Clinical trial NCT05109169: METformin and FINGER Intervention to Prevent Cognitive Impairment and Disability in Older Adults at Risk for Dementia
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cognitive Decline
Cognitive Impairment
Dementia
Keywords: Dementia prevention
FINGER multidomain lifestyle intervention
Metformin
World-Wide FINGERs
Drug repurposing
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Alzheimer's Association
name: Alzheimer's Drug Discovery Foundation
name: Alzheimerfonden
name: Region Stockholm
name: Merck KGaA, Darmstadt, Germany
name: Finnish Institute for Health and Welfare
name: Fingers Brain Health Institute
name: Karolinska University Hospital
name: Karolinska Institutet
First posted: 2021-11-05
Enrollment: 600
Sex: ALL
Minimum age (years): 60
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: PREVENTION

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in cognition, unit on a scale.
timeFrame: Baseline, 12- and 24-months
Secondary outcomes:
measure: Change in individual cognitive domains, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in functioning level - Clinical Dementia Rating (CDR), unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in functioning level - Katz index, unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in functioning level - Lawton-Brody scale, unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in healthy lifestyle, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in systolic blood pressure, mmHg.
timeFrame: Baseline, 12- and 24-months
measure: Change in diastolic blood pressure, mmHg.
timeFrame: Baseline, 12- and 24-months
measure: Change in Body Mass Index (BMI), kg/m2.
timeFrame: Baseline, 12- and 24-months
measure: Change in waist circumference, cm.
timeFrame: Baseline, 12- and 24-months
measure: Change in waist-hip ratio, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in blood lipids - Total Cholesterol, mmol/L.
timeFrame: Baseline, 12- and 24-months
measure: Change in blood lipids - HDL Cholesterol, mmol/L.
timeFrame: Baseline, 12- and 24-months
measure: Change in blood lipids - LDL Cholesterol, mmol/L.
timeFrame: Baseline, 12- and 24-months
measure: Change blood triglycerides, mmol/L.
timeFrame: Baseline, 12- and 24-months
measure: Change in plasma glucose, mmol/L
timeFrame: Baseline, 12- and 24-months
measure: Change in glycated haemoglobin (HbA1c), %
timeFrame: Baseline, 12- and 24-months
measure: Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in 2-hour plasma glucose, mmol/L.
timeFrame: Baseline, 12- and 24-months
measure: Change in dietary intake, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in physical activity - weekly frequency, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in physical activity - Minnesota questionnaire, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in physical activity - Actigraph, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in physical functioning - Short Physical Performance Battery (SPPB), unit on a scale.
timeFrame: Baseline, 24-months
measure: Change in physical functioning - Hand-grip strength, kg
timeFrame: Baseline, 12- and 24-months
measure: Change in physical functioning -Timed 10-metre dual task, seconds.
timeFrame: Baseline, 12- and 24-months
measure: Change in depressive symptoms, unit on a scale.
timeFrame: Baseline, 12- and 24-months
measure: Change in stress-related symptoms, unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in sleep problems, unit on a scale
timeFrame: 2 years
measure: Change in health-related quality of life - "Research And Development-36" (RAND-36), unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in health-related quality of life - "15D-questionnaire", unit on a scale
timeFrame: Baseline, 12- and 24-months
measure: Change in utilisation of health resources, unit on a scale
timeFrame: Baseline, 12- and 24-months
Other outcomes:
measure: Exploratory - potential interactions between metformin and lifestyle changes
timeFrame: Baseline, 12- and 24-months
measure: Exploratory - potential disease-modifying effects - Amyloid β42/40 ratio, unit on a scale
timeFrame: Baseline and 24-months
measure: Exploratory - potential disease-modifying effects - Neurofilament light chain protein, pg/ml
timeFrame: Baseline and 24-months
measure: Exploratory - potential disease-modifying effects - p-tau 181, ng/ul
timeFrame: Baseline and 24-months
measure: Exploratory - potential disease-modifying effects - p-tau 231, ng/ul
timeFrame: Baseline and 24-months
measure: Exploratory - feasibility of the metformin + lifestyle combination - Adherence to the lifestyle intervention.
timeFrame: 24-months
measure: Exploratory - feasibility of the metformin + lifestyle combination - Adherence to target metformin dose, unit on a scale
timeFrame: 24-months
measure: Exploratory - feasibility of the metformin + lifestyle combination - Retention rate, unit on a scale
timeFrame: 24-months
Locations:
city: Helsinki
country: Finland
facility: Finnish Institute of Health and Welfare - THL
city: Solna
country: Sweden
facility: Karolinska Institutet
city: London
country: United Kingdom
facility: Ageing Epidemiology Research Unit, Imperial College London
Study officials:
affiliation: Finnish Institute of Health and Welfare, Finland
name: Tiia Ngandu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska Institutet
name: Francesca Mangialasche, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.