Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment

• ClinicalTrials.gov Identifier: NCT03937908
• Recruitment Status: Terminated
• First Posted: May 6, 2019
• Results First Posted: May 4, 2022
• Last Update Posted: May 4, 2022
• Sponsor: Oregon Health and Science University
• Collaborator: National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): Amala Soumyanath, Oregon Health and Science University

Study Description

Brief Summary:

This study will measure the oral bioavailability and pharmacokinetics of known bioactive compounds from a standardized Centella asiatica water extract product (CAP) in mildly demented elders on cholinesterase inhibitor therapy. Compound levels will be measured in human plasma and urine over 10 hours after acute oral administration of two doses of the botanical extract product. The dose giving maximum plasma levels (Cmax)closest to those observed in the investigator's mouse studies, the area under the curve (AUC0-12), as well as the rate of clearance (t ½) of the known compounds and time of maximum concentration (tmax), will be identified. These data will be used to inform decisions on the dosage and dosing frequency for future clinical trials.

Condition or disease	Intervention/treatment	Phase
Cognitive Impairment; Elderly	Drug: 2g Centella asiatica water extract product; Drug: 4g Centella asiatica water extract product	Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

1. To assess the bioavailability and rate of clearance of Centella asiatica derived compounds in mildly demented elders on cholinesterase inhibitor therapy through a pharmacokinetic study.
2. To determine the acute tolerability of a Centella asiatica product in mildly demented elders on cholinesterase inhibitor therapy.

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 10 hours after administration of each of the doses.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: This is an outpatient open-label clinical study using a blinded randomized crossover design of two doses.
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: Randomization will use an arm equivalence design to promote equal numbers of participants for each order schema. All participants will be blinded to the dose they will be receiving at each visit. The investigators have developed a formulation that tastes and looks very similar at each dose. The investigator administering the intervention and the analyst performing the liquid chromatography analysis of collected plasma will be blinded as to the dose of the product administered. The liquid chromatography analyst will also be blinded as to the time point of collection.
• Primary Purpose: Screening
• Official Title: A Pharmacokinetic Study of Centella Asiatica Product (CAP) in Elderly Participants With Mild Cognitive Impairment Receiving Cholinesterase Inhibitor Therapy
• Actual Study Start Date: October 31, 2019
• Actual Primary Completion Date: December 21, 2020
• Actual Study Completion Date: December 21, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: 2g CAP; Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	Drug: 2g Centella asiatica water extract product; 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.; Other Name: CAP 2g
Experimental: 4g CAP; Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	Drug: 4g Centella asiatica water extract product; 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.; Other Name: CAP 4g

Outcome Measures

Primary Outcome Measures :

1. Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) [ Time Frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes). ]
   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 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (maximum concentration) for each of the two doses (2g and 4g).
2. Time of Maximum Concentration (Tmax) [ Time Frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes). ]
   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
3. Half-life (t1/2) [ Time Frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes). ]
   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.

Secondary Outcome Measures :

1. Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica [ Time Frame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes). ]
   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 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (area under the curve) for each of the two doses (2g and 4g).
2. Total Urinary Excretion [ Time Frame: Total 10 hours ]
   All urine produced over the 10 hours post-administration was collected into a single container. The concentration of bioactive compounds from Centella asiatica (triterpenes, caffeoylquinic acids, and their metabolites) was measured in the single total urine sample collected over 10 hours after CAP administration. Urine samples were treated with glucuronidase and sulfatase enzymes to release analyte from conjugated (Phase II metabolite) forms of the analyte. All samples were analyzed using high performance liquid chromatography tandem mass spectrometry. The concentrations obtained were multiplied by total urine volume to obtain the total amount of that analyte excreted. The total amount (free and conjugated forms) in micrograms of of each analyte in the 10h urine sample is reported.
3. NRF2 Expression [ Time Frame: 0, 1, 2, 3, 4, and 6h following study intervention ]
   NRF2 gene expression was measured in peripheral blood mononuclear cells following consumption of 2g and 4g of Centella asiatica water extract product (CAP).

Eligibility Criteria

• Ages Eligible for Study: 65 Years to 85 Years (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age 65-85, male and female
2. Meet the National Institute of Aging - Alzheimer's Association core clinical criteria for mild cognitive impairment or probable Alzheimer's disease dementia with a Clinical Dementia Rating (CDR) score of 0.5-1 and MMSE score of 20-28
3. Report a history of subjective memory decline with gradual onset and slow progression over the last one year before screening; MUST be corroborated by an informant
4. On cholinesterase inhibitor therapy for Alzheimer's disease (AD) and must be on a stable dose for at least 12 weeks prior to baseline
5. Caregiver/study partner that can accompany participant to all study visits
6. Sufficient English language skills to complete all tests
7. Sufficient vision and hearing to complete all tests
8. No known allergies to Centella asiatica or CAP excipients
9. Willingness to discontinue all botanical dietary supplements for one week prior to and during each study visit
10. Willingness to comply with a 48-hour low plant diet for each study visit
11. Absence of significant depression symptoms (Geriatric Depression Scale-15 score of <12)
12. Body Mass Index (BMI) greater than 17 and less than 35 at screening
13. General health status that will not interfere with the ability to complete the study

Exclusion Criteria:

1. Current smoking, alcohol or substance abuse according to DSM-V criteria
2. Women who are pregnant, planning to become pregnant or breastfeeding
3. Men who are actively trying to conceive a child or planning to within three months of study completion
4. Severe aversion to venipuncture
5. Abnormal laboratory evaluation indicating asymptomatic and untreated urinary tract infection
6. Cancer within the last five years, with the exception of localized prostate cancer (Gleason Grade <3) and non-metastatic skin cancers
7. Comorbid conditions such as diabetes mellitus, kidney failure, liver failure, hepatitis, blood disorders, clinical symptomatic orthostatic hypotension, and unstable or significantly symptomatic cardiovascular disease
8. Significant disease of the central nervous system such as brain tumor, seizure disorder, subdural hematoma, cranial arteritis, or clinically significant stroke
9. Major depression, schizophrenia, or other major psychiatric disorder defined by DSM-V criteria
10. 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)
11. Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus or Parkinson's disease
12. Mini Mental State Examination (MMSE) score of <20 or >28 or CDR score >1 or zero
13. Unwilling to maintain stable dosage of AD medications throughout study duration
14. Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
15. Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Contacts and Locations

Locations

United States, Oregon

Oregon Health and Science University Department of Neurology

Portland, Oregon, United States, 97239

Sponsors and Collaborators

Oregon Health and Science University

National Center for Complementary and Integrative Health (NCCIH)

Investigators

• Principal Investigator: Amala Soumyanath, PhD; OHSU Department of Neurology

  Study Documents (Full-Text)

Documents provided by Amala Soumyanath, Oregon Health and Science University:

Study Protocol and Statistical Analysis Plan  [PDF] May 1, 2020

More Information

Publications of Results:

Wright KM, Bollen M, David J, Speers AB, Brandes MS, Gray NE, Alcazar Magana A, McClure C, Stevens JF, Maier CS, Quinn JF, Soumyanath A. Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial. Antioxidants (Basel). 2022 Jan 23;11(2):215. doi: 10.3390/antiox11020215.

Other Publications:

Wright KM, McFerrin J, Alcazar Magana A, Roberts J, Caruso M, Kretzschmar D, Stevens JF, Maier CS, Quinn JF, Soumyanath A. Developing a Rational, Optimized Product of Centella asiatica for Examination in Clinical Trials: Real World Challenges. Front Nutr. 2022 Jan 14;8:799137. doi: 10.3389/fnut.2021.799137. eCollection 2021.

• Responsible Party: Amala Soumyanath, Associate Professor, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT03937908
• Other Study ID Numbers: STUDY00017985; R61AT009628 ( U.S. NIH Grant/Contract )
• First Posted: May 6, 2019
• Results First Posted: May 4, 2022
• Last Update Posted: May 4, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: ALL IPD that underlie results in a publication will be shared via a published journal article.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Analytic Code
• Time Frame: Immediately after publication and for a period of 3 years following publication.
• Access Criteria: Anyone who wishes access to the data, for any reason. Requests should be directed to Dr. Amala Soumyanath at soumyana@ohsu.edu

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders