Clinical trial NCT05081583
Conditions: Interaction, Adverse Herb-Drug Diabetes Mellitus, Type 2
Keywords: pharmacokinetics natural product-drug interactions transporters
Sponsor: Washington State University
Start date: 2021-09-16; Completion date: 2023-08-31
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

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.

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.

Arms: arm 1: 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. arm 2: 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. arm 3: 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.
Interventions: intervention 1: Midazolam Hcl 1Mg/Ml Inj intervention 2: Goldenseal (Hydrastis canadensis)
Intervention descriptions: intervention 1: 0.5 mL of an intravenous solution (1 mg/mL) will be administered. intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
CLINICAL EVALUATION OF THE PHARMACOKINETIC GOLDENSEAL-METFORMIN INTERACTION IN DIABETIC PATIENTS 
 
 
 
 
 
 
 
NCT05081583 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MAY 29, 2024 
 
 
 


 
 
STUDY PROCEDURES FLOWCHART 
 
Figure 1. Overview of procedures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
SUBJECTS 
Well-controlled diabetic adult volunteers (10 men and 10 non-pregnant, non-lactating women), aged from 18-65 years, of 
any race/ethnicity, and currently taking a stable dose of metformin (1-2 g daily) will be recruited from the Spokane 
community to participate in this three-arm, open-label, fixed-sequence, crossover study. The progression of subject 
recruitment and study participation are provided (Figure 1).   
PRE-SCREENING 
Inclusion criteria:  
• Men and women between the ages of 18 and 64 
• Medically diagnosed with type 2 diabetes and currently taking a stable dose of metformin (1-2 g daily) but 
otherwise healthy 
• HbA1c < 8% as determined by laboratory analysis on initial screening 
• Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known to alter 
the pharmacokinetics of midazolam, metformin, and/or goldenseal constituents 
• Willing to abstain from consuming dietary/herbal supplements and citrus juices for several weeks prior to study 
• Willing to abstain from consuming alcohol, caffeinated beverages, and/or other caffeine-containing products 
the evening before the first day of a study phase. 
• Willing to use an acceptable method of contraception that does not include oral contraceptive pills or patches 
(such as abstinence, copper IUD, condom) 
• Have the time to participate  
Exclusion criteria: 
• Any current major illness or chronic illness such as (but not limited to) type 1 diabetes, kidney disease, hepatic 
disease, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS 
• HbA1c ≥ 8% as determined by laboratory analysis from screening visit 
• History of anemia or any other significant hematologic disorder 
• History of drug or alcohol addiction or major psychiatric illness 
• Women who are pregnant or nursing 
• Have a history of intolerance or allergy to midazolam and/or goldenseal products 
• Taking medications, both prescription and non-prescription (including dietary supplements/ herbal products) 
known to alter the pharmacokinetics of midazolam, metformin, and/or goldenseal constituents 
SCREENING VISIT 
NO 
Meets 
inclusion/ 
exclusion 
criteria? 
Screening 
visit (2 h)  
Schedule 
study days 
One 14-h visit* 
followed by 1 
outpatient visit 
x 3 arms 
Do not 
screen  
Eligible to 
participate? 
NO 
Do not enroll 
YES 
YES 
ID potential 
subjects  
*Preceded by 27-day exposure to goldenseal for Arm 3  


Potential eligible subjects, based on the inclusion/exclusion criteria, will present for a screening visit at the Clinical 
Research Unit in the Nursing Building (SNRS 417) on the Spokane campus. The screening coordinator will consult with the 
participants and will address any questions or concerns. Informed consent and HIPAA authorization form will be obtained 
after full explanation of the study protocol. Consented subjects will undergo the following: 
• A medical history and physical exam 
• Complete blood count with differential, basic metabolic panel, liver function tests, and hemoglobin A1C 
• Routine urine analysis 
• Urine pregnancy test for female subjects of child-bearing potential (prior to enrollment in the study and prior to 
each phase of the study using in-home urinalysis pregnancy screens) 
STUDY DESIGN  
This clinical study will consist of three arms and will follow the fixed-sequence depicted (Figures 2 and 3). Arm 1 (control), 
Arm 2 (acute goldenseal exposure), and Arm 3 (chronic goldenseal exposure) will each consist of one 14-hour inpatient 
visit followed by 1 outpatient visit the subsequent day.  Subjects will be administered the following in each arm: 
Baseline (Arm 1) 
During the inpatient visit, a subtherapeutic dose of the control drug midazolam (0.5 mg) will be administered 
intravenously via a pre-placed indwelling peripheral catheter by a registered nurse. 
Acute goldenseal exposure (Arm 2) 
During the inpatient visit, participants will be administered a single 3-gram dose of a well-characterized, oral 
goldenseal product in conjunction with the subtherapeutic, intravenous dose of midazolam. 
Chronic goldenseal exposure (Arm 3) 
Participants will self-administer two capsules (1 g) of goldenseal by mouth 3 times daily (~4 hours apart) for 27 
consecutive days. On the 28th day, participants will return to SNRS 417 for the inpatient visit. During the visit, they 
will be administered the same intravenous dose of midazolam as in Arms 1/2 and two capsules (1 g) of goldenseal; 
the goldenseal product will be administered two additional times throughout the inpatient visit (~4 hours apart). 
Figure 2. Overview of study sequence. 
Figure 3. Detailed timelines of the sequential arms. 
Baseline (Arm 1) 
 
Acute exposure (Arm 2) 
 
 
 
Screening 
≥1 week  
washout  
Inpatient  
visit (Arm 1) 
≥1 week  
washout 
Inpatient  
visit (Arm 2) 
27 days of 
goldenseal 
exposure 
Inpatient  
visit (Arm 3) 


Chronic exposure (Arm 3) 
 
 
Study days. Subjects will be asked to present to the Clinical Research Unit on the morning of each inpatient study day. 
Vital signs will be checked and recorded on case forms. Subjects will be asked about any change to their health status; 
responses will be recorded on case forms. A peripheral IV line will be placed in one arm, and a blood sample (11 mL) will 
be drawn through the IV line, after which subjects will receive midazolam (control) or midazolam and goldenseal 
(acute/chronic exposure) in conjunction with them taking their prescribed oral metformin dose. Blood (6 mL) will be drawn 
from the IV line 20 minutes, 40 minutes, 1 hour, 1.5 hours, and 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours post-midazolam 
administration. Urine will be collected into a jug from 0-12 and 12-24 hours. An additional blood sample (3 mL) will be 
collected during Arm 1 for genotyping of drug metabolizing enzymes or transporters that may affect the pharmacokinetics 
of midazolam, metformin, and/or goldenseal constituents. After the 12-hour blood draw, subjects will be allowed to leave 
the Clinical Research Unit once deemed safe by the study coordinator. Subjects will be allowed to take the 12-24 urine jug 
home and will return it the subsequent day. Subjects will be asked to return to the Clinical Research Unit the subsequent 
day for the outpatient blood draw (6 mL) via venipuncture at 24 hours post-midazolam administration. All arms of the 
study will involve an identical blood sampling and urine collection strategy. 
Subjects will be asked to refrain from consuming any dietary/herbal supplements or citrus juices for at least 1 week prior 
to each inpatient visit and to refrain from alcohol and caffeinated beverages the evening before each inpatient day. 
Goldenseal product acquisition. A well-characterized, unadulterated goldenseal product will be supplied by our 
longstanding natural products chemist collaborators at the University of North Carolina at Greensboro led by Drs. Nicholas 
Oberlies and Nadja Cech. They have acquired the product manufactured by Solaray®, which has been chemically 
characterized and tested for contaminants, including microbes, heavy metals, pesticides, residual solvents, and other 
adulterants. All of these contaminants were confirmed to be below the allowable limits, thus suitable for human 
consumption. 
Midazolam acquisition. Dr. John White, a longstanding collaborator/co-investigator and registered pharmacist in WA, will 
oversee the acquisition and storage of the pharmaceutical-grade intravenous midazolam solution. 
Pharmacokinetic and statistical analysis. The pharmacokinetics of midazolam, midazolam metabolites, metformin, and 
goldenseal constituents will be determined using industry standard Phoenix WinNonlin (v8.3m, Certara, Princeton, NJ). 
The primary endpoints will be the AUC and Cmax of metformin, specifically the metformin/control ratio of log-transformed 
data, with a predefined no effect range of 0.80-1.25.1 A two one-sided testing procedure, as recommended by the FDA 
Guidance for Industry,1 will be used for the primary endpoint analysis. That is, if this ratio lies between 0.80 and 1.25, a 
goldenseal-midazolam interaction is not evident. A sample size of 20 evaluable subjects will provide 80% power to detect 
a 20% change in the primary endpoint with a Type I error of 0.05, assuming a 25% intra-individual variability in metformin 
AUC and Cmax. Secondary endpoints (e.g., exposure/control ratio of t1/2, tmax, and oral clearance for metformin and 
exposure/control ratio of AUC, Cmax, t1/2, tmax, and oral clearance for midazolam, midazolam metabolites, and goldenseal 
constituents) will be evaluated using a paired Student’s t-test or Wilcoxon signed-rank test as appropriate; a p-value <0.05 
will be considered statistically significant. 
ROLES OF STUDY PERSONNEL 
Mary Paine, RPh, PhD 
Principal investigator 
Oversee all aspects of the study 
Deena Hadi, BS  
Program manager 
Coordinate study days with staff and subjects 
Manage finances and study supply logistics 


Matt Layton, MD, PhD 
Physician of record/ co-investigator 
Obtain medical history and perform physical exam 
On-call physician for the duration of clinical activities 
John White, PA-C, PharmD 
Authorized licensed designee of Dr. Layton/ co-investigator 
Obtain medical history and perform physical exam 
Acquire study drugs 
James Nguyen, PharmD 
 
Study coordinator/ co-investigator  
 
Conduct screening and clinical activities 
 
Assist in all aspects of the study 
Sabrina Judson 
 
Study coordinator  
 
Conduct screening and clinical activities 
 
Process and analyze biofluids 
Rakshit Tanna 
 
Study assistant  
 
Process and analyze biofluids 
Kennedy Erickson 
 
Study assistant  
 
Process and analyze biofluids 
REFERENCES 
1. Food and Drug Administration Center for Drug Evaluation and Research (2017): Clinical Drug Interaction Studies—Study 
Design, Data Analysis, and Clinical Implications Guidance for Industry (draft guidance).