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.
- Trial ID
- 2022-500438-27-01
- Protocol
- 21CX6667
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the effect of the 24-month **FINGER 2.0** multimodal lifestyle-based intervention compared to a self-guided multimodal intervention on changes in cognition in an **APOE ε4**-enriched older population at increased risk for dementia. This is clinically relevant as it aims to prevent cognitive decline and dementia in older adults who are currently free from substantial cognitive impairment.
Secondary objectives include assessing the impact of the 24-month FINGER 2.0 intervention versus the self-guided intervention on various health and lifestyle factors:
- Changes in cognitive domains such as memory, executive function, and processing speed.
- Alterations in functioning level and healthy lifestyle.
- Modifications in cardiovascular and metabolic risk factors and markers, as well as cardiovascular morbidity and mortality.
- Adjustments in dietary intake and physical activity.
- Variations in physical functioning, depressive symptoms, stress-related symptoms, and sleep problems.
- Improvements in health-related quality of life and utilization of health resources.
Participants
The clinical trial involves a total of **300 participants** who are older adults aged between **60-79 years**. The study population includes both **male and female** subjects who are free from dementia and substantial cognitive impairment but possess risk factors for dementia. Participants were selected based on a **CAIDE Dementia Risk Score** of 6 or more points and cognitive performance at or slightly below the mean level for their age, as determined by the MoCA test and the CERAD verbal learning test. All participants are proficient in English, Finnish, or Swedish. The trial does not include a vulnerable population. Lifestyle considerations such as elevated adiposity or mildly impaired fasting glucose are relevant for those in the metformin/placebo group, provided they have no diagnosed diabetes or contraindications to metformin treatment. The intervention aims to prevent cognitive decline through a structured multimodal lifestyle-based approach.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled study to evaluate the efficacy of a 24-month multimodal lifestyle-based intervention combined with **metformin hydrochloride** in preventing cognitive decline in older adults at risk for dementia. The trial will include a double-blind approach for the metformin/placebo group, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The study will involve participants aged 60-79 years with a CAIDE Dementia Risk Score of 6 or more, who are dementia-free and have cognitive performance at or slightly below the mean level for their age. The trial will exclude individuals with diagnosed diabetes or known contraindications to metformin treatment.
The trial will commence with an inclusion (screening) visit to assess eligibility based on the principal inclusion criteria, including cognitive assessments using the MoCA test and the CERAD verbal learning test. Participants will be randomly assigned to either the active arm, receiving the structured multimodal intervention, or the control arm, receiving a self-guided multimodal intervention. The primary endpoint is the change in cognition measured by a composite z-score of an extended Neuropsychological Test Battery (NTB). Secondary endpoints include various cognitive and health-related measures such as memory, executive function, processing speed, and lifestyle indices.
Participants will be involved in the study for a total duration of 24 months, with regular follow-up visits scheduled to monitor progress and adherence to the intervention. These visits will include assessments of cognitive function, physical health, and lifestyle factors. The end-of-study visit will occur at the conclusion of the 24-month period, where final assessments will be conducted to evaluate the long-term effects of the intervention. Conditions that may lead to early termination from the study include the development of any exclusion criteria, adverse events, or withdrawal of consent by the participant.
Treatment
The clinical trial involves the administration of **METFORMIN HYDROCHLORIDE**, a biguanide with antihyperglycaemic effects, which lowers both basal and post-prandial plasma glucose levels. The pharmaceutical form of this experimental medication is **prolonged release tablets**. The active substance, **metformin hydrochloride**, is administered orally. The maximum daily dose is 2000 mg, with a total maximum dose of 2000 mg over the treatment period. The treatment duration is set for a maximum of 24 months. The medication is not formulated for pediatric use and is intended for adult participants at risk for dementia. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.
The study also includes a **placebo** group, where participants will receive a placebo manufactured to match the specifications of Glucophage® XR 500. This placebo is identical to the investigational medicinal product (IMP) in all respects, except for the absence of the active substance. The placebo is administered in the same pharmaceutical form and route as the experimental medication, ensuring blinding of the study. The placebo serves as a comparator to evaluate the efficacy of the experimental treatment in preventing cognitive impairment and disability in older adults at risk for dementia.
Efficacy
Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is the composite z-score of an extended Neuropsychological Test Battery (NTB) adapted from the FINGER trial. This will evaluate changes in cognitive function in the study population. Secondary endpoints include composite z-scores for NTB memory, executive function, and processing speed domains, as well as the Clinical Dementia Rating Sum of Boxes and Instrumental Activities of Daily Living. Additional secondary endpoints involve the Healthy Lifestyle Index, which is a composite score based on exercise, diet, lifestyle cardiovascular risk factors, and social and cognitive activity. Other parameters include **BMI**, waist, waist/hip ratio, blood pressure, lipid profile, glucose metabolism, and incident cardiovascular disease.
Further assessments will be made using the FINGER healthy diet index, nutrients and food intake, self-reported and objectively measured levels of physical activity, and the Short Physical Performance Battery. Hand grip strength and the timed 10-meter dual-task test will also be evaluated. Psychological and quality of life measures will be assessed using the Center for Epidemiological Studies-Depression Scale, Perceived Stress Scale, Insomnia Severity Index, and RAND36 and 15D scales for health-related quality of life. Data on the utilization of healthcare resources will be collected through self-reports and register data. These efficacy parameters will be measured and analyzed at various timepoints throughout the trial to determine the impact of the interventions on cognitive impairment and disability in older adults at risk for dementia.
Inclusion and Exclusion Criteria
Inclusion Criteria
- For all: Age 60-79 years
- For all: CAIDE Dementia Risk Score ≥6 points
- For all: Cognitive performance at the mean level or slightly lower than expected for age according to local population norms based on the MoCA test and the CERAD verbal learning test.
- For all: Proficiency in the local language (English, Finnish or Swedish)
- For metformin/placebo group: No diagnosed diabetes or known contraindications to metformin treatment.
- For metformin/placebo group: 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
- For all: Dementia or substantial cognitive impairment (e.g., memory clinic referral needed as judged by the study physician).
- For all: Current or past use of medications for AD or related diseases (e.g., cholinesterase inhibitors, memantine, aducanumab).
- For all: Diminished decision-making capacity, not capable of consenting or completing study assessments, based on clinical judgement.
- For all: 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).
- For all: Any other condition affecting safe engagement in the intervention (e.g., malignant disease, major depression, symptomatic cardiovascular disease, revascularisation within the previous year)
- For all: Severe loss of vision, hearing, or communicative ability; conditions preventing cooperation
- For all: Coincident participation in the active phase of another intervention trial.
- For all: A member of the household already enrolled in the MET-FINGER trial
- For metformin/placebo group: Use of metformin for any indication.
- For metformin/placebo group: History of intolerance to metformin used for any indication.
- For metformin/placebo group: Diabetes diagnosed or suspected at baseline (e.g., HbA1c≥6.5%, fasting glucose ≥7 mmol/l, or 2HPG≥11.1 mmol/l).
- For metformin/placebo group: Hypersensitivity to metformin or to any of the excipients or placebo compounds.
- For metformin/placebo group: Metformin contraindications, e.g., history/presence of known renal or liver disease, congestive heart failure, alcohol abuse, calculated GFR<60 ml/min.
- For metformin/placebo group: Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)
- For metformin/placebo group: Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.
- For metformin/placebo group: Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
- For metformin/placebo group: Women of childbearing potential (WOCBP)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Finland | Not Recruiting | 31 Dec 2022 | 200 |
 Sweden | Not Recruiting | 31 Dec 2022 | 100 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
The placebo will be manufactured based on the Glucophage® XR 500 specifications to be identical to the IMP in all respects, except that for the lack of active substance. | Placebo | N/A | — | — | — | N/A |
METFORMIN HYDROCHLORIDE | Test | — | ORAL | 2000 | 24 | SUB03200MIG |