Pharmacokinetics of Centella Asiatica in the Elderly

Study Overview
=================
Brief Summary
-----------------
This study will measure the oral bioavailability and pharmacokinetics of known bioactive compounds from a standardized Centella asiatica water extract (CAW) product (CAP) in cognitively healthy elders.

Detailed Description
-----------------
PRIMARY OBJECTIVES: To assess the bioavailability and rate of clearance of Centella asiatica derived compounds in the plasma and urine of cognitively healthy elders over 12 hours. To determine the acute tolerability of a Centella asiatica product in cognitively healthy elders. OUTLINE: Participants will orally consume a single administration of a standardized Centella asiatica water extract product (CAP). Two doses (2g and 4g CAW) will be administered on separate occasions, at least two weeks apart. The levels of known bioactive compounds present in Centella asiatica will be measured in human plasma and urine over 12 hours after administration of each of the doses.

Official Title
-----------------
A Pharmacokinetic Study of Centella Asiatica in the Elderly

Conditions
-----------------
Healthy, Elderly

Intervention / Treatment
-----------------
* Drug: 2g Centella asiatica water extract product
* Drug: 4g Centella asiatica water extract product


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 65-85, male and female Sufficient English language skills to complete all tests Sufficient vision and hearing to complete all tests No known allergies to Centella asiatica or CAP components Willingness to discontinue all botanical dietary supplements for one week prior to and during each study visit Willingness to comply with a 48-hour low plant diet for each study visit Absence of significant depression symptoms (Geriatric Depression Scale-15 score of <12) Body Mass Index (BMI) greater than 17 and less than 35 at screening Non-demented, defined as Clinical Dementia Rating (CDR) score of zero and Mini Mental State Examination (MMSE) score >28 General health status that will not interfere with the ability to complete the study Exclusion Criteria: Current smoking, alcohol or substance abuse according to DSM-V criteria Women who are pregnant, planning to become pregnant or breastfeeding Men who are actively trying to conceive a child or planning to within three months of study completion Severe aversion to venipuncture Abnormal laboratory evaluation indicating asymptomatic and untreated urinary tract infection Cancer within the last five years, with the exception of localized prostate cancer (Gleason Grade <3) and non-metastatic skin cancers Comorbid conditions such as diabetes mellitus, kidney failure, liver failure, hepatitis, blood disorders, clinical symptomatic orthostatic hypotension, and unstable or significantly symptomatic cardiovascular disease Significant disease of the central nervous system such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-V criteria Medications: sedatives (except those used occasionally for sleep), central nervous system active medications that have not been stable for two months (including beta blockers, cimetidine, SSRIs, SNRIs), anticoagulants (i.e. Warfarin), investigational drugs used within five half-lives of baseline visit, systemic corticosteroids, neuroleptics, anti-Parkinsonian agents, narcotic analgesics, nicotine (tobacco, patches, gum, lozenges, etc.), Cannabis sativa (herb or edibles) Diseases associated with dementia such as Alzheimer's disease, vascular dementia, normal pressure hydrocephalus or Parkinson's disease with a CDR score >0.5 and MMSE score <28 Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements

Ages Eligible for Study
-----------------
Minimum Age: 65 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomization will use an arm equivalence design to promote equal numbers of participants for each order schema.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2g CAW Dose<br>2g of Centella asiatica water extract in a standardized product. | Drug: 2g Centella asiatica water extract product<br>* 2g Centella asiatica water extract product is a powder containing Centella asiatica water extract and excipients to improve palatability, color matching and dispersability in water. It will be consumed on an empty stomach orally suspended in 10-12 ounces of water.<br>* Other names: CAP 2g;|
| Experimental: 4g CAW Dose<br>4g of Centella asiatica water extract in a standardized product. | Drug: 4g Centella asiatica water extract product<br>* 4g Centella asiatica water extract product is a powder containing Centella asiatica water extract and excipients to improve palatability, color matching and dispersability in water. It will be consumed on an empty stomach orally suspended in 10-12 ounces of water.<br>* Other names: CAP 4g;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Human plasma concentration of bioactives from Centella asiatica. | Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 12 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (maximum concentration and area under the curve) for each of the two doses (2g and 4g). | A 12-hour post-administration period (15, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of maximum concentration | The time of maximum concentration (tmax) of the known bioactive compounds and their metabolites will be calculated from the concentrations measured by high performance liquid chromatography tandem mass spectrometry in order to help determine dosage intervals | A 12-hour post-administration period (15, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes). | 
| Temporal changes in anti-oxidant status | Ferric reducing ability of plasma (FRAP) will be measured in the plasma collected at each time point to generate a graph of antioxidant potential over time. | A 12-hour post-administration period (15, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes). | 
| Urinary excretion | The concentration of bioactive compounds from Centella asiatica (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in a pooled urine sample collected over 12 hours after CAP administration and analyzed using high performance liquid chromatography tandem mass spectrometry. | Over 12 hours post-administration | 
| Half-life | The half-life (t1/2) of the known bioactive compounds and their metabolites will be calculated from the plasma concentrations measured by high performance liquid chromatography tandem mass spectrometry to help determine dosage intervals. | A 12-hour post-administration period (15, 30, 45, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes). | 
| Oral temperature | Oral temperature will be measured in degrees Celsius by means of a thermometer. Temperatures falling outside the normal range (33.2-38.2 degrees Celsius) will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if they are attributable to the study intervention. The investigators will also determine the proportion of all participants who develop changes in temperature following administration of CAP. | 0, 360 and 720 minutes after administration | 
| Pulse rate | Pulse rate will be measured peripherally over one minute. Pulse rates falling outside the normal range (60-80 beats per minute) will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if they are attributable to the study intervention. The investigators will also determine the proportion of all participants who develop changes in pulse rate following administration of CAP. | 0, 360 and 720 minutes after administration | 
| Seated blood pressure | Seated blood pressure will be measured in millimeters mercury. Blood pressure readings falling outside the normal range (90-130/60-80 millimeters Mercury) will be compared to baseline levels, and alternative clinical explanations considered, in order to determine if they are attributable to the study intervention. The investigators will also determine the proportion of all participants who develop changes in blood pressure following administration of CAP. | 0, 360 and 720 minutes after administration | 
| Body mass index | Height in centimeters and weight in kilograms will be measured and aggregated to measure body mass index in kilograms per meter squared (kg/m2). Changes in body mass index greater than two kilograms per meter squared from baseline levels, along with consideration of alternative clinical explanations, will be used to determine attribution to the study intervention. The investigators will also determine the proportion of all participants who develop changes in body mass index of greater than two units (kilograms per meter squared) following administration of CAP. | 0, 360 and 720 minutes after administration | 
| Electrocardiography | Resting electrocardiography will be measured for up to five minutes using a five lead mobile electrocardiogram. Changes in P wave shape or length, QRS complex shape or length, and QT interval 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 CAP administration. | 0, 360 and 720 minutes after administration | 
| 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 administration of CAP. | 0, 360 and 720 minutes after administration | 
| 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 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 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 administration of CAP. | 0, 360 and 720 minutes after administration | 
| Adverse events | A standard 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. The Investigators will evaluate any changes in symptoms from baseline, and consider alternative clinical explanations, to determine if the changes are adverse events attributable to the study intervention. The investigators will determine the proportion of participants who report each type of adverse event following administration of CAP. | 0, 6, 12 and 24 hours after administration |