Ashwagandha Pharmacokinetics Study in Older Adults

Early Phase 1TerminatedNCT06171724

Oregon Health and Science University11 enrolled

Overview

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

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

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Enrollment

Conditions

Healthy Aging

Interventions

ShodenDIETARY_SUPPLEMENT

Shoden® powder is a commercial, dried 70% ethanolic extract of Withania somnifera (ashwagandha, WS) root and leaf, standardized to 35% withanolide glycosides. Shoden® powder is manufactured by Arjuna Natural Pvt Ltd, based in Kochi, Kerala, India.

Eligibility

Sex: ALLMin age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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. Hemoglobin ≥13.0 g/dL or hematocrit ≥39% (males) OR hemoglobin ≥12.5 g/dL or hematocrit ≥38% (females), per FDA recommendations on blood donation 9. General health status that will not interfere with the ability to complete the study 10. Willingness to attend all study visits 11. 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 baseline visits 12. Willingness to adhere to special diet (no dairy, grapefruit products, poppy-containing foods, high-fat meals, caffeine, or xanthine-containing foods or beverages) during baseline visits and until after 24-hour visit 13. Mini-Mental State Exam (MMSE) score ≥26 Exclusion Criteria: 1. Current smoking, alcohol, or substance abuse according to 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 symptomatic and untreated urinary tract infection 9. History of prostate cancer 10. History of kidney transplant 11. Cancer within the last five years, with the exception of non-metastatic skin cancers 12. Comorbid conditions requiring medication such as diabetes, kidney failure, liver failure, hepatitis, blood disorders, hypotension, thyroid disease, respiratory disorders, or cardiovascular disease 13. Presence of sleep apnea, moderate to severe restless leg syndrome, major circadian rhythm changes, or narcolepsy 14. Significant disease of the Central Nervous System (CNS) such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke 15. Diagnosis of major depression, schizophrenia, bipolar disorder, or other major psychiatric disorder as defined by DSM-V criteria 16. Diseases associated with dementia such as Alzheimer's disease, vascular dementia, normal pressure hydrocephalus or Parkinson's disease

Locations (1)

Oregon Health & Science University

Portland, Oregon, United States

Outcomes

Primary Outcomes

Maximum Plasma Concentration (Cmax) of Withanolides After Shoden Administration

After oral administration of Shoden (240 or 480 mg), plasma concentrations of withanolides will be measured in plasma samples obtained over a 48-hour period, using liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS) to determine pharmacokinetic parameters.

Time frame: 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 Outcomes

Time of Maximum Concentration of Withanolides After Shoden Administration

The time of maximum (tmax) of withanolides over the first 48 hours post-Shoden administration will be calculated using liquid chromatography coupled to multiple reaction monitoring mass spectrometry (LC-MRM-MS).

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).

Steady-state Concentration of Selected Withanolides in Plasma

Concentration (ng/ml) of selected withanolides in plasma after four weeks' use

Time frame: For each study period, steady state concentration will be collected during week 4 following four weeks' daily use of Shoden.

Data from ClinicalTrials.gov

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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.

Time frame: For each study period, urine collected over the first 12 hours post-Shoden administration.

Number of Participants With Abnormal ECG Readings (7 Hours)

Resting electrocardiography will be measured using a ten-lead electrocardiogram at the zero-minutes timepoint and 7 hours post-Shoden administration. Electrocardiogram changes will be assessed and alternative clinical explanations considered, in order to determine if any changes are attributable to the study intervention. The number of participants with abnormal ECG readings at 7 hours compared to baseline will be reported.

Time frame: For each study period, electrocardiography will be assessed at 0 and 7 hours post-Shoden administration. For pharmacokinetics visits that were halted early, ECG was collected at 24 hours.

Number of Participants With Abnormal ECG Readings (4 Weeks)

Resting electrocardiography will be measured using a ten-lead electrocardiogram at the zero-minutes timepoint and 4-weeks post-Shoden administration. Electrocardiogram changes will be assessed and alternative clinical explanations considered, in order to determine if any changes are attributable to the study intervention. The number of participants with abnormal ECG readings at 4 weeks compared to baseline will be reported.

Time frame: For each study period, electrocardiography will be assessed at 0 and 4 weeks post-Shoden administration.

Mean Change in ALT (10 Hours)

A comprehensive metabolic panel will measure alanine aminotransferase and in units per liter as a marker of liver function. Enzyme levels falling outside the normal range will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if elevations are attributable to the study intervention. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, liver function will be assessed at 0 and 10 hours post-Shoden administration. For pharmacokinetics visits that were halted early, safety labs were collected at 24 hours.

Mean Change in ALT (4 Weeks)

Time frame: For each study period, liver function will be assessed at 0 and 4 weeks post-Shoden administration.

Mean Change in AST (10 Hours)

A comprehensive metabolic panel will measure aspartate aminotransferase and in units per liter as a marker of liver function. Enzyme levels falling outside the normal range will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if elevations are attributable to the study intervention. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Mean Change in AST (4 Weeks)

Time frame: For each study period, liver function will be assessed at 0 and 4 weeks post-Shoden administration.

Mean Change in Creatinine (10 Hours)

A comprehensive metabolic panel will measure creatinine as a marker of kidney function. Each parameter falling outside the normal range (0.5 to 1.2 milligrams per deciliter) 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. Changes in laboratory outcomes from the baseline visit to 10-hours post-Shoden administration for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Mean Change in Creatinine (4 Weeks)

A comprehensive metabolic panel will measure creatinine as a marker of kidney function. Each parameter falling outside the normal range (0.5 to 1.2 milligrams per deciliter) 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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, liver function will be assessed at 0 and 4 weeks post-Shoden administration.

Mean Change in Thyroid-stimulating Hormone (4 Weeks)

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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, thyroid-stimulating hormone will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Mean Change in Testosterone (4 Weeks)

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. Changes in testosterone will be analyzed by sex, by dose.

Time frame: For each study period, testosterone will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Mean White Blood Cell Count (4 Weeks)

White 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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, white blood cells will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Mean Change in Red Blood Cell Count (4 Weeks)

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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, red blood cells will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Mean Change in Hemoglobin (4 Weeks)

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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, hemoglobin will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Mean Change in Hematocrit (4 Weeks)

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. Changes in laboratory outcomes from the baseline visit to the four-week follow-up visit for each study period will be presented using descriptive statistics (e.g., means and standard deviations, frequency and percent).

Time frame: For each study period, hematocrit will be assessed at 0 minutes post-Shoden administration and four weeks post-Shoden administration.

Percentage of REDCap Surveys Completed

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.

Time frame: For each study period, prior to the pharmacokinetics visit and prior to the four-week follow-up visit