Red Clover Botanical Dietary Supplements - Metabolism and Safety in Women

Human safety studies were carried out to test whether red clover botanical dietary supplements used by peri- and post-menopausal women are safe to use with Food and Drug Administration (FDA)-approved drugs. To test this, a red clover dietary supplement (previously tested in women at the University of Illinois at Chicago without any harmful effects) was given with four selected FDA-approved drugs to determine if the red clover supplement can increase or decrease how these medications are absorbed, metabolized and excreted by the human body. Preclinical studies predicted that the red clover supplement might affect the metabolism or break down of these probe drugs.

Study Overview

• Status: Completed
• Conditions: Food-drug Interaction
• Intervention / Treatment: Dietary supplement: Trifolium pratense

Detailed Description

At the start of a study, subjects were administered low doses of a mixture of four FDA-approved drugs (caffeine, tolbutamide, dextromethorphan, and alprazolam), and serial blood samples were drawn and analyzed for the concentration of each drug over time. Afterwards, participants took the red clover dietary supplement twice orally daily for 14 days to allow for potential inhibition or induction of drug metabolizing enzymes and transporters. Thereafter, the same drugs were taken again to obtain a second measure of drug concentrations in blood over time. Changes in the concentration-time curve values for each probe drug obtained before and after ingestion of the supplement were evaluated to determine if metabolism of the probe drugs was impacted by the red clover dietary supplement.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• healthy peri- and post-menopausal women ages 40 - 79
• non-smokers
• no-significant medical conditions as assessed by subject-reported medical history, physical examination and blood and urine chemistry screens
• no medical condition that requires chronic use of medication

Exclusion Criteria:

• known allergies or hypersensitivity to caffeine, dextromethorphan, sulfonylureas (tolbutamide), benzodiazepines, or red clover
• positive pregnancy test
• use of hormone therapy within 8 weeks of study initiation for oral agents, 4 weeks for transdermal or other topical agents
• use of caffeine products 7 days before study participation or during the study
• use of citrus products 7 days before study participation or during the study
• other prescription (with the exception of the Mirena® IUD) or non-prescription medicines within the 2 weeks prior to study initiation or during the study
• chronic diseases, such as inflammatory bowel disease, that could alter the absorption or metabolism of the probe substrates
• unwillingness to comply with study requirements
• current participation in another clinical trial
• CYP2D6 deficiency based on phenotyping at screening
• smoker
• red clover or soy intake (whether as a botanical dietary supplement, food, drink or otherwise) within the previous two weeks and during the study
• use of any dietary supplements within the last 2 weeks prior to study initiation and during the study
• extreme obesity (defined as >40 BMI)
• alcohol or drug abuse
• chronic diseases such as diabetes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trifolium pratense; Red clover extract; 2 gelatin capsules (398 mg extract) per day for 14 days	Dietary supplement: Trifolium pratense; Red Clover extract standardized to isoflavone content.; Other Names: Red Clover

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC)	Concentrations of probe drugs from blood draws at the conclusion of the 14-day intervention were used to calculate areas under the (extrapolated) concentration-time curve to determine any changes compared to pre-intervention.	baseline and 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apparent Clearance	Concentrations of probe drugs from blood draws at the conclusion of the 14-day intervention were used to calculate changes in apparent clearance of each probe drug compared to pre-intervention.	baseline and 14 days
Peak Concentration	Concentrations of probe drugs from blood draws at the conclusion of the 14-day intervention were used to calculate changes in peak concentrations of probe drugs to compared to pre-intervention concentrations.	baseline and 14 days
Time for Peak Concentration	Concentrations of probe drugs from blood draws at the conclusion of the 14-day intervention were used to calculate changes in time for peak concentration of probe drugs compared to pre-intervention concentrations.	baseline and 14 days
Drug Half-life	Concentrations of probe drugs from blood draws at the end of the 14-day intervention were used to calculate half-lives of probe drugs to determine any changes compared to pre-intervention.	baseline and 14 days

Collaborators and Investigators

• Sponsor: University of Illinois at Chicago

Publications and helpful links

General Publications

• Muchiri RN, van Breemen RB. Single-Laboratory Validation of UHPLC-MS/MS Assays for Red Clover Isoflavones in Human Serum and Dietary Supplements. J AOAC Int. 2020 Jul 1;103(4):1160-1166. doi: 10.1093/jaoacint/qsaa033.

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2017
• Primary Completion (Actual): April 29, 2020
• Study Completion (Actual): July 1, 2020

Study Registration Dates

• First Submitted: June 29, 2017
• First Submitted That Met QC Criteria: June 29, 2017
• First Posted (Actual): July 2, 2017

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 1, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Other Study ID Numbers: 2017-0436

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No