SYNERGIC-2 Trial (SYNchronizing, Exercises and Remedies to GaIn Cognition@Home)

Study Overview
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Brief Summary
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In Canada, 1,700,000 adults are at risk of dementia, half of them with MCI,representing one of the largest groups at risk for an incurable disease. Epidemiological evidence suggests up to 40% of dementia cases might be preventable by targeting modifiable lifestyle and cardiovascular factors. Given that current treatments cannot modify the disease, prevention is critical. SYNERGIC-2 offers a personalized multidomain intervention that combines physical and cognitive training, sleep, diet, and vascular-metabolic interventions in individuals with MCI to synergistically enhance their overall brain health including cognition and contributes to maintaining their independence. Importantly, interventions will be provided at home using an existing virtual platform reducing delivery complexity and expanding the accessibility to a wider population, thus decreasing potential inequities. Improving older adults' brain health and achieving even a modest two-year dementia incidence delay will have a projected saving of $218 Billion in Canada's healthcare system over 30 years.

Detailed Description
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Epidemiological evidence suggests up to 40% of potential dementia cases might be preventable by targeting modifiable lifestyle and cardiovascular factors; given that current treatments cannot modify the disease, prevention is a critical aspect. SYNERGIC-2 is the first large Canadian clinical trial using a 12-month home-based personalized multidomain lifestyle intervention to improve cognition in 550 older adults with Mild Cognitive Impairment (MCI), a pre-dementia state. These personalized at-home interventions target 5 domains with tailored physical exercise, cognitive training, diet recommendations, sleep interventions, and vascular risk factor management and are all delivered using a digital platform. Specifically, SYNERGIC-2 will be conducted with participants in their homes using video-conference meetings to test participants and to coach them 1-on-1 through the interventions on a web-based digital platform. The effect of these combined interventions on cognition will be compared to an online-educational program Brain Health PRO (BHPro). Both interventions are part of CAN-THUMBS UP, the interventional platform of the CCNA related to Canada Dementia Research Strategy; and constitutes Canada's contribution to the World-Wide-FINGERS Network. Importantly, these interventions have been selected because there is evidence that they synergistically enhance overall brain health including cognition and contributes to maintaining independence for individuals at risk for developing dementia.

Official Title
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A Home-based Personalized Multidomain RCT From the Canadian Therapeutic Platform for Multidomain Interventions to Prevent Dementia (CAN-THUMBS UP)

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Other: PMI@Home
* Other: Brain Health Pro


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Ages 60-85 years. Having mild cognitive impairment (MCI) defined as meeting all of the following: Presence of subjective memory complaints from the participant and/or informant. Objective impairment on cognitive tests independent of outcome measures.† Preserved activities of daily living assessed (>14/23 in Lawton-Brody IADL score). For the study, impairment of daily living will be assessed based on cognitive abilities, not physical abilities. Absence of clinical dementia per DSM-IV criteria †Objective cognitive impairment is operationalized as: Montreal Cognitive Assessment (MoCA) total score between 16 and 25 (inclusive), and/or RAVLT delayed recall ≤6, and /or Clinical Dementia Rating Scale (CDR) =0.5 Have ≥2 additional dementia risk factors targeted by our intervention as follows: low physical activity (less than 150 minutes of moderate-to-vigorous-intensity physical activity per week, as per GAQ), poor diet (14-item Mediterranean Diet Assessment (MDA-14) score ≤7), insomnia ( Insomnia Severity Index (ISI) score ≥15), and vascular-metabolic risk (Cardiovascular Risk Factors Aging and Incidence of Dementia (CAIDE) score ≥6 and/or diabetes (type I or II) and/or obesity (BMI≥30) and/or diagnosis of high blood pressure (hypertension) and/or smoking). Have access to a home computer/laptop/tablet with home internet (have regular access to email) and ability to use technology (able to send and receive emails and join video conferences). Self-reported levels of proficiency in English for speaking and understanding spoken and written language. Have normal/corrected to normal vision in at least one eye to identify stimuli on computer/tablet screen. Have normal to corrected hearing ability, in order for the participant to engage in digital/virtual communication. Research personnel will determine and assess the hearing ability as per participant's performance. Able to comply with virtual visits, treatment plan, and trial-related activities. Ability to participate in the study's exercise training as determined by the Get Active Questionnaire (GAQ). Exclusion Criteria Having a diagnosis of dementia (based on DSM-IV criteria). Underlying severe disease that precludes engagement with interventions, including presence of psychiatric diagnoses (i.e., major depression (Geriatric Depression Scale (GDS-30) >19), schizophrenia, severe anxiety, neurological disorder with severe motor deficits, such as current parkinsonism or any neurological disorder with residual severe motor deficits (i.e., stroke with motor deficit), or presence of unstable (non-controlled e.g., symptoms that suggest instability or no treatment for their condition) chronic disease such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) that may preclude the participant from engaging properly with the trial interventions, or advanced-stage active cancer that at the study physician's discretion will prevent them from participating. Having had surgery within the last 2 months or having an upcoming planned surgery in the next 12 months that could interfere with the participant's vision, hearing, mobility, or any other abilities to participate in the study. Regular use of Benzodiazepine or neuroleptic drugs that may interfere with the participants ability to participate in the assessments and interventions. Recent (in the past 12 months) and/or current substance or alcohol abuse. Having had a transmural myocardial infarction (severe heart attack) within six months prior to enrollment in the clinical trial that according to the study physician may preclude physical activity performance. Intention to enroll in other interventional clinical trials during same time.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The SYNERGIC-2 Trial is a single-blind, two-arm, randomized controlled trial (RCT) evaluating the cognitive effect of personalized multidomain interventions that target physical exercise, cognitive training, sleep, diet, and vascular risk factors. The SYNERGIC-2 Trial will be administered virtually through online video conferencing platform systems (WeBex or Zoom Healthcare©). Figure 1 illustrates the trial design. The trial adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines for conducting and reporting clinical trials, as extended to non-pharmacological interventions. A total of 550 participants with MCI aged 60-85 will be enrolled and randomized into one of two arms, with 275 participants in each arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SYNERGIC 2<br>Personalized multidomain coached 1-to-1 interventions at home (PMI@Home) including: Physical Exercise Cognitive Training Diet Sleep Vascular Risk Factors Control | Other: PMI@Home<br>* Personalized multidomain interventional program by combining tailored lifestyle interventions that targets 5 domains: physical activity, cognition, diet, sleep, and vascular risk factors. These interventions are tailored based on participants' baseline profile and progress in intensity following the principles of personalized medicine. All aspects of the PMI@home will be delivered remotely, at participants' homes, using a digital platform with scheduled bi-weekly 1-to1 coaching sessions. Delivery of interventions and assessments are centralized with 5 trained staff at the sponsor site (London) to assure logistics, standardization, and quality control.<br>|
| Placebo Comparator: Brain Health PRO (BHPro)<br>Brain Health PRO (BHPROBHPRO) is an independent, educational program with content also related to: Physical Exercise Cognitive Training Diet Sleep Vascular Risk Factors Social engagement | Other: Brain Health Pro<br>* Online Modules: Motivation, Self-Efficacy, Positive Health, Environment and Genetic risk Physical Activity Cognitively Stimulating Activities Diet Sleep Social and Psychological Health Vascular health Vision and Hearing Lifestyle Risk Impact Surveys Goal Setting<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in global cognition assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) with 13 items (ADASCog-13) | Global cognition will be assessed using the cognitive section of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) with 13 items (ADASCog-13). This scale consists of 13 brief cognitive tests assessing attention, memory, language, executive function, praxis, orientation, and instrumental activities of daily living. The ADAS-Cog has been a significant outcome measure in numerous trials with MCI and AD to measure changes in cognitive performance in populations with cognitive impairment, it score ranges from 0 to 84, with higher scores indicating worse cognitive performance. | baseline and at 48 weeks (after interventions finalized) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Anthropometric Measures | Measurements of weight and hip/waist circumference will be done at home and self-reported by the participant. This can be used to characterize participant's body dimension and determine body mass index as kg/m^2 which can be used to estimate whether participants have obesity. A BMI greater than 30 is the cut off for obesity. Changes in waist circumference may also indicate visceral fat and cardiovascular risk. | Baseline, month 3, mid-intervention at 6 months, month 9, and follow-up at 12 months | 
| Change in Cardiovascular Risk Factors, Aging, and Incidence of Dementia | The Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) is a short questionnaire assessing midlife vascular risk for dementia, with scores ranging from 0 to 15 (higher scores suggesting higher risk) and has cut-off score of 5 for high risk. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in the CCNA Gait Assessments results-Walking performance | The CCNA gait assessment includes preferred and fast pace gait, and dual-task gait that comprises walking while performing three cognitively demanding tasks: counting backwards by ones, counting backwards by sevens, and naming animals. Participants will be asked to walk on a designated walking path(4 meters) in sight of camera | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Clinical Dementia Rating scores | The Clinical Dementia Rating (CDR) scale is a validated scale (0-3) used in longitudinal Alzheimer's Disease (AD) research to characterize the impact of cognitive decline on global function performance applicable to AD and related dementias. Information is obtained through a semi-structured interview of the patient and a reliable informant or collateral source (e.g. family member). A score of ) indicate no cognitive impairment; 0.5 for Mild cognitive impairment; 1 for early dementia; 2 for mild severe dementia; 3 for severe dementia | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Digit Symbol Modalities Test - Oral Version (mental processing speed) | The Digit Symbol Modalities Test is a 90-second, timed task that asks participants to orally match geometric figures with specific numbers according to a defined key (specifying which symbols are assigned to which numbers) that is provided at the top of the stimulus page. The oral Digit Symbol Modalities Test measures processing speed capabilities. The total number of numbers correctly matched with symbols is the final score for this test ranging from 0-110 correct numbers sequentially spoken. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Eating Pattern Self-Assessment | The Eating Pattern Self-Assessment (EPSA) is a 12-item questionnaire assessing participants' dietary intake profiles over the past 12 months. No score provided | Baseline, month 3, mid-intervention at 6 months, month 9, and follow-up at 12 months | 
| Changes in Fall Occurrence | The monthly falls calendar that will be sent to help track any participant falls. Participants are being asked to complete this calendar on a daily basis in order to help investigators better track whether or not they have fallen since last intervention. A fall is defined as any unintentional event in which a participant falls to the ground or onto an object (e.g., a chair) no caused by a syncope or loss of consciousness. Total number of falls and consequences of falls is provided. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Generalized Anxiety Disorder (GAD-7) | A questionnaire to score the frequency the participant experiences anxiety symptoms in the past 7 days with higher scores indicating worse anxiety symptoms. Score ranges from 0-21. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Change in Geriatric Depression Scale (GDS-30) | A questionnaire to establish a participant's experience with depressive symptoms with higher score indicating more severe depressive symptoms. Score ranges from 0-30. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Change in Health Utility Index (HUI-3) | The HUI-3 provides descriptive health profile measures on a generic scale with higher scores indicating better quality of life and global functionality. HUI also provides single-attribute scores of morbidities for the following attributes; vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. Score ranges from one 1 to 6 or 1 to 5 depending on the domain; and sum of all domains could range from 8 to 45. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Health Resource Utilization Questionnaire (HRUQ) | The HRUQ provides an overall assessment of a participants utilization of health-related resource use and costs for elderly adults with and without mild cognitive impairment.There is no scoring for the HRUQ | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Insomnia Severity Index | The Insomnia Severity Index (ISI) is a 7-item questionnaire assessing sleep onset, sleep maintenance, sleep satisfaction, and sleep problems. | Baseline, month 3, mid-intervention at 6 months, month 9, and follow-up at 12 months | 
| Changes in International Physical Activity Questionnaire scores | Modified for the elderly people, assesses older adults' level of physical activity, with a simple 7-item questionnaire. Scoring ranges from low, moderate and high. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in the Lawton-Brody Instrumental Activities of Daily Living (IADL) scale | Measures participant's ability to engage in instrumental activities of daily living via questionnaire assessing the ability to independently perform activities such as using the telephone, shopping, preparing meals, chores, household activities, managing prescriptions and medications, and managing personal finances. Score ranges from 0-23. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in the Mediterranean Diet Assessment | A 14-item questionnaire to help evaluate a participants Mediterranean ingredients in their diet. Score ranges from 0-14. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in global cognitive function using Montreal Cognitive Assessment(MoCA) | The MoCA is a brief screening instrument designed to detect global cognitive dysfunction. It assesses a range of different cognitive domains, including attention, executive functions, memory, language, visuo-constructional skills, abstract thinking, and orientation. Score ranges from 0-30. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in the Oral Trail Making Test - Attention Shifting capabilities/executive functions using | The Oral Trail Making Test (TMT) A & B is a two-part test that assesses attention speed, and mental flexibility and has been widely used in clinical settings for assessing deficits in attention and executive functioning. Score from part A ranges from 0-180; part B from 0-300 seconds. Longer times mean worse performance in the test. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Quality of Life Questionnaire (SF-36) | The Short-Form Quality of Life Questionnaire (SF-36) is a 36-item questionnaire assessing quality of life, with scores ranging from 0 to 100 and higher scores indicating better quality of life. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in Rey Auditory Verbal Learning Test (RAVLT)-Episodic memory | The Rey Auditory Verbal Learning Test (RAVLT) assesses episodic memory, in which the participant is presented with 15 words in five presentations or trials, after which they are asked to recall the words (immediately and after a delay). Score ranges from 0 to 15 words recalled. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in the Cognitive Expectancies Questionnaire | It is a version developed by the CCNA to measures participant's expectancies about the cognitive benefits of the intervention. Score ranges from 1 to 88. This questionnaire measures the participant's perception about the interventions. The questionnaire outcome is not related to participant's cognition, but participant's subjective perception about the interventions. | Baseline and follow-up at 12 months | 
| Changes in sleep pattern | The Sleep Diary is self-administered of 10-days of sleep patterns to assess sleep quality and total of sleep time. It also helps to identify possible sleep disruptions that may affect sleep quality and identify certain habits that may explain sleeping issues. | Baseline, month 3, mid-intervention at 6 months, month 9, and follow-up at 12 months | 
| Changes in physical activity in the elderly | The Wrist (AX3) Accelerometer is used to detect movement, vibrations, and orientation changes to assess physical activity trends in older population. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in behavior | This questionnaire asks about eleven health behaviors, to be rated on a 0 (low) to 10 (high) scale. Prior research has demonstrated that a 1-point change on these 0 to 10 items is clinically meaningful. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in BHPro questionnaires | These questionnaires ask about cognition (6-item questionnaire), vascular health (4-item questionnaire), and social and psychological health (8-item questionnaire). BHPro Questionnaire - Cognition: This questionnaire asks about participant's engagement in activities such as reading, crafting, and instrument playing. It does not provide any quantitative range score. BHPro Questionnaire - Social and Psychological Health: This questionnaire asks about participant's emotions and mood. It does not provide any quantitative range score. BHPro Questionnaire - Vascular Health: This questionnaire asks about participant's updated medical history. It does not provide any quantitative range score. | Baseline, month 3, mid-intervention at 6 months, month 9, and follow-up at 12 months | 
| Changes in EEG | Participants will use the MUSE-S EEG Headband for 3 consecutive nights. The MUSE S Headband is a commercially available consumer headband that has 7 sensors, 2 on the forehead, 2 behind the ears, plus 3 reference sensors, to detect and measure EEG signals when sleeping. | Baseline and follow-up at 12 months | 
| Identification of APO-E variants, a planned panel of 31 single nucleotide polymorphisms (SNPs), and untargeted metabolomics | Participants will use the DNA-Genotek, which is a self-administered saliva collection kit to analyze saliva sample for possible identification of APO-E variants, a planned panel of 31 single nucleotide polymorphisms (SNPs), and untargeted metabolomics. | Baseline and follow-up at 12 months | 
| Changes in Resource Use Inventory Q7 & Q8 (RUI Q7 &Q8) | Questions 7 and 8 from the Resource Use Inventory (RUI)28 questionnaire assess health-related resource use for caregivers. This instrument has been used for tracking resource use and costs in cognitively intact older adults, as well as with Alzheimer disease (AD). This is a self-report questionnaire investigates if participants received any help while preforming daily living tasks e.g., bathing, brushing, and getting the phone. It does not provide any quantitative range score. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in 60s Chair Standing Test | Participants will be performing the one-minute chair stand test while being assessed via video conferencing by a research team member to evaluate mobility. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in The Activities-specific Balance Confidence Scale (ABC) questionnaire | The ABC questionnaire consists of 16 questions where the participants rate their confidence that they will not lose their balance or become unsteady while performing different activities. They need to rate 16 different activities from 0 to 100, 0 being not confident at all, and 100 being completely confident on their abilities to perform the activity. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 
| Changes in The Short Physical Performance Battery (SPPB) | The SPPB is an objective assessment tool for evaluating lower extremity functioning in older adults. Score ranges from 0 to 12. 0 being frail (disabled), and 12 being no mobility disability issues. | Baseline, mid-intervention at 6 months, and follow-up at 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia, Mild Cognitive Impairment, Virtual Interventions, Geriatric Medicine