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

Early Phase 1WithdrawnNCT07008300

Oregon Health and Science University

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 single-blind, crossover trial evaluating (a) the pharmacokinetics of withanolides from two doses (120 and 240 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. 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, where they will receive a single dose of either 120 or 240 mg Shoden®, 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 (120 or 240 mg) for four weeks, at which time they will return for a follow-up visit.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

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

Plasma concentration of withanolides after Shoden administration

After oral administration of Shoden (120 or 240 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)).

Time frame: For each study period, collected over a 48-hour post-administration period (0 minutes, 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 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

Data from ClinicalTrials.gov

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Time frame: At four weeks for each study period

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.

Time frame: For each study period, collected from 0-12 hours, 24 hours, and 48 hours of each pharmacokinetics visit, and at four weeks

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.

Time frame: For each study period, baseline and 12 hours of each pharmacokinetics visit, and at 2 weeks and 4 weeks. Also collected at 2 weeks post-study completion.

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.

Time frame: For each study period, baseline (0 hours) and 7 hours of each pharmacokinetics visit, and at 4 weeks.

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

Time frame: For each study period, baseline (0 hours) and at 10 hours of each pharmacokinetics visit, and at 4 weeks

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

Time frame: For each study period, baseline (0 hours) and at 10 hours of each pharmacokinetics visit, and at 4 weeks

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.