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Insulin Resistance and Mild Cognitive Impairment (IRMCI) Study (IRMCI)

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ClinicalTrials.gov Identifier: NCT02409238
Recruitment Status : Unknown
Verified March 2016 by Andrew Wee Kien Han, SingHealth Polyclinics.
Recruitment status was:  Recruiting
First Posted : April 6, 2015
Last Update Posted : March 31, 2016
Sponsor:
Collaborators:
National University, Singapore
Singapore General Hospital
Changi General Hospital
National University Hospital, Singapore
Singapore Clinical Research Institute
Agency for Science, Technology and Research
Khoo Teck Puat Hospital
Duke-NUS Graduate Medical School
Information provided by (Responsible Party):
Andrew Wee Kien Han, SingHealth Polyclinics

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Insulin Resistance Diabetes Mellitus, Type 2 Drug: Metformin Behavioral: Intensive Lifestyle Intervention Behavioral: Standard LIfestyle Recommendation Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : April 2015
Estimated Primary Completion Date : December 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Lifestyle Intervention and Metformin
Intensive lifestyle interventions at Lifestyle Intervention Centres and Metformin (if Diabetic)
Drug: Metformin
Metformin dosage schedule: 250 mg thrice a day titrated from 250 mg once a day. Patients will first be started on Metformin 250 mg once a day with meals, and the dose increased to 250 mg twice a day at Day 8, to 250 mg three times a day at Day 15, subject to reports of poor tolerance of gastrointestinal symptoms or other side effects.

Behavioral: Intensive Lifestyle Intervention

The intensive lifestyle interventions for the Active Intervention groups will be done at the Lifestyle Intervention Centres. The aim would to achieve and maintain a weight reduction of at least 7 percent of initial body weight through a healthy reduced-calorie, low-fat diet and engagement in physical activity of moderate intensity for at least 150 minutes per week.

This will be accomplished through a programme of individualized fitness assessment and exercise prescription for cardiovascular, strength and functional training that is standardized across study sites and facilities. The programme comprises an initial 32 sessions (2 times weekly) for supervised gym workout over 16 weeks, followed by maintenance programme of regular unsupervised exercises.


Active Comparator: Standard Level of Care
Standard lifestyle recommendations for the Control groups
Behavioral: Standard LIfestyle Recommendation
The standard lifestyle recommendations for the Control groups are in the form of standard diabetic education pamphlets and a 20-to-30-minute individual session that emphasizes the importance of a healthy lifestyle to reduce their weight and to increase their physical activity. Activity will be monitored using a pedometer.




Primary Outcome Measures :
  1. Primary efficacy endpoint (Cerebral Glucose Metabolic Rate) [ Time Frame: 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.

  2. Primary cognitive endpoint (Neuropsychological Performance) [ Time Frame: 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.


Secondary Outcome Measures :
  1. Secondary clinical endpoints Subjective Memory and Cognitive Complaint (SMCC [ Time Frame: 2 years ]
    Change in Subjective Memory and Cognitive Complaint (SMCC) as measured at baseline and at 2 years.

  2. Secondary clinical endpoints Basic Activities of Daily Liver (ADL) [ Time Frame: 2 years ]
    Change in Basic Activities of Daily Liver (ADL) as measured at baseline and at 2 years.

  3. Secondary clinical endpoints Cognitive Instrumental Activities of Daily Living Scale [ Time Frame: 2 years ]
    Change in Cognitive Instrumental Activities of Daily Living Scale (Cog-IADL) as measured at baseline and at 2 years.

  4. Secondary clinical endpoints Global Clinical Dementia Rating Sum of Boxes [ Time Frame: 2 years ]
    Change in Global Clinical Dementia Rating Sum of Boxes (version with Informant and version without need for Informant- CDR-SB) as measured at baseline and at 2 years.

  5. Secondary clinical endpoints Mini-Mental State Examination [ Time Frame: 2 years ]
    Change in Mini-Mental State Examination [MMSE]as measured at baseline and at 2 years.

  6. Secondary clinical endpoints Montreal Cognitive Assessment scale [ Time Frame: 2 years ]
    Change in Montreal Cognitive Assessment scale [MoCA] as measured at baseline and at 2 years.

  7. Secondary adherence endpoints fasting plasma insulin [ Time Frame: 2 years ]
    Markers of lowered insulin resistance (Change in fasting plasma insulin) as measured at baseline and at 2 years.

  8. Secondary adherence endpoints Homeostatic Model Assessment (HOMA) [ Time Frame: 2 years ]
    Markers of lowered insulin resistance [Change in Homeostatic Model Assessment (HOMA)] as measured at baseline and at 2 years.

  9. Secondary adherence endpoints Lifestyle Intervention (Change in Weight) [ Time Frame: 2 years ]
    Lifestyle Intervention (Change in Weight) as measured at baseline and at 2 years.

  10. Secondary adherence endpoints Body Mass Index [ Time Frame: 2 years ]
    Lifestyle Intervention [Change in Body Mass Index (BMI)] as measured at baseline and at 2 years.

  11. Secondary adherence endpoints Waist Circumference [ Time Frame: 2 years ]
    Lifestyle Intervention (Change in Waist Circumference) as measured at baseline and at 2 years.

  12. Secondary adherence endpoints Fasting plasma glucose [ Time Frame: 2 years ]
    Glycemic Control (Change in Fasting plasma glucose) as measured at baseline and at 2 years.

  13. Secondary adherence endpoints Glycated Hemoglobin (HbA1c) [ Time Frame: 2 years ]
    Glycemic Control [Change in Glycated Hemoglobin (HbA1c)] as measured at baseline and at 2 years.

  14. Secondary adherence endpoints Fasting Lipids [ Time Frame: 2 years ]
    Metabolic control [Change in Fasting Lipids (total cholesterol, HDL-Chol, LDL-Chol, triglycerides)] as measured at baseline and at 2 years.



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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Chinese Singapore Citizen or Permanent Resident.
  2. 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.
  3. 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)
  4. 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.
  5. 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:

Exclusion Criteria:

  1. 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.,
  2. Severe Neuro-Musculoskeletal and Sensory Disabilities
  3. Severe Psychiatric disorders (eg; alcohol abuse, severe depression, schizophrenia, bipolar disorder)
  4. Illnesses that seriously reduce life expectancy or ability to participate in the trial
  5. 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.
  6. 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.
  7. 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: .
  8. History of Hypersensitivity to any of the Study Drug or to Drugs of similar chemical classes
  9. Use of an Investigative Drug within 30 days or 5 half-lives of the drug whichever is longer
  10. Potentially Unreliable and/or judged by the investigator to be Unsuitable for the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02409238


Contacts
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Contact: WEE KIEN HAN ANDREW, MCI 65-96615423 andrew.wee@singhealth.com.sg
Contact: TAN KEE TUNG, MB,BS 65-93671780 tan.kee.tung@singhealth.com.sg

Locations
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Singapore
SingHealth Polyclinics - Marine Parade Polyclinic Recruiting
Singapore, Singapore, 440080
Contact: WEE KIEN HAN ANDREW, MCI    (65) 63450049    andrew.wee@singhealth.com.sg   
Contact: NG CHIAT ENG    (65)90718977    ng.chiat.eng@singhealth.com.sg   
Sponsors and Collaborators
SingHealth Polyclinics
National University, Singapore
Singapore General Hospital
Changi General Hospital
National University Hospital, Singapore
Singapore Clinical Research Institute
Agency for Science, Technology and Research
Khoo Teck Puat Hospital
Duke-NUS Graduate Medical School
Investigators
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Principal Investigator: WEE KIEN HAN ANDREW, MCI SingHealth Polyclinics
Study Director: NG TZE PIN, MD National University, Singapore

Publications:

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Responsible Party: Andrew Wee Kien Han, Family Physician, SingHealth Polyclinics
ClinicalTrials.gov Identifier: NCT02409238     History of Changes
Other Study ID Numbers: MCI-LM 3
First Posted: April 6, 2015    Key Record Dates
Last Update Posted: March 31, 2016
Last Verified: March 2016
Keywords provided by Andrew Wee Kien Han, SingHealth Polyclinics:
Mild Cognitive Impairment
Insulin Resistance
Diabetes Mellitus, Type 2
Additional relevant MeSH terms:
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Diabetes Mellitus
Insulin Resistance
Diabetes Mellitus, Type 2
Cognitive Dysfunction
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Hyperinsulinism
Insulin
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs