Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention

NCT03978052 | Completed

• 1 other identifier: IMIM/PENSA
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 2

Brief Summary

Alzheimer's disease (AD) neuropathology is characterized by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. Current knowledge, has allowed a shift in the definition of AD from a syndromal to a biological construct, based on biomarkers that are proxies of pathology. However, little is known about mechanisms underlying the disease progression at its early stages. The loss of dendritic spines, the primary locus of excitatory synaptic transmission in the mammalian central nervous may be linked to cognitive and memory impairment in AD: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD). In humans, alterations in functional connectivity (FC) have been observed in early AD stages, subjective cognitive decline (SCD) and mild cognitive impairment (MCI). A hyper-synchronized anterior network and a posterior network characterized by a decrease in FC are the spatial features. These disruptions also seen in AD indicate that FC alterations appear very early in the course of the disease . Experimental research strongly suggests that in order to increase our cerebral reserves, we have to follow a lifestyle that takes into account many factors. Clinical studies provided evidence that individuals with more cerebral reserves are those who have a high level of education, who maintain regular physical activity and who eat in a healthy way. The environmental enrichment (EE) animal models confirmed that the experience plays a key role in increasing brain plasticity phenomena .There is a growing understanding that a valid therapeutic emerging approach in AD is prevention. A large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that primary prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. The therapeutic approach proposed in the present project aims at improving synaptic plasticity and functional connectivity in early stages of AD, and specifically in SCD in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. In this context the proposed clinical trial design will evaluate the efficacy of EGCG in the context of a personalized medicine approach that includes a multimodal intervention (nutritional, physical, cognitive and medical) looking at improving person-centered outcomes. Early phase I studies in Down syndrome young adults showed that while subjects were under EGCG, improvements in cognition were observed but these vanished when treatment was discontinued. Phase II studies combining EGCG with cognitive training showed improvements in cognitive performance and adaptive functionality but interestingly sustained effects after treatment discontinuation. Observations made in humans are in agreement with preclinical studies showing that EGCG combined with environmental enrichment resulted in an improvement of age-related cognitive decline. These observations are in favor of the option of combining EGCG with a personalized multimodal intervention. The personalized multimodal intervention will take into account medical comorbidities (i.e. metabolic syndrome, T2DM), diet (including nutritional status), physical exercise, and will incorporate cognitive training and a behavioral intervention to aid subject's adherence and empowerment to the intervention proposed. This will be in-line with other clinical studies in AD showing the superiority of multimodal interventions vs. a single life style intervention (i.e. single nutrient, physical activity). Hypothesis: A multimodal lifestyle change intervention (dietary, physical activity and cognition) combined with epigallocatechin gallate (EGCG) will slow down cognitive decline and improve brain connectivity in a population of participants with subjective cognitive decline (SCD).

Conditions

Alzheimer Disease; Cognitive Decline

Keywords

EGCG; Dietary supplement; Personalized medicine; Subjective Cognitive Decline (SCD); Apolipoprotein E4; Lifestyle Risk Reduction; Epigallocatechin gallate; Multimodal lifestyle intervention

Outcome Measures

Primary Outcomes (1)

• Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe

  Changes in the PACC-exe, that include: The Total Recall score from the Free and Cued Selective Reminding Test (FCSRT) (which range from 0-48 words),The Delayed Recall score on the Logical Memory IIa subtest from the Wechsler Memory Scale (which range from 0-25 story units), the Coding Test Total score from the Wechsler Adult Intelligence Scale-Revised (which range from 0-93 symbols), The Montreal Cognitive assessment (MOCA) total score (which range from 0-30 points), and additionally, the Interference score from the Stroop Colour and Word Test (SCWT) and the Five Digit Test. Each of the component change scores is divided by the baseline sample standard deviation of that component, to form standardized z scores. These z scores are summed to form the composite.

  Screening and 12 months

Secondary Outcomes (6)

• Safety outcome of the intervention with EGCG: AEs and SAEs

  Baseline, 6 and 12

• Safety outcome of the intervention with EGCG: Biomarkers thyroid

  Baseline, 6 and 12

• Safety outcome of the intervention with EGCG: Biomarkers liver

  Baseline, 6 and 12

• Safety outcome of the intervention with EGCG: Biomarkers

  Baseline, 6 and 12

• Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging)

  Screening and 12 months.

Other Outcomes (34)

• Changes in Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe

  Screening, 6, 12 and 15 months.

• Changes in the microbiota composition

  Baseline, and 12 months.

• Change in the dietary patterns (metabolomics) Plasma samples

  Baseline, 6, 12 and 15 months

Study Arms (3)

EGCG + multimodal intervention

EXPERIMENTAL

EGCG + multimodal intervention (n=50) EGCG: (Font-UP, Laboratoires Grand Fontaine), a daily dose of 5-6 mg/kg up to 500 mg/day for 12 months \+ multimodal lifestyle personalized intervention

Dietary Supplement: EGCG; Other: Multimodal lifestyle intervention

Placebo + multimodal intervention

PLACEBO COMPARATOR

Placebo Font-Up (n=50) \+ multimodal lifestyle personalized intervention

Dietary Supplement: Placebo EGCG; Other: Multimodal lifestyle intervention

Control

SHAM COMPARATOR

Healthy lifestyle recommendations (n=50)

Other: Healthy lifestyle recommendations

Interventions

EGCG DIETARY_SUPPLEMENT

FontUp capsules (100 mg of EGCG each) 12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight \>50kg: 5 capsules/day.

EGCG + multimodal intervention

Placebo EGCG DIETARY_SUPPLEMENT

Placebo FontUp (same appearance as active). 12 months, three to five capsules per day (participant's weight ≤ 50kg: 3 capsules/day; weight \>50kg: 5 capsules/day.

Placebo + multimodal intervention

Healthy lifestyle recommendations OTHER

Personalized advice on diet, physical activity, cognitive training, and social stimulation activities.

Control

Multimodal lifestyle intervention OTHER

* Dietary intervention: personalized dietary recommendations based on MedDiet, 9 individual counseling sessions. * Physical activity intervention: Guided gymnasium (aerobic, strength, and balance activities). Minimum one class/week the first 6months, and two classes/week from month 7 to 12). Achieve a physically active lifestyle (10,000 steps/day; individuals living with disability 8,500 steps/day). Achieve moderate physical exercise in older adults (150 to 210 minutes/week or 90 to 150 minutes depending on medical history. * Cognitive training: NeuronUP, 3/week, 30 min sessions * Psychoeducation: ten 90-minute sessions * Social stimulation activities: ten to twelve 90-to-120-minute sessions.

EGCG + multimodal intervention; Placebo + multimodal intervention

Eligibility Criteria

• Age: 60 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• iii. Age between 60 and 80 with a BMI ≥18.5 and \<35 kg/m2. iv. Carrying the APOE-ɛ4 allele. v. Participants are willing to participate and perform all study procedures.
• i. Inability or unwillingness to give written informed consent or communicate with study staff or illiteracy.
• ii. Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to DSM-V).
• iii. Neurological conditions that may affect cognition or may imply a prodromal stage of neurodegenerative disease other than AD (e.g., cranioencephalic trauma with permanent neurologic effects, epilepsy, multiple sclerosis, previous stroke, extrapyramidal signs at physical exploration, history of brain tumor...).
• iv. History or evidence of any medical condition or use of medication that in the opinion of the investigator could affect subjects' safety or interfere with the study assessments (e.g. use of neuroleptic drugs, anticonvulsant medications (except gabapentin and pregabalin for non-seizure indications) corticosteroids or immunosuppressive therapies that may affect inflammatory parameters).
• v. Any contraindication to perform brain MRI (e.g. pacemaker, MRI-incompatible aneurysm clips).
• vi. Clinically significant abnormalities in laboratory test or MRI scan results at screening unless acceptable by the investigator (e.g. mild/moderate kidney failure, benign tumor that does not require surgical intervention…).
• vii. Any medical condition that may affect the study assessments in the opinion of the principal investigators or medical advisors.
• viii. Current intake of vitamin supplements, catechins, or products containing EGCG (i.e. TEAVIGO, Mega Green Tea Capsules Life Extension, or Font-UP Grand Fontaine Laboratories) for at least 3 months previous to the screening visit.
• ix. History within the last 2 years of treatment for primary or recurrent malignant disease, excluding non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or situ prostate cancer with normal prostate-specific antigen post-treatment.

Sponsors & Collaborators

• Parc de Salut Mar: lead
• Hospital del Mar Research Institute: collaborator
• Barcelonabeta Brain Research Center, Pasqual Maragall Foundation: collaborator

Study Sites (2)

Barcelonabeta Brain Research Center

Barcelona, Barcelona, Spain, 08005, Spain

Location

Hospital del Mar Research Institute Barcelona

Barcelona, 08003, Spain

Location

Related Publications (23)

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MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Risk Reduction Behavior

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Behavior

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomized, double-blind clinical trial (participant, investigator, outcomes assessor)
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Neurosciences Research Programme

Model Details: Arm I: EGCG and a multimodal intervention (n=50) Arm II: Placebo EGCG and a multimodal intervention (n=50) Arm III: Healthy lifestyle recommendations (n=50)

Study Record Dates

• First Submitted: May 29, 2019
• First Posted: June 6, 2019
• Study Start: October 30, 2019
• Primary Completion: March 29, 2023
• Study Completion: June 28, 2023
• Last Updated: March 15, 2024

Record last verified: 2024-03

Locations

ES (2)