydrastis canadensis)

What is being measured

The primary outcome is the main question the study is designed to answer.

Metformin AUC
Area under the plasma concentration time curve of metformin
Measured: 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
Measured: 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
half-life of metformin
Measured: 0-24h
Metformin Renal Clearance
renal clearance of metformin
Measured: 0-24h
Midazolam AUC
area under the concentration vs. time curve of midazolam
Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

16 Sep 202131 Aug 2023

First posted18 Oct 2021
Study start16 Sep 2021
Primary completion16 Jan 2023
Study completion31 Aug 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Interaction, Adverse Herb-DrugStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Early Phase 1
Primary purpose: Basic science
Allocation: Non-randomised
Intervention model: Crossover
Masking: None (open label)
Enrolment: 22 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT05081583
Sponsor's protocol ID: 18889-002
Other IDs: U54AT008909
Status last verified: Dec 2024
First submitted: 4 Oct 2021
Last updated: 19 Dec 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 33174626
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.
PubMed 28495567
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.
PubMed 39943692

Study at a glance

From the registry record, last updated by the sponsor on 19 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Clinical Evaluation of the Pharmacokinetic Goldenseal-Metformin Interaction in Diabetic Patients
ClinicalTrials.gov ID: NCT05081583
Acronym / sponsor ID: 18889-002
Conditions: Interaction, Adverse Herb-Drug, Diabetes Mellitus, Type 2
Keywords: pharmacokinetics, natural product-drug interactions, transporters
Phase: Early Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 22 participants (actual)
Lead sponsor: Washington State UniversityUniversity, hospital or other
Collaborators: National Center for Complementary and Integrative Health (NCCIH)
Study start: 16 Sep 2021 (actual)
Primary completion: 16 Jan 2023 (actual)
Study completion: 31 Aug 2023 (actual)
First posted: 18 Oct 2021 (actual)
Results: Posted 19 Dec 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Non-randomised
Intervention model: Crossover
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Study Arm 1: Baseline	Experimental	Drug: Midazolam Hcl 1Mg/Ml InjAn 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	Drug: Midazolam Hcl 1Mg/Ml Inj, Dietary Supplement: Goldenseal (Hydrastis canadensis)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	Drug: Midazolam Hcl 1Mg/Ml Inj, Dietary Supplement: Goldenseal (Hydrastis canadensis)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.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

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

Key exclusion criteria (8 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Midazolam Hcl 1Mg/Ml InjAlso: Versed0.5 mL of an intravenous solution (1 mg/mL) will be administered.	Drug	Study Arm 1: Baseline, Study Arm 2: Acute Goldenseal Exposure, Study Arm 3: Chronic Goldenseal Exposure
Goldenseal (Hydrastis canadensis)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.	Dietary supplement	Study Arm 2: Acute Goldenseal Exposure, Study Arm 3: Chronic Goldenseal Exposure

Primary outcome

Metformin AUC
Time frame: 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.
Area under the plasma concentration time curve of metformin
Metformin Cmax
Time frame: 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.
maximum concentration of metformin

3 secondary outcomes

Metformin Half-Life
Time frame: 0-24h
Metformin Renal Clearance
Time frame: 0-24h
Midazolam AUC
Time frame: 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.

Results and safety

Results posted to the registry on 19 Dec 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Midazolam Alone - Washout - Midazolam + Acute Goldenseal - Washout - Midazolam + Chronic Goldenseal	22	22

Primary outcome: Metformin AUC

Time frame: 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.. Geometric mean (90% Confidence Interval). Unit: mcg*hr/mL

Measure	Study Arm 1: Baseline n = 22	Study Arm 2: Acute Goldenseal Exposure n = 22	Study Arm 3: Chronic Goldenseal Exposure n = 22
Value	59.6 (52.0 to 68.5)	54.5 (48.2 to 61.7)	57.3 (50.3 to 65.3)

Study Arm 1: Baseline vs Study Arm 2: Acute Goldenseal Exposure vs Study Arm 3: Chronic Goldenseal Exposure: AUC ratio (geometric mean): 0.88 (90% CI 0.82 to 0.96)

Population analysed: All 22 participants completed the 3 arms of the study (baseline, acute goldenseal exposure, and chronic goldenseal exposure).

Primary outcome: Metformin Cmax

Time frame: 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.. Geometric mean (90% Confidence Interval). Unit: nM

Measure	Study Arm 1: Baseline n = 22	Study Arm 2: Acute Goldenseal Exposure n = 22	Study Arm 3: Chronic Goldenseal Exposure n = 22
Value	8.92 (7.86 to 10.1)	8.36 (7.55 to 9.27)	8.26 (7.37 to 9.25)

Study Arm 1: Baseline vs Study Arm 2: Acute Goldenseal Exposure vs Study Arm 3: Chronic Goldenseal Exposure: Cmax ratio (geometric mean): 0.93 (90% CI 0.85 to 1.01)

3 secondary outcomes are reported in the full results.

Adverse events

Time frame: All participants were monitored up to whenever they completed the final arm of the study, which was on average ~2 months.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Study Arm 1: Baseline	0 of 22 (0%)	9 of 22 (40.9%)	0 of 22
Study Arm 2: Acute Goldenseal Exposure	0 of 22 (0%)	4 of 22 (18.2%)	0 of 22
Study Arm 3: Chronic Goldenseal Exposure	0 of 22 (0%)	2 of 22 (9.1%)	0 of 22

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 33174626Nguyen 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.
Background: PubMed 28495567Liang 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.
Derived from this study: PubMed 39943692Nguyen 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.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Metformin AUC (time frame: 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.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05081583, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2024.