METformin and FINGER Intervention to Prevent Cognitive Impairment and Disability in Older Adults at Risk for Dementia

Study Overview
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Brief Summary
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Dementia is the main cause of disability in older adults, currently affecting about 50 million people world-wide with this number estimated to triple in the next 30 years. In MET-FINGER, we aim to understand whether the FINGER 2.0 multidomain intervention, combining healthy lifestyle changes and a drug for diabetes (metformin), may help reduce the risk of dementia and improve health and independence among older adults. The study primary objective is to test the effect of the intervention, compared to healthy lifestyle advice, on the change in cognition, measured as a composite score including 14 of neuropsychological/cognitive tests. The secondary objective is to test the intervention effect on change in individual cognitive domains, functioning level, and risk factors for dementia (e.g., lifestyle, medical, and psychosocial). To this aim, a range of personal/health-related data and blood samples, will be collected. Potential interactions between metformin and lifestyle changes; potential disease-modifying effects; and feasibility of the metformin + lifestyle combination will be explored. 600 older people with risk factors for dementia, but without dementia/substantial cognitive impairment, will be recruited in the United Kingdom, Finland, and Sweden (at least 50% with higher genetic risk of Alzheimer's Disease/dementia based on the Apolipoprotein E (APOE) gene). Participants will be randomly assigned 1:1 to either a self-guided multidomain lifestyle intervention or to the FINGER 2.0 multidomain lifestyle-based intervention. Outcome assessors will be blinded to group allocation. Within the FINGER 2.0 intervention group, participants at increased risk of diabetes, will be randomly assigned 1:1:1 to either the metformin 2000mg/day, metformin 1000mg/day, or placebo group (double blinded). The intervention duration is 24 months. The lifestyle intervention includes four main components: physical exercise, diet, brain training and health checks. In the self-guided group, participants will create their own program, based on health advice and recommendations which will be provided during the study. In the FINGER 2.0 intervention group, participants will receive intensive lifestyle guidance, and participate in structured activities, which will be as tailored as possible on each person's daily habits and needs. Over the 2-year study period, all participants will attend four assessment visits: baseline, 6-, 12-, and 24-months.

Detailed Description
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After being identified and pre-screened in relevant registers, potential participants will undergo a screening assessment (after providing informed consent for the screening procedures) where inclusion criteria related to both cognition and cardiovascular/lifestyle risk factors will be checked. Participants meeting the inclusion criteria will undergo the exclusion criteria assessment with the study physician. Eligible participants will be invited to the baseline visit where informed consent for the full study will be signed, baseline assessment will be conducted, and participants will be randomized to either the FINGER 2.0 multidomain lifestyle-based intervention or self-guided multidomain lifestyle intervention group. Based on the results of the baseline assessment, the eligibility to the metformin/placebo treatment will be assessed in all participants randomized to the FINGER 2.0 intervention group. Eligible participants will be further randomized to one of the three metformin treatment groups (metformin 2000mg/day, metformin 1000mg/day, or placebo). Non eligible participants will continue the study by following the structured lifestyle intervention alone. In the self-guided intervention group, participants will build their own healthy lifestyle program based on standard healthy lifestyle advice that they will receive at individual consultations with the study physician/nurse as part of the visits. Within the FINGER 2.0 intervention group, participants will be invited to attend individual consultations and group meeting sessions in relation to the four intervention components (diet, physical activity, cognitive training, and cardiovascular/metabolic risk monitoring). As part of the physical activity component, group training sessions with a physiotherapist/professional trainer will be organized both at a gym as well as online. Within the cognitive training component, participants will have access to an online cognitive training program for independent training sessions. Individually tailored recommendations and plans will be provided to each participant. Metformin and placebo will be dispensed every 3 months, both administered orally. The active drug is Glucophage® XR 500. All participants randomized to the metformin/placebo groups will receive 4 identical tablets per day as follows: 2000mg/day: 4x500mg metformin 1000mg/day: 2x500mg metformin + 2x500mg placebo Placebo: 4x500mg placebo. Metformin will be titrated weekly from 500mg/day up to 2000mg/day over 4 weeks. Participants who do not tolerate the treatment will be allowed to remain in the study either in a lower dose treatment group, or receiving the structured lifestyle intervention only. Participants will not be actively told to what lifestyle intervention group they have been assigned and assessors for primary and secondary outcomes will be blinded to the lifestyle group allocation. The metformin/placebo treatment will be conducted in double blind.

Official Title
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Multimodal METformin and FINGER Lifestyle Intervention to Prevent Cognitive Impairment and Disability in Older Adults at Risk for Dementia: a Phase IIb Multi-national Randomised, Controlled Trial

Conditions
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Dementia, Cognitive Decline, Cognitive Impairment

Intervention / Treatment
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* Combination Product: FINGER 2.0 multidomain lifestyle-based intervention
* Other: Self-guided multidomain lifestyle intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Main inclusion criteria (all participants) Age 60-79 years. Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Risk Score ≥6 points. Cognitive performance at the mean level or slightly lower than expected for age according to local population norms based on the Montreal Cognitive Assessment (MoCA) test and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) verbal learning test. Proficiency in the local language (English, Finnish or Swedish) Inclusion criteria for metformin/placebo treatment (only for participants in the FINGER 2.0 multimodal lifestyle-based intervention arm) No diagnosed diabetes or known contraindications to metformin treatment. Elevated adiposity (BMI≥25 kg/m2 OR waist circumference > 102 cm in men and > 88 cm in women) OR mildly impaired fasting glucose (6.1-6.9 mmol/l). Exclusion Criteria: Main exclusion criteria (all participants) Dementia or substantial cognitive impairment (e.g., memory clinic referral needed as judged by the study physician). Current or past use of medications for Alzheimer's Disease or related diseases (e.g., cholinesterase inhibitors, memantine, aducanumab). Diminished decision-making capacity, not capable of consenting or completing study assessments, based on clinical judgement. Other known significant neurologic disease (including e.g., Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, brain tumour, progressive, supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma with persistent neurologic sequelae or known structural brain abnormalities). Any other condition affecting safe engagement in the intervention (e.g., malignant disease, major depression, symptomatic cardiovascular disease, revascularisation within the previous year). Severe loss of vision, hearing, or communicative ability; conditions preventing cooperation. Coincident participation in the active phase of another intervention trial. A member of the household already enrolled in the MET-FINGER trial Exclusion criteria for metformin/placebo treatment (only for participants in the FINGER 2.0 multimodal lifestyle-based intervention group) Use of metformin for any indication. History of intolerance to metformin used for any indication. Diabetes diagnosed or suspected at baseline (e.g., HbA1c≥6.5%, fasting glucose ≥7 mmol/l, or 2HPG≥11.1 mmol/l). Metformin contraindications, e.g., history/presence of known renal or liver disease, congestive heart failure, alcohol abuse, calculated Glomerular Filtration Rate<60 ml/min.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 79 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: Participants are initially randomized 1:1 to two parallel arms: self-guided multidomain lifestyle intervention FINGER 2.0 multidomain lifestyle-based intervention Participants in the FINGER 2.0 intervention who are eligible for metformin treatment will be further randomized 1:1:1 to either: metformin 2000mg/day metformin 1000mg/day placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Self-guided multidomain lifestyle intervention<br>In this group, participants will build their own healthy lifestyle program based on standard healthy lifestyle advice that they will receive at individual consultations with the study physician/nurse as part of the study visits, covering four main components (diet, physical activity, cognitive training, and cardiovascular/metabolic risk monitoring). The intervention duration is 2 years. | Other: Self-guided multidomain lifestyle intervention<br>* Participants build their own healthy lifestyle program based on standard healthy lifestyle advice on diet, physical activity, cognitive training and cardiovascular/metabolic risk<br>|
| Active Comparator: FINGER 2.0 multidomain lifestyle-based intervention<br>Within this group, participants will receive a structured intensive lifestyle intervention through individual consultations and group meeting sessions. Four main lifestyle components will be included (diet, physical activity, cognitive training, and cardiovascular/metabolic risk monitoring) as well as social interaction through the group meetings/sessions. In this group, participants eligible for metformin treatment will be further randomised to either: 2000mg/day 1000mg/day placebo. Metformin and placebo will be dispensed every 3 months, both administered orally. The intervention duration is 2 years | Combination Product: FINGER 2.0 multidomain lifestyle-based intervention<br>* Multimodal lifestyle-based precision prevention intervention, including: Optimized FINGER multidomain lifestyle intervention (diet, physical activity, cognitive training and cardiovascular/metabolic risk monitoring and social interaction) Metformin (Glucophage® XR)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognition, unit on a scale. | Composite z-score of an extended Neuropsychological Test Battery (NTB) adapted from the FINGER trial and including: Wechsler Memory Scale Revised (WMS-III, WMS-R) logical memory, immediate WMS-R logical memory, delayed WMS-R visual paired associates, immediate WMS-R visual paired associates, delayed WMS-R Digit Span, total Hopkins Verbal Learning Test (HVLT), learning HVLT, recall CERAD category fluency Category fluency (fruits and vegetables) Trail Making Test (TMT) A TMT B, shifting score B-A Stroop Test, shortened 40-stimulus version, condition 2 Stroop Test, condition 3, interference score 3 - 2 Wechsler Adult Intelligence Scale (WAIS) Digit Symbol Substitution Test (DSST). The z-score values range from -3 standard deviations to +3 standard deviations of the result distribution with higher score indicating better outcome. | Baseline, 12- and 24-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in individual cognitive domains, unit on a scale. | Composite z-scores for the: memory executive function processing speed domains that are included in the NTB used as measure for the primary outcome. The z-score values range from -3 standard deviations to +3 standard deviations of the result distribution with higher score indicating better outcome. | Baseline, 12- and 24-months | 
| Change in functioning level - Clinical Dementia Rating (CDR), unit on a scale | CDR Sum of Boxes (0-18), with lower score indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in functioning level - Katz index, unit on a scale | Activity of Daily Living, Katz Index. Self-reported questionnaire ranking the independence in six basic daily functions. For each activity, the participant is rated either dependent (0 points) or independent (1 point). The total score ranges 0-6 with a higher score indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in functioning level - Lawton-Brody scale, unit on a scale | Activity of Daily Living, Lawton-Brody Scale. Self-reported questionnaire assessing the level of functioning in eight daily activities necessary for living in the community. For each activity, the participant is rated either dependent (0 points) or independent (1 point). Score ranges 0-8, with a higher score indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in healthy lifestyle, unit on a scale. | Healthy Lifestyle Index, a composite score (range 0-24, with higher score indicating a better outcome) including self-reported data on diet, physical activity, smoking and alcohol, and cognitive/social activities. | Baseline, 12- and 24-months | 
| Change in systolic blood pressure, mmHg. | Lower systolic blood pressure indicates a better outcome. | Baseline, 12- and 24-months | 
| Change in diastolic blood pressure, mmHg. | Lower diastolic blood pressure indicates a better outcome. | Baseline, 12- and 24-months | 
| Change in Body Mass Index (BMI), kg/m2. | Calculated using baseline height, with lower BMI value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in waist circumference, cm. | Lower value indicates a better outcome, with lower waist circumference value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in waist-hip ratio, unit on a scale. | Values ranging up to 1 with lower waist/hip ratio value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in blood lipids - Total Cholesterol, mmol/L. | Measured from serum with lower cholesterol value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in blood lipids - HDL Cholesterol, mmol/L. | Measured from serum with cholesterol higher value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in blood lipids - LDL Cholesterol, mmol/L. | Measured from serum with lower cholesterol value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change blood triglycerides, mmol/L. | Measured from serum with lower triglycerides value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in plasma glucose, mmol/L | Measured from fasting blood sample, with lower glucose value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in glycated haemoglobin (HbA1c), % | Measured from fasting blood sample, with lower HbA1c value indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), unit on a scale. | Calculated using fasting plasma glucose and fasting serum insulin, with lower values indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in 2-hour plasma glucose, mmol/L. | Measured with Oral Glucose Tolerance Test, only in participants included in the metformin/placebo treatment, and with lower glucose values indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in dietary intake, unit on a scale. | FINGER Diet Index, with values ranging 0-9, and higher score indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in physical activity - weekly frequency, unit on a scale. | Self-reported number of sessions moderate-to-vigorous intensity exercise per week. Higher number of sessions indicate a better outcome. | Baseline, 12- and 24-months | 
| Change in physical activity - Minnesota questionnaire, unit on a scale. | Self-reported physical exercise in the previous two weeks, using a modified version of the Minnesota Leisure Time Physical Activity Questionnaire, as number of sessions and average duration for each of the activities listed in the questionnaire. Higher levels of physical activity indicate a better outcome. | Baseline, 12- and 24-months | 
| Change in physical activity - Actigraph, unit on a scale. | Objective measure of time spent carrying out physical activity using a hip accelerometer (ActiGraph model wGT3X-BT) that the participants will wear for 7 consecutive days. Higher levels of physical activity indicate better outcome. | Baseline, 12- and 24-months | 
| Change in physical functioning - Short Physical Performance Battery (SPPB), unit on a scale. | The SPPB is assessed in three domains: balance standing (score range: 0-4), chair standing (score range: 0-4), and gait speed (score range: 0-4). The total score (range: 0-12) is the sum of the three scores. Higher scores indicate a better outcome. | Baseline, 24-months | 
| Change in physical functioning - Hand-grip strength, kg | Measured using a hand-grip dynamometer, with higher measures indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in physical functioning -Timed 10-metre dual task, seconds. | The test measure the time needed to walk 10 metres while carrying out a cognitive task (e.g. naming letters of the alphabet), with shorter times indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in depressive symptoms, unit on a scale. | Center for Epidemiological Studies Depression scale. Values ranging 0-60, with lower scores indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in stress-related symptoms, unit on a scale | Perceived Stress Scale. Values ranging 0-40, with lower scores indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in sleep problems, unit on a scale | Insomnia Severity Index. Values ranging 0-28, with lower scores indicating a better outcome. | 2 years | 
| Change in health-related quality of life - Research And Development-36 (RAND-36), unit on a scale | The scale values are ranging 0-100, with higher scores indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in health-related quality of life - 15D-questionnaire, unit on a scale | The scale values range 0-1, with higher scores indicating a better outcome. | Baseline, 12- and 24-months | 
| Change in utilisation of health resources, unit on a scale | Number of e.g., hospitalization and doctors appointments, either self-reported and/or, if possible, from General Practitioners, and/or electronic health records of national healthcare registries. Lower use of healthcare resources indicates a better outcome. | Baseline, 12- and 24-months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dementia prevention, FINGER multidomain lifestyle intervention, Metformin, World-Wide FINGERs, Drug repurposing