Insulin Resistance and Mild Cognitive Impairment (MCI) in Older Chinese Adults With Pre-Diabetes and Diabetes: Cognitive Effects of Lifestyle Intervention and Metformin Treatment in a Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 105
- 试验地点
- 1
- 主要终点
- Primary efficacy endpoint (Cerebral Glucose Metabolic Rate)
研究概览
简要总结
Dementia (Alzheimer's Disease) is sometimes called "Type 3 Diabetes" because of the strong connection between Type 2 diabetes (a function of insulin resistance) with Dementia.
The investigators therefore hypothesize that Reducing Insulin Resistance using Intensive Lifestyle Intervention (Exercise and Weight loss) + Metformin Treatment in Prediabetic & diet-control-only Diabetic overweight and mildly cognitively impaired individuals 55 years or older would lead to better Cognitive Function (compared to standard care) after 2 years.
Subjects will be monitored and assessed using a battery of Cognitive and psychological tests and PET scans to demonstrate glucose utilization in the relevant areas of the brain.
This 3-year open-label study aims to recruit 360 subjects with 50% (180 subjects) randomized to receiving Intensive lifestyle intervention with Metformin (if diabetic) vs the other 50% who would receive only the usual standard level of care in the primary care setting.
详细描述
General Introduction In this trial, the drug to be studied is Metformin. It is an insulin-sensitizing biguanide which has long been used safely as an effective antidiabetic drug for patients with type II diabetes.
Rationale for the Study Purpose Dementia is a clinical syndrome due to multiple aetiologies, of which Alzheimer disease (AD) and Vascular Dementia (VaD) are the two most common. Dementia represents the advanced stage of a syndrome spectrum of cognitive impairment, an age-associated neurodegenerative condition that includes ageing related cognitive disorder (aka age-associated memory impairment or subject memory impairment, i.e. memory loss without other cognitive problems and are within normal limits given the person's age), and Mild Cognitive Impairment (MCI), a clinical entity that includes memory and cognitive impairment but no significant functional disability to meet threshold criteria for diagnosis of dementia. Of note, MCI is considered a prodromal state of dementia that increases the risk of subsequently developing dementia.
MCI can be classified into two main categories: (1) amnestic MCI and (2) non-amnestic MCI. Each MCI subtype can be further classified according to the presumed aetiology: degenerative; vascular; psychiatric; or traumatic.
- Amnestic MCI (aMCI, prominent memory impairment with possibly mild degrees of impairment in other cognitive domains),
- Non-amnestic MCI (non-aMCI, in which memory is largely unaffected but other domains of cognitive and behavioural functioning are impaired).
Currently available drugs approved for AD (anticholinesterases and Memantine) have limited efficacy and do not alter the pathophysiological basis of disease nor disease progression. No drugs are currently approved by regulatory authorities specifically for the treatment of MCI. Because treatments are less effective when the disease is far advanced, individuals with MCI at earlier stages of their illness are likely better candidates for clinical trials. Neuropathology-based studies of "clinically non-demented" individuals show high burdens of vascular and AD types of pathology. MCI may therefore be a pathologically-based preclinical or early clinical phase of dementia that is likely to progress to AD or VaD, and is hence an appropriate predementia syndrome for therapeutic intervention.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Chinese Singapore Citizen or Permanent Resident.
- •BMI of 23 or higher (Asian criteria for overweight and obese, Ministry of Health Recommendation, Singapore); and/or Waist Circumference: ≥ 90cm and ≥ 80cm for Chinese men and women respectively.
- •Prediabetes (if Not diabetic):
- •Impaired fasting glucose (IFG): (ADA criteria: fasting plasma glucose level from 5.6 mmol/L (100 mg/dL) to 6.9 mmol/L (125 mg/dL), and/or
- •Impaired glucose tolerance (IGT) (WHO and ADA criteria: two-hour glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol) on the 75-g oral glucose tolerance test,. and/or
- •HbA1C: 5.7- 6.4% (ADA criteria)
- •Type 2 Diabetes (if Not prediabetic) yet to be treated with anti-diabetic drug treatment ('on diet control only'), with HbA1c <8.0% OR Diabetics who have been taken off medication for =/> 1 year with HbA1c< 8.0% will be considered for recruitment.
- •If HbA1c is 8.0- 8.4% at any follow-up visit, then try diet and lifestyle control and repeat at next visit (i.e. 3 months later). If 2 consecutive repeat HbA1c readings are still 8.0-8.4% or if subjects choose to start on or increase medication for diabetes, then take out of study and start medication.
- •If HbA1c =/>8.5% at any time after Recruitment, take out of study and start medication.
- •Mild Cognitive Impairment:
- •The individual is neither normal nor demented;
- •There is evidence of cognitive deterioration, shown by either objectively measured decline over time or subjective report of decline by self or informant in conjunction with objective cognitive deficits; and
- •Activities of daily life are preserved and complex instrumental functions are either intact or minimally impaired.
- •This will be operationalized in the study as:
- •A Subjective memory or cognitive complaint by the patient and/or by the caregiver
- •Objective cognitive deficit documented by performance on a battery of multiple-domain neuropsychological tests (See below): a score that is 1.0 SD or more below age- and education-adjusted local norms
- •aMCI: Deficit in delayed recall subtest of the Rey Auditory Verbal Learning Test (RAVLT) and Story Memory test
- •mdMCI: Deficit in language, executive function, visuospatial/constructional ability, block design, and attention.
- •Generally intact Activities of Daily Living as measured by Instrumental and Basic Activities of Daily Living (IADL and BADL).
- •No dementia:
排除标准
- •Contraindications to Metformin treatment: Creatinine of > 150umol/L, history of decompensated liver disease, liver cirrhosis, or unexplained elevated hepatic transaminases (ALT or AST >3x Upper Limit of Normal; Upper Limits as accepted by SingHealth Polyclinics as 66 U/L for ALT and 42 U/L). This contraindication would not affect Subjects with a history of high baseline ALT and/or AST which have been evaluated by a Hepatologist to be due to Non-alcoholic Fatty Liver Disease without cirrhosis.,
- •Severe Neuro-Musculoskeletal and Sensory Disabilities
- •Severe Psychiatric disorders (eg; alcohol abuse, severe depression, schizophrenia, bipolar disorder)
- •Illnesses that seriously reduce life expectancy or ability to participate in the trial
- •Congestive heart failure (New York Heart Association cardiac status classes 2, 3 or 4), Myocardial infarction or Coronary artery Bypass surgery or percutaneous coronary intervention within the past 6 months, Cardiac Arrhythmias, Severe Hypertension.
- •Concurrent use or recent use (within 1 week or 5 half lives of the drug whichever is longer) of drugs with anticholinesterase, sedating or central nervous system (CNS) side effects: antispasmodics, antiemetics, antidiarrhoeals, antihistamines, hypnotics, antidepressants, antipsychotics, bronchodilators.
- •Concurrent use of drugs (for >4 consecutive weeks) or use of drugs within 12 weeks of screening) that are known to adversely affect glucose tolerance and its interpretation: .
- •History of Hypersensitivity to any of the Study Drug or to Drugs of similar chemical classes
- •Use of an Investigative Drug within 30 days or 5 half-lives of the drug whichever is longer
- •Potentially Unreliable and/or judged by the investigator to be Unsuitable for the study.
研究组 & 干预措施
Lifestyle Intervention and Metformin
Intensive lifestyle interventions at Lifestyle Intervention Centres and Metformin (if Diabetic)
干预措施: Metformin (Drug)
Lifestyle Intervention and Metformin
Intensive lifestyle interventions at Lifestyle Intervention Centres and Metformin (if Diabetic)
干预措施: Intensive Lifestyle Intervention (Behavioral)
Standard Level of Care
Standard lifestyle recommendations for the Control groups
干预措施: Standard LIfestyle Recommendation (Behavioral)
结局指标
主要结局
Primary efficacy endpoint (Cerebral Glucose Metabolic Rate)
时间窗: 2 years
Change in Cerebral glucose metabolic rate \& MRI Measures of Cerebral Volumetric and functional changes and white matter structural and functional connectivity as measured by Fluorodeoxyglucose Positron Emission Tomography \& 3T MRI (FDG-PET/MRI) scans at Baseline and at 2 years.
Primary cognitive endpoint (Neuropsychological Performance)
时间窗: 2 years
Change in Composite z-score of memory and multi-domain non-amnestic cognitive test performance using a Neuropsychological Assessment performed at Baseline and at 2 years.
次要结局
- Secondary clinical endpoints Cognitive Instrumental Activities of Daily Living Scale(2 years)
- Secondary clinical endpoints Montreal Cognitive Assessment scale(2 years)
- Secondary adherence endpoints Body Mass Index(2 years)
- Secondary adherence endpoints Waist Circumference(2 years)
- Secondary adherence endpoints Fasting plasma glucose(2 years)
- Secondary clinical endpoints Subjective Memory and Cognitive Complaint (SMCC(2 years)
- Secondary adherence endpoints Lifestyle Intervention (Change in Weight)(2 years)
- Secondary clinical endpoints Basic Activities of Daily Liver (ADL)(2 years)
- Secondary clinical endpoints Global Clinical Dementia Rating Sum of Boxes(2 years)
- Secondary clinical endpoints Mini-Mental State Examination(2 years)
- Secondary adherence endpoints fasting plasma insulin(2 years)
- Secondary adherence endpoints Homeostatic Model Assessment (HOMA)(2 years)
- Secondary adherence endpoints Glycated Hemoglobin (HbA1c)(2 years)
- Secondary adherence endpoints Fasting Lipids(2 years)
研究者
Andrew Wee Kien Han
Family Physician- SITE Investigator
SingHealth Polyclinics