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

Dementia Clinical Trial

— MET-FINGER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05109169
• Other study ID #: 21CX6667
• Secondary ID: 2021-005213-1420
• Status: Recruiting
• Phase: Phase 2
• Start date: January 25, 2023
• Est. completion date: June 28, 2027

Study information

• Verified date: February 2024
• Source: Imperial College London
• Contact: Miia Kivipelto, MD, PhD
• Phone: +46(0)739940922
• Email: miia.kivipelto[@]ki.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: June 28, 2027
• Est. primary completion date: February 28, 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 79 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cognitive Decline
• Cognitive Dysfunction
• Cognitive Impairment
• Dementia

Intervention

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)

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

Locations

Country	Name	City	State
Finland	Finnish Institute of Health and Welfare - THL	Helsinki
Sweden	Karolinska Institutet	Solna
United Kingdom	Ageing Epidemiology Research Unit, Imperial College London	London

Sponsors (10)

Lead Sponsor	Collaborator
Imperial College London	Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Alzheimerfonden, Fingers Brain Health Institute, Finnish Institute for Health and Welfare, Karolinska Institutet, Karolinska University Hospital, Merck KGaA, Darmstadt, Germany, Region Stockholm

Countries where clinical trial is conducted

Finland,  Sweden,  United Kingdom, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Exploratory - potential disease-modifying effects - Amyloid ß42/40 ratio, unit on a scale	Calculated based on blood levels of Amyloid ß42 and 40. Possible values range from a minimum of 0, with higher Amyloid ß42/40 ratio indicating a better outcome.	Baseline and 24-months
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in systolic blood pressure, mmHg.	Lower systolic blood pressure indicates a better outcome.	Baseline, 12- and 24-months
Secondary	Change in diastolic blood pressure, mmHg.	Lower diastolic blood pressure indicates a better outcome.	Baseline, 12- and 24-months
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in blood lipids - Total Cholesterol, mmol/L.	Measured from serum with lower cholesterol value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	Change in blood lipids - HDL Cholesterol, mmol/L.	Measured from serum with cholesterol higher value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	Change in blood lipids - LDL Cholesterol, mmol/L.	Measured from serum with lower cholesterol value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	Change blood triglycerides, mmol/L.	Measured from serum with lower triglycerides value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	Change in plasma glucose, mmol/L	Measured from fasting blood sample, with lower glucose value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	Change in glycated haemoglobin (HbA1c), %	Measured from fasting blood sample, with lower HbA1c value indicating a better outcome.	Baseline, 12- and 24-months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in sleep problems, unit on a scale	Insomnia Severity Index. Values ranging 0-28, with lower scores indicating a better outcome.	2 years
Secondary	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
Secondary	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
Secondary	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