Insulin Resistance and Mild Cognitive Impairment (IRMCI) Study

NCT02409238 | Terminated Phase 4

• 1 other identifier: MCI-LM 3
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 1

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.

Conditions

Mild Cognitive Impairment; Insulin Resistance; Diabetes Mellitus, Type 2

Keywords

Mild Cognitive Impairment; Insulin Resistance; Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (2)

• Primary efficacy endpoint (Cerebral Glucose Metabolic Rate)

  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 years

• Primary cognitive endpoint (Neuropsychological Performance)

  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.

  2 years

Secondary Outcomes (14)

• Secondary clinical endpoints Subjective Memory and Cognitive Complaint (SMCC

  2 years

• Secondary clinical endpoints Basic Activities of Daily Liver (ADL)

  2 years

• Secondary clinical endpoints Cognitive Instrumental Activities of Daily Living Scale

  2 years

• Secondary clinical endpoints Global Clinical Dementia Rating Sum of Boxes

  2 years

• Secondary clinical endpoints Mini-Mental State Examination

  2 years

Study Arms (2)

Lifestyle Intervention and Metformin

EXPERIMENTAL

Intensive lifestyle interventions at Lifestyle Intervention Centres and Metformin (if Diabetic)

Drug: Metformin; Behavioral: Intensive Lifestyle Intervention

Standard Level of Care

ACTIVE COMPARATOR

Standard lifestyle recommendations for the Control groups

Behavioral: Standard LIfestyle Recommendation

Interventions

Metformin DRUG

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.

Lifestyle Intervention and Metformin

Intensive Lifestyle Intervention BEHAVIORAL

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.

Lifestyle Intervention and Metformin

Standard LIfestyle Recommendation BEHAVIORAL

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.

Standard Level of Care

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• SingHealth Polyclinics: lead
• National University of Singapore: collaborator
• Singapore General Hospital: collaborator
• Changi General Hospital: collaborator
• National University Hospital, Singapore: collaborator
• Singapore Clinical Research Institute: collaborator
• Agency for Science, Technology and Research: collaborator
• Khoo Teck Puat Hospital: collaborator
• Duke-NUS Graduate Medical School: collaborator

Study Sites (1)

SingHealth Polyclinics - Marine Parade Polyclinic

Singapore, 440080, Singapore

Location

Related Publications (11)

• Pathan AR, Gaikwad AB, Viswanad B, Ramarao P. Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats. Eur J Pharmacol. 2008 Jul 28;589(1-3):176-9. doi: 10.1016/j.ejphar.2008.06.016. Epub 2008 Jun 7.

  PMID: 18602098 BACKGROUND

• Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005 Nov;13(11):950-8. doi: 10.1176/appi.ajgp.13.11.950.

  PMID: 16286438 BACKGROUND

• Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. doi: 10.1038/sj.tpj.6500369. Epub 2006 Jan 31.

  PMID: 16446752 BACKGROUND

• Abbatecola AM, Lattanzio F, Molinari AM, Cioffi M, Mansi L, Rambaldi P, DiCioccio L, Cacciapuoti F, Canonico R, Paolisso G. Rosiglitazone and cognitive stability in older individuals with type 2 diabetes and mild cognitive impairment. Diabetes Care. 2010 Aug;33(8):1706-11. doi: 10.2337/dc09-2030. Epub 2010 Apr 30.

  PMID: 20435794 BACKGROUND

• Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, Craft S, Landreth G, Linnamagi U, Sawchak S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131-46. doi: 10.1159/000318845. Epub 2010 Aug 21.

  PMID: 20733306 BACKGROUND

• Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM, Irizarry M, Jeter B, Zvartau-Hind M, van Dyck CH, Gold M. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res. 2011 Aug;8(5):592-606. doi: 10.2174/156720511796391935.

  PMID: 21592048 BACKGROUND

• Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis. 2014;41(1):61-8. doi: 10.3233/JAD-131901.

  PMID: 24577463 BACKGROUND

• Brackett CC. Clarifying metformin's role and risks in liver dysfunction. J Am Pharm Assoc (2003). 2010 May-Jun;50(3):407-10. doi: 10.1331/JAPhA.2010.08090.

  PMID: 20452916 BACKGROUND

• American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.

  PMID: 24357209 BACKGROUND

• American Diabetes Association. (6) Glycemic targets. Diabetes Care. 2015 Jan;38 Suppl:S33-40. doi: 10.2337/dc15-S009. No abstract available.

  PMID: 25537705 BACKGROUND

• Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care. 2015 Jan;38 Suppl:S4. doi: 10.2337/dc15-S003. No abstract available.

  PMID: 25537706 BACKGROUND

MeSH Terms

Conditions

Cognitive Dysfunction; Insulin Resistance; Diabetes Mellitus, Type 2

Interventions

Metformin

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• NG TZE PIN, MD

  National University of Singapore

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Family Physician- SITE Investigator

Study Record Dates

• First Submitted: March 26, 2015
• First Posted: April 6, 2015
• Study Start: March 11, 2015
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: January 11, 2023

Record last verified: 2023-01

Locations

SG (1)