Ashwagandha Pharmacokinetics Study in Older Adults

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06171724
• Other study ID #: 26055
• Secondary ID: KL2TR002370
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: April 2, 2024
• Est. completion date: August 31, 2025

Study information

• Verified date: April 2024
• Source: Oregon Health and Science University
• Contact: Alex Speers, ND
• Phone: 405-418-5896
• Email: speers[@]ohsu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: August 31, 2025
• Est. primary completion date: August 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aging
• Healthy

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Oregon Health & Science University	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Oregon Health and Science University	National Center for Advancing Translational Sciences (NCATS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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-3ß-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	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)
Secondary	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)
Secondary	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.
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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