Alzheimer Disease(PENSA)NCT03978052
Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention
A study testing EGCG, Healthy lifestyle recommendations and Multimodal lifestyle intervention in people with Alzheimer Disease and Cognitive Decline, run by Parc de Salut Mar at 2 sites in Spain.
Trial 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. Read more about this study
- Who is it for?
- Ages 60 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Alzheimer Disease, Cognitive Decline
- What is being tested?
- EGCG, Healthy lifestyle recommendations and Multimodal lifestyle intervention
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 129 participants
- Where
- 2 sitesSpain
- Study dates
- 30 Oct 2019to 28 Jun 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 60 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Meet all selection criteria and no exclusion criteria. ii. Fulfill SCD criteria (Jessen et al. 2014) including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education).
- 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.
Who cannot join
- Inability or unwillingness to give written informed consent or communicate with study staff or illiteracy.
- Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to DSM-V).
- 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...).
- 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).
- Any contraindication to perform brain MRI (e.g. pacemaker, MRI-incompatible aneurysm clips).
- 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…).
Show all 9Show fewer
- Any medical condition that may affect the study assessments in the opinion of the principal investigators or medical advisors.
- 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.
- 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.
Trial locations and contacts
2 sites in 1 country.
Spain2 sites
Barcelonabeta Brain Research Center
Barcelona, Barcelona, Spain, 08005
Hospital del Mar Research Institute Barcelona
Barcelona, 08003
About this study
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).
Read the detailed description
Study Design: Randomized, double-blind, personalized clinical trial with 150 subjects with subjective cognitive decline (SCD) of both genders, with 3 arms of treatment Duration of the Study: The total duration of the study is expected to be 24 months (subject recruitment, baseline period, treatment period, follow-up, data analysis, and study report).
Primary Objective(s): To evaluate the efficacy of a multimodal intervention (dietary, physical activity, and cognition) combined with epigallocatechin gallate (EGCG) in slowing down cognitive decline.
Secondary Objective(s): 1 To evaluate the safety of the interventions 2 To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) Changes in brain connectivity, (ii) changes in AD biomarkers, (iii) changes in biomarkers of oxidation/inflammation, (iv) changes in gut microbiota composition and the metabolome derived by the action of microorganisms, v) changes in biological aging predictors.
Target Population: Subjects diagnosed with Subjective Cognitive Decline (SCD) criteria including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education), carriers of the Apolipoprotein E4 allele, recruited either from either the Parc de Salut Mar and its primary care providers, from Barcelona Beta Brain Research Centre or through a web-based system.
Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii. Ad-hoc Subjective Cognitive Decline Questionnaire (SCD-Q) item "do you perceive memory or cognitive difficulties?" positive.
iii. Subjects willing to participate and perform all study procedures, including Apolipoprotein E4 genotyping iv. The subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject to provide accurate information about the subject's cognitive and functional abilities.
Study Arm(s):
- Arm I: EGCG and multimodal intervention (n=50)
- Arm II: Placebo EGCG and multimodal intervention (n=50)
- Arm III: Healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of patient participation is expected to be 17 months. Run-in period (1 month): Basal assessment of cognitive performance (cognitive battery), diet and physical activity, daily living activities (self-reported tests), and mood (self-reported tests at basal assessment and EMA's). Interventions will last 12 months. Follow-up after intervention discontinuation: at least 3 months Treatment: EGCG (Font-UP, laboratories Grand Fontaine), a daily dose of approximately 5-6 mg/kg up to 500 mg/day will be administered to subjects for 12 months or a matched placebo Multimodal intervention (12 months): 1) Social stimulation, ten 90-120 minutes guided group activities; 2) Cognitive training, trice per week, 30-minute sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity.
End point: modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC), including additional tests of executive functions: the PACC-exe.
- Conditions
- Alzheimer Disease, Cognitive Decline
- Being tested
- EGCG, Placebo EGCG, Healthy lifestyle recommendations, Multimodal lifestyle intervention
- Keywords
- EGCG, Dietary supplement, Personalized medicine, Subjective Cognitive Decline (SCD), Apolipoprotein E4, Lifestyle Risk Reduction, Epigallocatechin gallate, Multimodal lifestyle intervention
- Medical subject headings
- Alzheimer Disease, Cognitive Dysfunction, Risk Reduction Behavior
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EGCGDietary 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.
Placebo EGCGDietary 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.
Healthy lifestyle recommendationsOther
Personalized advice on diet, physical activity, cognitive training, and social stimulation activities.
Multimodal lifestyle interventionOther
- 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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Dietary Supplement: EGCG; Other: Multimodal lifestyle intervention |
| Placebo + multimodal intervention | Placebo comparator | Placebo Font-Up (n=50)
+ multimodal lifestyle personalized intervention Receives: Dietary Supplement: Placebo EGCG; Other: Multimodal lifestyle intervention |
| Control | Sham comparator | Healthy lifestyle recommendations (n=50) Receives: Other: Healthy lifestyle recommendations |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Screening and 12 months
Secondary outcomes (6)
Safety outcome of the intervention with EGCG: AEs and SAEs
evaluated by means of Incidence, nature, severity and causality of adverse events (AEs) and serious adverse events (SAEs)
Measured: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers thyroid
Assessment of thyroid function parameters: both TSH and freeT4 within normal values according to the reference population
Measured: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers liver
Assessment of liver function parameters: ALP and ALT within normal values according to the reference population
Measured: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers
Assessment of renal function parameters: creatinine within normal values according to the reference population
Measured: Baseline, 6 and 12
Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging)
Changes in Maps of change in connectivity of the Default mode network Changes in Maps of change in connectivity of the Limbic network Changes in Maps of change in connectivity of the Salience network
Measured: Screening and 12 months.
Changes in structural connectivity networks known to be affected in Alzheimer Disease
Changes in Connectivity changes of the parahippocampus/fornix Changes in Connectivity changes of the cingulum/cingulate fiber bundle Changes in connectivity changes of the caudate heads
Measured: Screening and 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jun 2019
- Study start30 Oct 2019
- Primary completion29 Mar 2023
- Study completion28 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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)
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Parc de Salut Mar
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital del Mar Research Institute (IMIM), Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
- Responsible party
- Principal investigator, Rafael de la Torre, Parc de Salut Mar
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03978052
- Sponsor's protocol ID
- IMIM/PENSA
- Acronym
- (PENSA)
- Status last verified
- Mar 2024
- First submitted
- 29 May 2019
- Last updated
- 15 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Skaper SD, Facci L, Zusso M, Giusti P. Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol Disord Drug Targets. 2017;16(3):220-233. doi: 10.2174/1871527316666170113120853.
PubMed 28088900Lopez-Sanz D, Bruna R, Garces P, Martin-Buro MC, Walter S, Delgado ML, Montenegro M, Lopez Higes R, Marcos A, Maestu F. Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations. Front Aging Neurosci. 2017 Apr 21;9:109. doi: 10.3389/fnagi.2017.00109. eCollection 2017.
PubMed 28484387Mandolesi L, Gelfo F, Serra L, Montuori S, Polverino A, Curcio G, Sorrentino G. Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies. Neural Plast. 2017;2017:7219461. doi: 10.1155/2017/7219461. Epub 2017 Jun 14.
PubMed 28740740Galvin JE. Prevention of Alzheimer's Disease: Lessons Learned and Applied. J Am Geriatr Soc. 2017 Oct;65(10):2128-2133. doi: 10.1111/jgs.14997. Epub 2017 Aug 2.
PubMed 28766695De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farre M, Fito M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014 Feb;58(2):278-88. doi: 10.1002/mnfr.201300325. Epub 2013 Sep 14.
PubMed 24039182de la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, Xicota L, Janel N, Catuara-Solarz S, Sanchez-Benavides G, Blehaut H, Duenas-Espin I, Del Hoyo L, Benejam B, Blanco-Hinojo L, Videla S, Fito M, Delabar JM, Dierssen M; TESDAD study group. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jul;15(8):801-810. doi: 10.1016/S1474-4422(16)30034-5.
PubMed 27302362Pons-Espinal M, Martinez de Lagran M, Dierssen M. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A. Neurobiol Dis. 2013 Dec;60:18-31. doi: 10.1016/j.nbd.2013.08.008. Epub 2013 Aug 20.
PubMed 23969234Catuara-Solarz S, Espinosa-Carrasco J, Erb I, Langohr K, Notredame C, Gonzalez JR, Dierssen M. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. Front Behav Neurosci. 2015 Dec 11;9:330. doi: 10.3389/fnbeh.2015.00330. eCollection 2015.
PubMed 26696850McEwen SC, Siddarth P, Rahi B, Kim Y, Mui W, Wu P, Emerson ND, Lee J, Greenberg S, Shelton T, Kaiser S, Small GW, Merrill DA. Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. J Alzheimers Dis. 2018;62(2):795-806. doi: 10.3233/JAD-170846.
PubMed 29480182Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. World Alzheimer Report 2016 Improving healthcare for people living with dementia. Coverage, Quality and costs now and in the future. Alzheimer's Disease International (ADI). London; 2016.
Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbaek G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. No abstract available.
PubMed 28735855Buckley RF, Maruff P, Ames D, Bourgeat P, Martins RN, Masters CL, Rainey-Smith S, Lautenschlager N, Rowe CC, Savage G, Villemagne VL, Ellis KA; AIBL study. Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease. Alzheimers Dement. 2016 Jul;12(7):796-804. doi: 10.1016/j.jalz.2015.12.013. Epub 2016 Feb 4.
PubMed 26852195Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015 Jun 6;385(9984):2255-63. doi: 10.1016/S0140-6736(15)60461-5. Epub 2015 Mar 12.
PubMed 25771249Crous-Bou M, Minguillon C, Gramunt N, Molinuevo JL. Alzheimer's disease prevention: from risk factors to early intervention. Alzheimers Res Ther. 2017 Sep 12;9(1):71. doi: 10.1186/s13195-017-0297-z.
PubMed 28899416Vellas B, Carrie I, Gillette-Guyonnet S, Touchon J, Dantoine T, Dartigues JF, Cuffi MN, Bordes S, Gasnier Y, Robert P, Bories L, Rouaud O, Desclaux F, Sudres K, Bonnefoy M, Pesce A, Dufouil C, Lehericy S, Chupin M, Mangin JF, Payoux P, Adel D, Legrand P, Catheline D, Kanony C, Zaim M, Molinier L, Costa N, Delrieu J, Voisin T, Faisant C, Lala F, Nourhashemi F, Rolland Y, Van Kan GA, Dupuy C, Cantet C, Cestac P, Belleville S, Willis S, Cesari M, Weiner MW, Soto ME, Ousset PJ, Andrieu S. MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA. J Prev Alzheimers Dis. 2014 Jun;1(1):13-22.
PubMed 26594639
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prevention of Cognitive Decline in ApoE4 Carriers With Subjective Cognitive Decline After EGCG and a Multimodal Intervention
- ClinicalTrials.gov ID
- NCT03978052
- Acronym / sponsor ID
- (PENSA) / IMIM/PENSA
- 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
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Parc de Salut MarUniversity, hospital or other
- Collaborators
- Hospital del Mar Research Institute (IMIM), Barcelonabeta Brain Research Center, Pasqual Maragall Foundation
- Study start
- 30 Oct 2019 (actual)
- Primary completion
- 29 Mar 2023 (actual)
- Study completion
- 28 Jun 2023 (actual)
- First posted
- 6 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
Study Design: Randomized, double-blind, personalized clinical trial with 150 subjects with subjective cognitive decline (SCD) of both genders, with 3 arms of treatment Duration of the Study: The total duration of the study is expected to be 24 months (subject recruitment, baseline period, treatment period, follow-up, data analysis, and study report).
Primary Objective(s): To evaluate the efficacy of a multimodal intervention (dietary, physical activity, and cognition) combined with epigallocatechin gallate (EGCG) in slowing down cognitive decline.
Secondary Objective(s): 1 To evaluate the safety of the interventions 2 To evaluate several underlying mechanisms that could explain the efficacy of the intervention in preventing the progression of cognitive decline: (i) Changes in brain connectivity, (ii) changes in AD biomarkers, (iii) changes in biomarkers of oxidation/inflammation, (iv) changes in gut microbiota composition and the metabolome derived by the action of microorganisms, v) changes in biological aging predictors.
Target Population: Subjects diagnosed with Subjective Cognitive Decline (SCD) criteria including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education), carriers of the Apolipoprotein E4 allele, recruited either from either the Parc de Salut Mar and its primary care providers, from Barcelona Beta Brain Research Centre or through a web-based system.
Preselection criteria i.Adults aged 60-80 years with a BMI ≥18.5 and <32 kg/m2. ii. Ad-hoc Subjective Cognitive Decline Questionnaire (SCD-Q) item "do you perceive memory or cognitive difficulties?" positive.
iii. Subjects willing to participate and perform all study procedures, including Apolipoprotein E4 genotyping iv. The subject has one informant partner who, in the investigator's judgment has frequent and sufficient contact with the subject to provide accurate information about the subject's cognitive and functional abilities.
Study Arm(s):
- Arm I: EGCG and multimodal intervention (n=50)
- Arm II: Placebo EGCG and multimodal intervention (n=50)
- Arm III: Healthy lifestyle recommendations (n=50) Duration of Patient Participation: The total duration of patient participation is expected to be 17 months. Run-in period (1 month): Basal assessment of cognitive performance (cognitive battery), diet and physical activity, daily living activities (self-reported tests), and mood (self-reported tests at basal assessment and EMA's). Interventions will last 12 months. Follow-up after intervention discontinuation: at least 3 months Treatment: EGCG (Font-UP, laboratories Grand Fontaine), a daily dose of approximately 5-6 mg/kg up to 500 mg/day will be administered to subjects for 12 months or a matched placebo Multimodal intervention (12 months): 1) Social stimulation, ten 90-120 minutes guided group activities; 2) Cognitive training, trice per week, 30-minute sessions; 3) Psychoeducational support groups, 10 sessions, 4) personalized diet 8 sessions, 5) personalized physical activity.
End point: modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC), including additional tests of executive functions: the PACC-exe.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 3
- Model description
- 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)
| Arm | Type | Receives |
|---|---|---|
| EGCG + multimodal intervention | Experimental | Dietary Supplement: EGCG, Other: Multimodal lifestyle interventionEGCG + 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 |
| Placebo + multimodal intervention | Placebo comparator | Dietary Supplement: Placebo EGCG, Other: Multimodal lifestyle interventionPlacebo Font-Up (n=50) + multimodal lifestyle personalized intervention |
| Control | Sham comparator | Other: Healthy lifestyle recommendationsHealthy lifestyle recommendations (n=50) |
Who may qualify
- Ages
- 60 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Meet all selection criteria and no exclusion criteria. ii. Fulfill SCD criteria (Jessen et al. 2014) including cognitive performance within normal values (Normal scoring on psychometric evaluation, adjusted for age and education).
- 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.
Key exclusion criteria (9 listed)
- Inability or unwillingness to give written informed consent or communicate with study staff or illiteracy.
- Clinically significant unstable psychiatric disorder that may affect cognition (e.g. major depression disorder, schizophrenia, bipolar or psychotic disorder according to DSM-V).
- 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...).
- 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).
- Any contraindication to perform brain MRI (e.g. pacemaker, MRI-incompatible aneurysm clips).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EGCGFontUp 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. | Dietary supplement | EGCG + multimodal intervention |
| Placebo EGCGPlacebo 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. | Dietary supplement | Placebo + multimodal intervention |
| Healthy lifestyle recommendationsPersonalized advice on diet, physical activity, cognitive training, and social stimulation activities. | Other | Control |
| Multimodal lifestyle intervention* 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. | Other | EGCG + multimodal intervention, Placebo + multimodal intervention |
Primary outcome
Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe
Time frame: Screening and 12 months
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.
6 secondary outcomes
Safety outcome of the intervention with EGCG: AEs and SAEs
Time frame: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers thyroid
Time frame: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers liver
Time frame: Baseline, 6 and 12
Safety outcome of the intervention with EGCG: Biomarkers
Time frame: Baseline, 6 and 12
Changes in Functional neuronal connectivity (assessed by a functional magnetic resonance imaging)
Time frame: Screening and 12 months.
Changes in structural connectivity networks known to be affected in Alzheimer Disease
Time frame: Screening and 12 months.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2024.
- Background: PubMed 28088900Skaper SD, Facci L, Zusso M, Giusti P. Synaptic Plasticity, Dementia and Alzheimer Disease. CNS Neurol Disord Drug Targets. 2017;16(3):220-233. doi: 10.2174/1871527316666170113120853.
- Background: PubMed 28484387Lopez-Sanz D, Bruna R, Garces P, Martin-Buro MC, Walter S, Delgado ML, Montenegro M, Lopez Higes R, Marcos A, Maestu F. Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations. Front Aging Neurosci. 2017 Apr 21;9:109. doi: 10.3389/fnagi.2017.00109. eCollection 2017.
- Background: PubMed 28740740Mandolesi L, Gelfo F, Serra L, Montuori S, Polverino A, Curcio G, Sorrentino G. Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies. Neural Plast. 2017;2017:7219461. doi: 10.1155/2017/7219461. Epub 2017 Jun 14.
- Background: PubMed 28766695Galvin JE. Prevention of Alzheimer's Disease: Lessons Learned and Applied. J Am Geriatr Soc. 2017 Oct;65(10):2128-2133. doi: 10.1111/jgs.14997. Epub 2017 Aug 2.
- Background: PubMed 24039182De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farre M, Fito M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014 Feb;58(2):278-88. doi: 10.1002/mnfr.201300325. Epub 2013 Sep 14.
- Background: PubMed 27302362de la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, Xicota L, Janel N, Catuara-Solarz S, Sanchez-Benavides G, Blehaut H, Duenas-Espin I, Del Hoyo L, Benejam B, Blanco-Hinojo L, Videla S, Fito M, Delabar JM, Dierssen M; TESDAD study group. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Jul;15(8):801-810. doi: 10.1016/S1474-4422(16)30034-5.
- Background: PubMed 23969234Pons-Espinal M, Martinez de Lagran M, Dierssen M. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A. Neurobiol Dis. 2013 Dec;60:18-31. doi: 10.1016/j.nbd.2013.08.008. Epub 2013 Aug 20.
- Background: PubMed 26696850Catuara-Solarz S, Espinosa-Carrasco J, Erb I, Langohr K, Notredame C, Gonzalez JR, Dierssen M. Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. Front Behav Neurosci. 2015 Dec 11;9:330. doi: 10.3389/fnbeh.2015.00330. eCollection 2015.
- Background: PubMed 29480182McEwen SC, Siddarth P, Rahi B, Kim Y, Mui W, Wu P, Emerson ND, Lee J, Greenberg S, Shelton T, Kaiser S, Small GW, Merrill DA. Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. J Alzheimers Dis. 2018;62(2):795-806. doi: 10.3233/JAD-170846.
- BackgroundPrince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. World Alzheimer Report 2016 Improving healthcare for people living with dementia. Coverage, Quality and costs now and in the future. Alzheimer's Disease International (ADI). London; 2016.
- Background: PubMed 28735855Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbaek G, Teri L, Mukadam N. Dementia prevention, intervention, and care. Lancet. 2017 Dec 16;390(10113):2673-2734. doi: 10.1016/S0140-6736(17)31363-6. Epub 2017 Jul 20. No abstract available.
- Background: PubMed 26852195Buckley RF, Maruff P, Ames D, Bourgeat P, Martins RN, Masters CL, Rainey-Smith S, Lautenschlager N, Rowe CC, Savage G, Villemagne VL, Ellis KA; AIBL study. Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease. Alzheimers Dement. 2016 Jul;12(7):796-804. doi: 10.1016/j.jalz.2015.12.013. Epub 2016 Feb 4.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing EGCG, Healthy lifestyle recommendations and Multimodal lifestyle intervention in people with Alzheimer Disease and Cognitive Decline, run by Parc de Salut Mar at 2 sites in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Modified Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC) including additional tests of executive functions: the PACC-exe (time frame: Screening and 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03978052, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2024.