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Safety and Target Engagement of Centella Asiatica in Cognitive Impairment

Primary Purpose

Mild Cognitive Impairment, Alzheimer's Disease

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Centella asiatica product

Placebo

About this trial

This is an interventional treatment trial for Mild Cognitive Impairment

Eligibility Criteria

65 Years - 85 Years (Older Adult)All SexesDoes not accept healthy volunteers

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
Absence of significant depression symptoms (Geriatric Depression Scale-15 score of < 5)
Total score of <2 on the suicidal ideation subscale (measures 3, 7, 11, 12 and 14) of the Geriatric Depression Scale.
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
Willingness to discontinue all botanical dietary supplements for one week prior to and during the study
Willingness to undertake multiple magnetic resonance imaging scans
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 score of 0.5-1 and Mini Mental State Examination score of 20-28 at screening and baseline
Participants who report a history of participative memory decline with gradual onset and slow progression over the last one year before screening MUST be corroborated by an informant.
Participants on acetylcholinesterase inhibitor or memantine therapy for Alzheimer's disease must be on a stable dose for at least 12 weeks prior to baseline visit.
Participants must have an identified caregiver/study partner that can accompany participant to all study visits.

Exclusion Criteria:

Current smoking, alcohol, or substance abuse according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-Five(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 labs 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 (CNS) 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: Anti-epileptics, sedatives, amitriptyline, anticoagulants (e.g. 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); Beta blockers and anti-depressant medications that have not been at stable dosage for two months (including SSRIs, SNRIs)
Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus, or Parkinson's disease
Mini Mental State Examination (MMSE) score of < 20 or > 28
Unwilling to maintain stable dosage of Alzheimer's disease medications throughout study duration
Unwilling to maintain stable dosage of intervention throughout the course of the study
Contraindications to Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopic Imaging (MRSI) scans (metal implants, pacemakers, claustrophobia)

Sites / Locations

Oregon Health & Science UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Centella asiatica water extract product (CAP) 4g

Placebo

Arm Description

A sachet of containing 4g dried hot water extract (CAW) of Centella asiatica combined with inactive ingredients (excipients) will be dissolved in water and orally consumed daily as a drink for six weeks. Assessments will be collected at baseline and after six weeks of daily intervention.

A sachet of inactive ingredients (excipients) identical in composition to those found in the active arm will be be dissolved in water and orally consumed daily for six weeks. Assessments will be collected at baseline and after six weeks of daily intervention.

Outcomes

Primary Outcome Measures

Change from baseline in brain N-acetylaspartate (NAA) to creatine (Cr) metabolite ratio (NAA/Cr) after 6 weeks on intervention.

N-acetylaspartate (NAA)/creatine (Cr) metabolite ratio (NAA/Cr) in the brain determined through 1H-Magnetic Resonance Spectroscopic Imaging of a single brain slice as an indicator of neuronal viability and mitochondrial activity.

Secondary Outcome Measures

Change from baseline in urinary 8-hydroxy-2-deoxyguanosine (8 OHdG)/creatinine ratio after 6 weeks on intervention.

Ratio of 8-hydroxy-deoxyguanosine (8 OHdG) to creatinine in urine, as a measure of oxidative stress as determined by means of enzyme linked immunosorbent assay.

Change from baseline in plasma 8-hydroxy-2-deoxyguanosine (8-OhdG) after 6 weeks on intervention.

A peripheral venous sample will be collected. Levels of plasma 8-hydroxy-deoxyguanosine will be determined by means of the 8-hydroxy-2-deoxyguanosine enzyme linked immunosorbent assay as a measure of oxidative stress.

Adverse events (AE) arising during, and up to 4 weeks after, 6 weeks on intervention.

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 compared to placebo.

Oral temperature measured at study visits.

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 determine the proportion of all participants who develop changes in temperature following administration of CAP compared to placebo.

Pulse rate measured at study visits.

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 determine the proportion of all participants who develop changes in pulse rate following administration of CAP compared to placebo.

Change from baseline in seated blood pressure after 6 weeks on intervention.

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 determine the proportion of all participants who develop changes in blood pressure following administration of CAP compared to placebo.

Change from baseline in body mass index after 6 weeks on intervention.

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 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 compared to placebo.

Change from baseline in electrocardiography signals after 6 weeks on intervention.

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 baseline will be measured, and alternative clinical explanations considered, in order to determine if any changes are attributable to the study intervention. The investigators will determine the proportion of all participants who develop changes in electrocardiography from baseline following CAP administration compared to placebo.

Change from baseline liver function after 6 weeks on intervention.

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 determine the proportion of all participants who develop abnormal laboratory values following administration of CAP compared to placebo.

Change from baseline in kidney function after 6 weeks on intervention.

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 determine the proportion of all participants who develop abnormal laboratory values following administration of CAP compared to placebo.

Full Information

NCT ID

NCT05591027

First Posted

October 16, 2022

Last Updated

March 30, 2023

Sponsor

Oregon Health and Science University

Collaborators

Alzheimer's Association

1. Study Identification

Unique Protocol Identification Number

NCT05591027

Brief Title

Safety and Target Engagement of Centella Asiatica in Cognitive Impairment

Official Title

Safety and Target Engagement of Centella Asiatica in Cognitive Impairment

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 1, 2022 (Actual)

Primary Completion Date

November 30, 2024 (Anticipated)

Study Completion Date

March 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oregon Health and Science University

Collaborators

Alzheimer's Association

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This clinical trial is focused on determining whether biological signatures of target engagement by a Centella asiatica water extract product administered orally for 6 weeks can be measured in comparison to placebo. This study will also assess the safety and tolerability of the Centella asiatica water extract product.

Detailed Description

This Phase I study is a randomized, double-blind, placebo-controlled, clinical trial of 48 participants to evaluate safety, tolerability, and biological signatures of target engagement of brain neuronal viability, oxidative stress, and brain mitochondrial activity of a Centella asiatica water extract product (CAP) in older adults aged 65-85 years with mild cognitive impairment or mild Alzheimer's disease (AD). The intervention is taken orally daily for six weeks and pre and post assessments will be collected.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mild Cognitive Impairment, Alzheimer's Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Model Description

48 participants will be randomized to receive either Centella asiatica water extract product (CAP) or placebo treatment. Participants will be stratified by sex so that CAP and placebo arms have equal numbers of each sex.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Drug product and placebo will be prepared at Oregon's Wild Harvest using a formula that matches taste, smell, and appearance. The Research Pharmacy at Oregon Health and Science University will maintain information on product allocation (drug or placebo) to individual participants.

Allocation

Randomized

Enrollment

48 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Centella asiatica water extract product (CAP) 4g

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Centella asiatica product

Other Intervention Name(s)

CAP

Intervention Description

A sachet of powdered product containing 4 g of a dried hot water extract of Centella asiatica as the active ingredient, combined with inactive ingredients (excipients) for color and taste dissolved in 10 oz of warm or room temperature water and consumed orally.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

A sachet of powdered inactive ingredients (excipients) for color and taste identical in volume to those found in the active arm (CAP) dissolved in 10 oz of warm or room temperature water and consumed orally.

Primary Outcome Measure Information:

Title

Change from baseline in brain N-acetylaspartate (NAA) to creatine (Cr) metabolite ratio (NAA/Cr) after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Secondary Outcome Measure Information:

Title

Change from baseline in urinary 8-hydroxy-2-deoxyguanosine (8 OHdG)/creatinine ratio after 6 weeks on intervention.

Description

Ratio of 8-hydroxy-deoxyguanosine (8 OHdG) to creatinine in urine, as a measure of oxidative stress as determined by means of enzyme linked immunosorbent assay.

Time Frame

Baseline and 6 weeks

Title

Change from baseline in plasma 8-hydroxy-2-deoxyguanosine (8-OhdG) after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Title

Adverse events (AE) arising during, and up to 4 weeks after, 6 weeks on intervention.

Description

Time Frame

Baseline, 2 weeks, 4 weeks, 6 weeks, 8 weeks and 10 weeks

Title

Oral temperature measured at study visits.

Description

Time Frame

Baseline and 6 weeks

Title

Pulse rate measured at study visits.

Description

Time Frame

Baseline and 6 weeks

Title

Change from baseline in seated blood pressure after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Title

Change from baseline in body mass index after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Title

Change from baseline in electrocardiography signals after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Title

Change from baseline liver function after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Title

Change from baseline in kidney function after 6 weeks on intervention.

Description

Time Frame

Baseline and 6 weeks

Other Pre-specified Outcome Measures:

Title

Change from baseline in cortical and hippocampal levels of Adenosine triphosphate (ATP)/total phosphate after 6 weeks on intervention.

Description

Cortical and hippocampal levels of ATP as a proportion of total phosphate as detected through 31P- Magnetic Resonance Spectroscopic Imaging.

Time Frame

Baseline and 6 weeks

Title

Change from baseline in cortical and hippocampal levels of phosphocreatine (PCr)/total phosphate after 6 weeks on intervention.

Description

Cortical and hippocampal levels of phosphocreatine (PCr) as a proportion of total phosphate as detected through 31P- Magnetic Resonance Spectroscopic Imaging.

Time Frame

Baseline and six weeks

Title

Change from baseline in cortical and hippocampal levels of inorganic phosphate (Pi)/total phosphate after 6 weeks on intervention.

Description

Cortical and hippocampal levels of inorganic phosphate (Pi) as a proportion of total phosphate as detected through 31P- Magnetic Resonance Spectroscopic Imaging.

Time Frame

Baseline and 6 weeks

Title

Change from baseline in cortical and hippocampal phosphocreatine/inorganic phosphate ratio (PCr/Pi) after 6 weeks on intervention.

Description

Ratio of Cortical and hippocampal levels of phosphocreatine and inorganic phosphate as detected through 31P- Magnetic Resonance Spectroscopic Imaging.

Time Frame

Baseline and 6 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

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 Absence of significant depression symptoms (Geriatric Depression Scale-15 score of < 5). Total score of <2 on the suicidal ideation subscale (measures 3, 7, 11, 12 and 14) of the Geriatric Depression Scale. 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 Willingness to discontinue all botanical dietary supplements for one week prior to and during the study. Willingness to undertake multiple MRI scans Meet the National Institute of Aging - Alzheimer's Association core clinical criteria for MCI or probable AD dementia with a Clinical Dementia Rating score of 0.5-1 and Mini Mental State Examination score of 20-28 at screening and baseline Participants who report a history of participative memory decline with gradual onset and slow progression over the last one year before screening MUST be corroborated by an informant. Participants on acetylcholinesterase inhibitor or memantine therapy for AD must be on a stable dose for at least 12 weeks prior to baseline visit. Participants must have an identified caregiver/study partner that can accompany participant to all study visits. 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 labs 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 type I diabetes mellitus, poorly controlled type II diabetes mellitus (HbA1c > 7%), 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 (CNS) 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: anti-epileptics, sedatives, amitriptyline, anticoagulants (e.g., 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), beta blockers and anti-depressant medications that have not been at stable dosage for two months (including SSRIs, SNRIs) Non-Alzheimer dementia such as vascular dementia, normal pressure hydrocephalus, or Parkinson's disease MMSE score of < 20 or > 28 Unwilling to maintain stable dosage of AD medications throughout study duration Unwilling to maintain stable dosage of intervention throughout the course of the study Contraindications to Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopic Imaging (MRSI) scans (some metal implants, pacemakers, claustrophobia)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Amala Soumyanath, PhD

Phone

503-494-6878

soumyana@ohsu.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Lucy Allison, MS

Phone

503-418-8197

allisolu@ohsu.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amala Soumyanath, Ph.D

Organizational Affiliation

Oregon Health and Science University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Joseph Quinn, MD

Organizational Affiliation

Oregon Health and Science University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oregon Health & Science University

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Amala Soumyanath, PhD

Phone

503-494-6878

soumyana@ohsu.edu

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

There is no plan to release individual participant data.

Citations:

PubMed Identifier

35096945

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.

Results Reference

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PubMed Identifier

35204098

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.

Results Reference

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