Ashwagandha Pharmacokinetics Study in Older Adults

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

Detailed Description
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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.

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

Conditions
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Healthy, Aging

Intervention / Treatment
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* Dietary Supplement: Shoden 240 mg
* Dietary Supplement: Shoden 480 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 65 and older, male and female Body Mass Index (BMI) greater than 17 and less than 35 at screening Sufficient vision and hearing to complete all tests Willingness to discontinue all botanical supplementation for one week prior to and throughout study No known sensitivity to Withania somnifera or any of its derivatives Normal or clinically not significant 12-lead electrocardiogram (ECG) recording Hepatic (alanine transaminase, aspartate aminotransferase, bilirubin), renal (creatinine, estimated glomerular filtration rate), and thyroid-stimulating hormone (TSH) parameters within normal range General health status that will not interfere with the ability to complete the study Willingness to attend all study visits Mini-Mental State Exam (MMSE) score ≥24 Exclusion Criteria: Current smoking, alcohol, or substance abuse according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-V criteria Participants who are currently pregnant, actively trying to conceive a child, or planning to within three months of study completion Severe aversion to venipuncture Donation of blood within 90 days of screening Participation in drug research study within 90 days of screening 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 Allergy to nightshade plants (Solanaceae family) Abnormal labs indicating asymptomatic and untreated urinary tract infection History of prostate cancer Cancer within the last five years, with the exception of non-metastatic skin cancers Comorbid conditions requiring medication such as diabetes, kidney failure, liver failure, hepatitis, blood disorders, hypotension, thyroid disease, respiratory disorders, or cardiovascular disease Presence of sleep apnea, moderate to severe restless leg syndrome, major circadian rhythm changes, or narcolepsy Significant disease of the Central Nervous System (CNS) such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke Diagnosis of major depression, schizophrenia, bipolar disorder, or other major psychiatric disorder as defined by DSM-V criteria Diseases associated with dementia such as Alzheimer's disease, vascular dementia, normal pressure hydrocephalus or Parkinson's disease Inability or unwillingness to adhere to special diet (no dairy, no grapefruit products, no high-fat meals) during pharmacokinetics (PK) visits

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 240 mg Shoden<br>Shoden, administered as two 120 mg capsules per dose (240 mg total) | Dietary Supplement: Shoden 240 mg<br>* 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.<br>|
| Active Comparator: 480 mg Shoden<br>Shoden, administered as two 240 mg capsules per dose (480 mg total) | Dietary Supplement: Shoden 480 mg<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Withania, Herbal Medicine, Dietary Supplements