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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cognitive Impairment; Dementia; Cognitive Decline
• Intervention / Treatment: Other: Self-guided multidomain lifestyle intervention; Combination product: FINGER 2.0 multidomain lifestyle-based intervention

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Miia Kivipelto, MD, PhD; Phone Number: +46(0)739940922; Email: miia.kivipelto@ki.se
• Study Contact Backup: Name: Alina Solomon, MD, PhD; Phone Number: +358(0)403552015; Email: alina.solomon@uef.fi

Study Locations

• Finland
  • Helsinki, Finland, FI-00271
    • Recruiting
    • Finnish Institute of Health and Welfare - THL
    • Contact: Tiia Ngandu; Phone Number: +358(0)405241759; Email: tiia.ngandu@thl.fi
• Sweden
  • Solna, Sweden, 171 64
    • Recruiting
    • Karolinska Institutet
    • Contact: Francesca Mangialasche; Phone Number: +46(0)703019466; Email: francesca.mangialasche@ki.se
• United Kingdom
  • London, United Kingdom, W6 8RP
    • Recruiting
    • Ageing Epidemiology Research Unit, Imperial College London
    • Contact: Miia Kivipelto; Phone Number: +46739940922; Email: miia.kivipelto@ki.se
    • Contact: Naia Headland-Vanni; Phone Number: +442033117290; Email: n.headland-vanni@imperial.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Main inclusion criteria (all participants)

  1. Age 60-79 years.
  2. Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Risk Score ≥6 points.
  3. 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.
  4. 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)

  1. No diagnosed diabetes or known contraindications to metformin treatment.
  2. 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)

  1. Dementia or substantial cognitive impairment (e.g., memory clinic referral needed as judged by the study physician).
  2. Current or past use of medications for Alzheimer's Disease or related diseases (e.g., cholinesterase inhibitors, memantine, aducanumab).
  3. Diminished decision-making capacity, not capable of consenting or completing study assessments, based on clinical judgement.
  4. 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).
  5. Any other condition affecting safe engagement in the intervention (e.g., malignant disease, major depression, symptomatic cardiovascular disease, revascularisation within the previous year).
  6. Severe loss of vision, hearing, or communicative ability; conditions preventing cooperation.
  7. Coincident participation in the active phase of another intervention trial.
  8. 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)

  1. Use of metformin for any indication.
  2. History of intolerance to metformin used for any indication.
  3. Diabetes diagnosed or suspected at baseline (e.g., HbA1c≥6.5%, fasting glucose ≥7 mmol/l, or 2HPG≥11.1 mmol/l).
  4. Metformin contraindications, e.g., history/presence of known renal or liver disease, congestive heart failure, alcohol abuse, calculated Glomerular Filtration Rate<60 ml/min.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Self-guided multidomain lifestyle intervention; 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; Participants build their own healthy lifestyle program based on standard healthy lifestyle advice on diet, physical activity, cognitive training and cardiovascular/metabolic risk
Active Comparator: FINGER 2.0 multidomain lifestyle-based intervention; 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; 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)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory - potential interactions between metformin and lifestyle changes	Differences between metformin/placebo treatment groups will be assessed for the lifestyle changes as described for the secondary outcomes.	Baseline, 12- and 24-months
Exploratory - potential disease-modifying effects - Amyloid β42/40 ratio, unit on a scale	Calculated based on blood levels of Amyloid β42 and 40. Possible values range from a minimum of 0, with higher Amyloid β42/40 ratio indicating a better outcome.	Baseline and 24-months
Exploratory - potential disease-modifying effects - Neurofilament light chain protein, pg/ml	Blood levels of neurofilament light chain protein range from a minimum of 0, with lower levels indicating a better outcome.	Baseline and 24-months
Exploratory - potential disease-modifying effects - p-tau 181, ng/ul	Blood levels of p-tau 181 range from a minimum of 0, with lower levels indicating a better outcome.	Baseline and 24-months
Exploratory - potential disease-modifying effects - p-tau 231, ng/ul	Blood levels of p-tau 231 range from a minimum of 0, with lower levels indicating a better outcome.	Baseline and 24-months
Exploratory - feasibility of the metformin + lifestyle combination - Adherence to the lifestyle intervention.	Based on consultations and group meetings attended, as well as lifestyle changes implemented. Possible values ranging from a minimum of 0, with higher adherence indicating a better outcome.	24-months
Exploratory - feasibility of the metformin + lifestyle combination - Adherence to target metformin dose, unit on a scale	Proportion of participants in each arm of the metformin/placebo treatment who complete the 2-year intervention period on the initially assigned drug dose. Values range 0-1, with higher proportion indicating a better outcome.	24-months
Exploratory - feasibility of the metformin + lifestyle combination - Retention rate, unit on a scale	Proportion of randomised participants in each group who complete the 2-year intervention period. Values range 0-1, with higher proportion indicating a better outcome.	24-months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Karolinska University Hospital; Karolinska Institutet; Merck KGaA, Darmstadt, Germany; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Region Stockholm; Finnish Institute for Health and Welfare; Alzheimerfonden; Fingers Brain Health Institute
• Investigators: Principal Investigator: Tiia Ngandu, MD, PhD, Finnish Institute of Health and Welfare, Finland; Principal Investigator: Francesca Mangialasche, MD, PhD, Karolinska Institutet

Publications and helpful links

General Publications

• Ngandu 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.
• Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H, Baker L, Belleville S, Brodaty H, Brucki SM, Calandri I, Caramelli P, Chen C, Chertkow H, Chew E, Choi SH, Chowdhary N, Crivelli L, Torre R, Du Y, Dua T, Espeland M, Feldman HH, Hartmanis M, Hartmann T, Heffernan M, Henry CJ, Hong CH, Hakansson K, Iwatsubo T, Jeong JH, Jimenez-Maggiora G, Koo EH, Launer LJ, Lehtisalo J, Lopera F, Martinez-Lage P, Martins R, Middleton L, Molinuevo JL, Montero-Odasso M, Moon SY, Morales-Perez K, Nitrini R, Nygaard HB, Park YK, Peltonen M, Qiu C, Quiroz YT, Raman R, Rao N, Ravindranath V, Rosenberg A, Sakurai T, Salinas RM, Scheltens P, Sevlever G, Soininen H, Sosa AL, Suemoto CK, Tainta-Cuezva M, Velilla L, Wang Y, Whitmer R, Xu X, Bain LJ, Solomon A, Ngandu T, Carrillo MC. World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia. Alzheimers Dement. 2020 Jul;16(7):1078-1094. doi: 10.1002/alz.12123. Epub 2020 Jul 5.
• Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther. 2016 Jul 30;8(1):23. doi: 10.1186/s13195-016-0188-8.

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2023
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): June 28, 2027

Study Registration Dates

• First Submitted: October 26, 2021
• First Submitted That Met QC Criteria: November 4, 2021
• First Posted (Actual): November 5, 2021

Study Record Updates

• Last Update Posted (Actual): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Metformin; Drug repurposing; Dementia prevention; FINGER multidomain lifestyle intervention; World-Wide FINGERs
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Dementia; Cognitive Dysfunction
• Other Study ID Numbers: 21CX6667; 2021-005213-14 (EudraCT Number); 2022-500438-27-01 (Other Identifier: EMA (EU-CT number))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The MET-FINGER Steering Committee and Management Group are open to requests from external researchers for data collected in this study. Applicants will be asked to submit a study protocol, including the research question, planned analysis, and data required. Committee will evaluate this plan (i.e., relevance of the research question, suitability of data, quality of proposed analyses, planned/ongoing MET-FINGER analyses, and other matters) on a case-by-case basis and provide the data or reject the request. Shared data will encompass the data dictionary and de-identified data only. Any analysis will be conducted in collaboration with the MET-FINGER Management Group. Access is subject to the MET-FINGER legal framework. An access agreement will be prepared and signed by both parties.
• IPD Sharing Time Frame: The trial Steering Committee and Management Group will consider applications for data after the trials results have been published and data will be made available according to the terms of the access agreement.
• IPD Sharing Access Criteria: As described above in the Plan Description.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No