A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol
Authors: Barbera Mariagnese , Lehtisalo Jenni , Perera Dinithi , Aspö Malin , Cross Mary , De Jager Loots Celeste A. , Falaschetti Emanuela , Friel Naomi , Luchsinger José A. , Gavelin Hanna Malmberg , Peltonen Markku , Price Geraint , Neely Anna Stigsdotter , Thunborg Charlotta , Tuomilehto Jaakko , Mangialasche Francesca , Middleton Lefkos , Ngandu Tiia , Solomon Alina , Kivipelto Miia ,   on behalf of the MET-FINGER study team, Adeleke Seliat Adebanke , Arvidsson Clara , Barton Isobel , Bas Mehmet , Cosby Katrina , Crispin Jennifer , Dunn Lucy , Durkina Margarita , Elebring Ottilia , Ford Jamie , Giannakopoulou Parthenia , Gilkes Hanne , Graham Hannah , Hagman Göran , Hall Ruby , Hallinder Helena , Haqqee Arzish , Hartmanis Maris , Hemiö Katri , Istvánfyová Zuzana , Kafetsouli Dimitra , Lakey Kristina , Lehtimäki Saara , Lindström Lotta , MacDonald Peter , Mäkelä Aaro , McGinn-Summers Stefan , Meius Carolina , Mirza Amnah , Oesterling Christine , Ojala Joanna , Olawale Abdulwarrith , Ramanath Isabela , Roitto Hanna-Maria , Sahib Bilal , Singh Shonella , Sundell Maria , Taylor Shannon , Tharumaratnam Devika , Uusimäki Kerttu , Vaarala Johanna , Voutilainen Heta , Åsander Jessica 
Published: January 2024

Abstract
Background
Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence).
MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia.

Methods
MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes.
The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.

Conclusion
MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.

Trial registration
ClinicalTrials.gov (NCT05109169).