Ashwagandha Pharmacokinetics Study in Older Adults

Safety, Tolerability, and Pharmacokinetics of an Oral Withania Somnifera Product in Older Adults

This study will measure the oral bioavailability and pharmacokinetics of known compounds from a standardized Withania somnifera botanical dietary supplement in healthy older adults.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Aging
• Intervention / Treatment: Dietary supplement: Shoden 240 mg; Dietary supplement: Shoden 480 mg

Detailed Description

This is a randomized, double-blind, crossover trial evaluating (a) the pharmacokinetics of withanolides from two doses (240 and 480 mg) of a commercially available Withania somnifera root and leaf extract (Shoden®), (b) the safety and tolerability of these doses over four weeks' use and (c) the feasibility of remotely measuring sleep- and stress-related outcomes in older adults. Participants will be randomized to one of two dose sequence groups. There will be two four-week study periods separated by a two-week washout period. During each study period, participants will attend a 13-hour pharmacokinetics study visit and return for 24- and 48-hour blood and urine collections. After the 48-hour visit, they will continue taking Shoden® at the administered dose (240 or 480 mg) for four weeks, at which time they will return for a follow-up visit.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Amala Soumyanath, PhD; Phone Number: 503-494-6878; Email: soumyana@ohsu.edu
• Study Contact Backup: Name: Alex Speers, ND; Phone Number: 405-418-5896; Email: speers@ohsu.edu

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
      • Contact: Amala Soumyanath, PhD; Phone Number: 503-494-6878; Email: soumyana@ohsu.edu
      • Sub-Investigator: Joseph Quinn, MD
      • Contact: Alex Speers, ND; Phone Number: 503-418-5896; Email: speers@ohsu.edu
      • Sub-Investigator: Amala Soumyanath, PhD
      • Principal Investigator: Alex Speers, ND

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age 65 and older, male and female
2. Body Mass Index (BMI) greater than 17 and less than 35 at screening
3. Sufficient vision and hearing to complete all tests
4. Willingness to discontinue all botanical supplementation for one week prior to and throughout study
5. No known sensitivity to Withania somnifera or any of its derivatives
6. Normal or clinically not significant 12-lead electrocardiogram (ECG) recording
7. Hepatic (ALT, AST, bilirubin), renal (creatinine, estimated GFR), and TSH parameters within normal range
8. General health status that will not interfere with the ability to complete the study
9. Willingness to attend all study visits
10. Willingness to avoid caffeine and xanthine-containing foods or beverages (e.g., coffee, tea, chocolate, caffeine-containing sodas, colas, etc.), as well as grapefruit juice and poppy-containing foods for 48 hours prior to PK visits
11. Willingness to adhere to special diet (no dairy, grapefruit products, poppy-containing foods, high-fat meals, caffeine, or xanthine-containing foods or beverages) during PK visits and until after 24-hour visit
12. Mini-Mental State Exam (MMSE) score ≥27

Exclusion Criteria:

1. Current smoking, alcohol, or substance abuse according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-V criteria
2. Participants who are currently pregnant, actively trying to conceive a child, or planning to within three months of study completion
3. Severe aversion to venipuncture
4. Donation of blood within 90 days of screening
5. Participation in drug research study within 90 days of screening
6. Serious health condition (i.e., illness, injury, impairment, or physical or mental condition which requires a) overnight hospitalization or b) continuing treatment that may cause episodic periods of incapacity of more than 3 consecutive days) within 30 days of screening
7. Allergy to nightshade plants (Solanaceae family)
8. Abnormal labs indicating asymptomatic and untreated urinary tract infection
9. History of prostate cancer
10. Cancer within the last five years, with the exception of non-metastatic skin cancers
11. Comorbid conditions requiring medication such as diabetes, kidney failure, liver failure, hepatitis, blood disorders, hypotension, thyroid disease, respiratory disorders, or cardiovascular disease
12. Presence of sleep apnea, moderate to severe restless leg syndrome, major circadian rhythm changes, or narcolepsy
13. Significant disease of the Central Nervous System (CNS) such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke
14. Diagnosis of major depression, schizophrenia, bipolar disorder, or other major psychiatric disorder as defined by DSM-V criteria
15. Diseases associated with dementia such as Alzheimer's disease, vascular dementia, normal pressure hydrocephalus or Parkinson's disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 240 mg Shoden; Shoden, administered as two 120 mg capsules per dose (240 mg total)	Dietary supplement: Shoden 240 mg; Participants will receive a single dose of 240 mg Shoden at pharmacokinetics visit 1 or 2 depending on their sequence group. Forty-eight hours later, participants will receive a 35-day supply of Shoden at a dose of 240 mg per day.
Active Comparator: 480 mg Shoden; Shoden, administered as two 240 mg capsules per dose (480 mg total)	Dietary supplement: Shoden 480 mg; Participants will receive a single dose of 480 mg Shoden at pharmacokinetics visit 1 or 2 depending on their sequence group. Forty-eight hours later, participants will receive a 35-day supply of Shoden at a dose of 480 mg per day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration of withanolides after Shoden administration	After oral administration of Shoden (240 or 480 mg), plasma concentrations of eleven withanolides (withanolide A, withanolide B, withaferin A, withanone, withanoside IV, withanoside V, 12-deoxywithastramonolide, sominone, viscosalactone B, 4-oxo withaferin A, and 2,3-dihydro-3β-methoxy withaferin-A) will be measured in blood samples obtained over a 48-hour period, using liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS) to determine pharmacokinetic parameters (maximum concentration, area under the curve(0-t), and area under the curve(0-infinity)).	For each study period, a 48-hour post-administration period (15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 24 hours, and 48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time of maximum concentration of withanolides after Shoden administration	The time of maximum (tmax) of withanolides will be calculated using liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS).	For each study period, a 48-hour post-administration period (15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 24 hours, and 48 hours)
Half-life of withanolides after Shoden administration	The half-life (t1/2) of withanolides will be calculated using liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS).	For each study period, a 48-hour post-administration period (15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 24 hours, and 48 hours)
Steady-state concentration of selected withanolides in plasma	Concentration (ng/ml) of selected withanolides in plasma after four weeks' use	For each study period, steady state concentration will be collected during week 4 following four weeks' daily use of Shoden.
Urine concentration of withanolides after Shoden administration	The concentration (ng/ml) of withanolides in urine will be measured in a pooled urine sample over 12 hours post-Shoden administration, at 24 and 48 hours post-administration, and after four weeks' use.	For each study period, over 12 hours post-Shoden administration, 24-hour sample, 48-hour sample, four-week sample
Adverse events	A multi-system questionnaire will record the type and severity (range 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = fatal) of any adverse events. Adverse events will be assessed to determine if any changes are attributable to the study intervention. The proportion of participants who report each type of adverse event will be reported.	For each study period, adverse events will be assessed at the beginning and end of each pharmacokinetics visit, 2-weeks post-administration, and 4-weeks post-administration.
Number of participants with abnormal ECG readings	Resting electrocardiography will be measured using a ten-lead electrocardiogram. Electrocardiogram changes from the zero-minute (baseline) timepoint will be measured, and alternative clinical explanations considered, in order to determine if any changes are attributable to the study intervention. The investigators will also determine the proportion of all participants who develop changes in electrocardiography compared to the zero-minute timepoint following Shoden administration.	For each study period, electrocardiography will be assessed at 0 and 420 minutes post-Shoden administration and at the four week follow-up visit
Liver function	A comprehensive metabolic panel will measure alanine aminotransferase and aspartate aminotransferase in units per liter as markers of liver function. Enzyme levels falling outside the normal range (0-35 Units per liter for alanine aminotransferase and 17-59 Units per liter for aspartate aminotransferase) will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if elevations are attributable to the study intervention. The investigators will aggregate the measures by using an elevation in either enzyme function as a reflection of overall liver function. The investigators will also determine the proportion of all participants who develop abnormal laboratory values following Shoden administration	For each study period, liver function will be assessed at 0 and 600 minutes post-Shoden administration, and at the four-week follow-up visit
Kidney function	A comprehensive metabolic panel will measure creatinine and blood urea nitrogen levels in milligrams per deciliter as markers of kidney function. Each parameter falling outside the normal range (0.5 to 1.2 milligrams per deciliter for creatinine and 7 to 20 milligrams per deciliter for blood urea nitrogen) will be compared to baseline values. If elevations are observed, alternative clinical explanations will be considered to determine if elevations are attributable to the study intervention. The investigators will aggregate the measures by using an elevation in either blood urea nitrogen or creatinine as a reflection of overall kidney function. The investigators will also determine the proportion of all participants who develop abnormal laboratory values following Shoden administration	For each study period, liver function will be assessed at 0 and 600 minutes post-Shoden administration, and at the four-week follow-up visit
Thyroid-stimulating hormone	Thyroid-stimulating hormone will be measured in units of milli-international units per liter as a marker of thyroid function. Any changes in hormone levels will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in hormone levels are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in thyroid-stimulating hormone following Shoden administration.	For each study period, thyroid-stimulating hormone will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
Testosterone	Testosterone will be measured in units of nanograms per deciliter. Any changes in hormone levels will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in testosterone levels are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in testosterone following Shoden administration.	For each study period, testosterone will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
White blood cell count	White blood cells will be measured in units of cells per cubic millimeter. Any changes in white blood cell levels will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in white blood cells are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in white blood cells following Shoden administration.	For each study period, white blood cells will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
Red blood cell count	Red blood cells will be measured in units of cells per cubic millimeter. Any changes in red blood cell levels will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in red blood cells are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in red blood cells following Shoden administration.	For each study period, red blood cells will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
Hemoglobin	Hemoglobin will be measured in grams per deciliter. Any changes in hemoglobin will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in hemoglobin are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in hemoglobin following Shoden administration.	For each study period, hemoglobin will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
Hematocrit	Hematocrit will be measured in percent. Any changes in hematocrit will be compared to baseline levels. Alternative clinical explanations will be considered in order to determine if any changes in hematocrit are attributable to the study intervention. The investigators will also determine the proportion of all participants who have observed changes in hematocrit following Shoden administration.	For each study period, hematocrit will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.
Feasibility of administering REDCap surveys	The feasibility of administering REDCap surveys will be assessed by calculating the percentage of administered questionnaires that are returned and fully completed by participants, with feasibility defined as at least 80% of all administered questionnaires returned and completed.	For each study period, prior to the pharmacokinetics visit and prior to the four-week follow-up visit

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: National Center for Advancing Translational Sciences (NCATS)
• Investigators: Principal Investigator: Alex Speers, ND, Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start (Estimated): April 2, 2024
• Primary Completion (Estimated): August 31, 2025
• Study Completion (Estimated): August 31, 2025

Study Registration Dates

• First Submitted: December 5, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 15, 2023

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Dietary Supplements; Herbal Medicine; Withania
• Other Study ID Numbers: 26055; KL2TR002370 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The individual coded participant data that support the published results will be available to be shared for research purposes. Data, plasma, and urine specimens will be stored for future research in a repository. All data/specimens will be coded with each participant's identification code, visit number, and date of collection. Data will be available four months after publication ending five years post article publication.

For repository requests, the repository guardian Alex Speers (speers@ohsu.edu) or designee will review the requestor's institutional review board approval memo, protocol, and repository sharing agreement before samples/data are released. Separate institutional review board approval/determination will be required for each specific human subject research activity that uses coded data/specimens from the repository.

• IPD Sharing Time Frame: Data will be available four months after publication, ending five years post-publication.
• IPD Sharing Access Criteria: For repository requests, the repository guardian will review the requestor's institutional review board approval memo, protocol, and repository sharing agreement before samples/data are released. The Guardian will check for genetic opt out status, withdrawn consent for data/samples, and limitations on future use of data/samples. A signed Repository Sharing Agreement will be collected before data or samples are released. The Repository Guardian will ensure that material transfer agreements for the transfer of biological materials and data use agreements for data shared outside of Oregon Health & Science University are executed as applicable. Specimens and data will be coded with the participant's identification code, visit number, and date of collection. The key for requested specimens and data will be provided separately and with appropriate institutional review board approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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