Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment

NCT03937908 | Terminated Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: STUDY00017985R61AT009628
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Cognitive Impairment; Elderly

Outcome Measures

Primary Outcomes (3)

• Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax)

  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).

  A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes).

• Time of Maximum Concentration (Tmax)

  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 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes).

• Half-life (t1/2)

  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 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes).

Secondary Outcomes (3)

• Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica

  A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes).

• Total Urinary Excretion

  Total 10 hours

• NRF2 Expression

  0, 1, 2, 3, 4, and 6h following study intervention

Study Arms (2)

2g CAP

EXPERIMENTAL

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

4g CAP

EXPERIMENTAL

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

Interventions

2g Centella asiatica water extract product DRUG

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.

Also known as: CAP 2g

2g CAP

4g Centella asiatica water extract product DRUG

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.

Also known as: CAP 4g

4g CAP

Eligibility Criteria

• Age: 65 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Age 65-85, male and female
• 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
• 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
• On cholinesterase inhibitor therapy for Alzheimer's disease (AD) and must be on a stable dose for at least 12 weeks prior to baseline
• Caregiver/study partner that can accompany participant to all study visits
• Sufficient English language skills to complete all tests
• Sufficient vision and hearing to complete all tests
• No known allergies to Centella asiatica or CAP excipients
• 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
• General health status that will not interfere with the ability to complete the study

You may not qualify if:

• 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)
• Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus or Parkinson's disease
• Mini Mental State Examination (MMSE) score of \<20 or \>28 or CDR score \>1 or zero
• Unwilling to maintain stable dosage of AD medications throughout study duration
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

Sponsors & Collaborators

• Oregon Health and Science University: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

Oregon Health and Science University Department of Neurology

Portland, Oregon, 97239, United States

Location

Related Publications (2)

• 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.

  PMID: 35096945 BACKGROUND

• 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.

  PMID: 35204098 RESULT

MeSH Terms

Conditions

Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Limitations and Caveats

Study was discontinued before the target number of participants were enrolled due to pandemic-related restrictions.

Results Point of Contact

• Title: Dr. Amala Soumyanath
• Organization: Oregon Health & Science University

soumyana@ohsu.edu

503-494-6878

Study Officials

• Amala Soumyanath, PhD

  OHSU Department of Neurology

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: SCREENING
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: This is an outpatient open-label clinical study using a blinded randomized crossover design of two doses.

Study Record Dates

• First Submitted: April 23, 2019
• First Posted: May 6, 2019
• Study Start: October 31, 2019
• Primary Completion: December 21, 2020
• Study Completion: December 21, 2020
• Last Updated: May 4, 2022
• Results First Posted: May 4, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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

Locations

US (1)