Clinical trial NCT03937908: Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment
Official title: A Pharmacokinetic Study of Centella Asiatica Product (CAP) in Elderly Participants With Mild Cognitive Impairment Receiving Cholinesterase Inhibitor Therapy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Cognitive Impairment
Elderly
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2019-05-06
Enrollment: 5
Sex: ALL
Minimum age (years): 65
Maximum age (years): 85
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is an outpatient open-label clinical study using a blinded randomized crossover design of two doses.
Primary purpose: SCREENING

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.

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.

Eligibility 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.

Primary outcomes:
measure: Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax)
timeFrame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes).
measure: Time of Maximum Concentration (Tmax)
timeFrame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes).
measure: Half-life (t1/2)
timeFrame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes).
Secondary outcomes:
measure: Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica
timeFrame: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes).
measure: Total Urinary Excretion
timeFrame: Total 10 hours
measure: NRF2 Expression
timeFrame: 0, 1, 2, 3, 4, and 6h following study intervention
Other outcomes:
Locations:
city: Portland
country: United States
facility: Oregon Health and Science University Department of Neurology
state: Oregon
Study officials:
affiliation: OHSU Department of Neurology
name: Amala Soumyanath, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.