Pioglitazone Or Exercise to Treat Mild Cognitive Impairment (MCI)

Mild Cognitive Impairment Clinical Trial

— POEM  

Official title:

Pioglitazone and Exercise Effects on Older Adults With MCI and Metabolic Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00736996
• Other study ID #: 07-1215
• Secondary ID: R01AG028746
• Status: Completed
• Phase: Phase 2
• First received: August 14, 2008
• Last updated: December 10, 2015
• Start date: November 2008
• Est. completion date: December 2013

Study information

• Verified date: December 2015
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to investigate novel treatments to delay progression to dementia in patients with mild cognitive impairment (MCI) and metabolic syndrome (MS). The hypothesis is that treatment with pioglitazone or endurance exercise training will improve, stabilize, or attenuate decline in cognitive function compared to controls. This study will also discover potential mechanisms for the improvements and determine the baseline prevalence of amnestic versus non-amnestic MCI.

Description:

The Metabolic Syndrome (MS) is a rapidly growing public health problem. This constellation of metabolic abnormalities increases the risk of diabetes, heart disease and death. Recently evidence has linked MS with cognitive impairment and dementia, including Alzheimer's Disease (AD). AD is preceded by a state called Mild Cognitive Impairment (MCI), characterized by subjective and objective memory impairment, but no functional impairment. Although not all persons with MCI will develop AD, the conversion rate from MCI to AD is about 15% per year, or 5-10 times that of cognitively normal individuals. There is great interest in finding treatments to prevent AD by intervening at an earlier stage, i.e. MCI.

The mechanism(s) linking MS and cognitive impairment are not clear, although there is evidence that insulin resistance and inflammation play key roles. Thiazolidinediones (TZDs) are medications approved for the treatment of Type 2 Diabetes, which work by reducing insulin resistance. In addition, these drugs have anti-inflammatory properties. A recent pilot study showed improvements in some areas of cognition in patients with MCI or mild AD treated with the TZD rosiglitazone. Endurance exercise training (EET) is an established treatment for MS and insulin resistance. There is also evidence that EET may improve cognitive function as well.

Adults aged 55 years or older with both MS and MCI at baseline will be randomized to a 6-month intervention with either (1) treatment with pioglitazone, (2) endurance exercise training, or (3) control (placebo and no exercise). The hypothesis is that treatment with the TZD pioglitazone or EET will improve cognitive function compared to controls, as evidenced by either improvement, stabilization, or lesser decline in performance on cognitive testing. Participants will undergo a physical exam including blood and urine tests, a complete neurologic exam, and a comprehensive battery of cognitive tests. They will also have a DEXA scan, exercise treadmill test, non-invasive tests of vascular function and a hyperglycemic-euglycemic clamp procedure to measure insulin resistance.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 55 Years and older

Eligibility

Inclusion Criteria:

• Community-dwelling, over 55 years old, able to give full informed consent, willing to be randomized

• Able to perform a telephone interview

• Able to speak, read and understand English

• Potential volunteers on a statin drug, angiotensin converting enzyme inhibitor (ACE-I), angiotensin II receptor blocker (ARB), non-steroidal anti-inflammatory drug (NSAID), or Vitamin E supplement, are eligible but must be on a stable dose for at least 2 months

• Women must be post-menopausal, as defined by no menses for 12 months

• Must meet 3 of the 5 requirements for Metabolic Syndrome:

• Waist measurement: greater than 102 cm for men and 88 cm for women

• Fasting hypertriglyceridemia: 150 mg/dl (1.7 mmol/L) or higher

• Low HDL cholesterol: less than 40 mg/dl (1.0 mmol/L) for men and 50 mg/dl (1.3 mmol/L) for women

• Hypertension: higher than 130 mmHg systolic or 85 mmHg diastolic (average of 2 seated measurements) or currently using an antihypertensive medication

• Elevated (untreated) fasting glucose: 100 mg/dl (5.6 mmol/L) or higher

• Meet the study's 4-step screening process for MCI (to rule out dementia)

Exclusion Criteria:

• Diagnosis of diabetes mellitus (DM), defined as: Fasting Blood Sugar 126 or higher, a history of known DM, or treatment with any glucose lowering medication

• Current diagnosis of dementia (or MMSE less than 24) or a neurological co-morbidity other than MCI that might affect cognition including: large vessel stroke, brain tumor, severe brain injury, multiple sclerosis, or Parkinson's disease

• Current diagnosis of depression assessed by a Centers for Epidemiologic Studies Depression Scale (CES-D) score of 36 or less

• Major psychiatric conditions such as bipolar disorder, psychosis, schizophrenia, or alcoholism that could affect the ability to understand and/or cooperate fully with the protocol

• Significant cerebral vascular disease

• Modified Hachinski score greater than 4

• Pregnant, lactating or having child bearing potential

• Concomitant medications with significant cholinergic or anticholinergic effects or adverse effects on cognition including: antipsychotics, tricyclic antidepressants, anticonvulsants, sedative/hypnotics, anxiolytics, glucocorticoids (chronic or frequent intermittent), gingko biloba, NMDA receptor antagonists, cholinesterase inhibitors, strongly lipid soluble beta blockers (e.g., propranolol)

• Hormone replacement therapy (male or female)

• Visual/hearing impairment that would significantly impact the ability to undergo psychometric testing

• Significant medical illness or organ failure including hepatic or renal failure, unstable cardiac disease, or life expectancy less than 18 months

• Exercise-limiting conditions including: neuromuscular, joint/bone, cardiovascular, peripheral vascular, cerebrovascular or pulmonary disease; recent MI, pulmonary embolus, significant aortic stenosis; or exercise limiting obesity

• Untreated B12 deficiency or hypothyroidism (stable treatment for at least 3 months is allowable)

• Uncontrolled hypertension: over 160 mmHg systolic or 100 mmHg diastolic (stable treatment is allowable)

• Endurance exercise training more than twice a week for 20 minutes (at a level that produces sweating) consistently during the last 6 months

• Unstable weight in the last 6 months

• Increased risk for Pio toxicity including: a) baseline liver dysfunction (over 2.5xULN for AST, ALT); b) hematocrit less than 33% men or 30% women; c) problematic edema; or d) congestive heart failure NYHA class II or greater

• Stage 5 renal impairment (GFR less than 15 or dialysis)

• Already taking a TZD or other drug that would modify insulin resistance (e.g. metformin), or has taken a TZD in the past and experienced a significant adverse effect or allergy

• Currently taking any of following medications that may interact with Pio metabolism:

atorvastatin at 80mg/day (lower doses are allowed), and medications with major CYP 3A4 inhibiting effects, such as nefazodone or systemic antifungal agents

• Participating in another clinical trial

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cognition Disorders
• Mild Cognitive Impairment

Intervention

Drug:
• Pioglitazone
30 - 45mg tablet daily for 6 months
• Placebo
Matching tablet daily for 6 months

Behavioral:
• Endurance Exercise Training
Individualized exercise prescription, 45-75 minutes (progressive increments) three times a week

Locations

Country	Name	City	State
United States	University of Colorado, Denver	Denver	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Denver	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (5)

Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain. J Appl Physiol (1985). 2006 Oct;101(4):1237-42. Epub 2006 Jun 15. Review. — View Citation

Lytle ME, Vander Bilt J, Pandav RS, Dodge HH, Ganguli M. Exercise level and cognitive decline: the MoVIES project. Alzheimer Dis Assoc Disord. 2004 Apr-Jun;18(2):57-64. — View Citation

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? J Alzheimers Dis. 2005 Feb;7(1):63-80. — View Citation

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. — View Citation

Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004 Nov 10;292(18):2237-42. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Cognitive Performance	Participants were administered a neuropsychological testing battery consisting of assessments in four cognitive domains: memory (Visual Reproduction II, Logical Memory II, Rey Auditory Verbal Learning Test), language (Boston Naming Test , Category Fluency), visuospatial (Block Design, Picture Completion), and executive function (Trail Making Test B, Digit Symbol Test). Raw test scores for these primary cognitive domain measures were transformed into age-adjusted scaled scores with a mean of 10 and a standard deviation (SD) of 3, with higher numbers indicating better cognitive performance, using the Mayo's Older American Normative Studies data. Cognitive domain scores were calculated as the arithmetic mean of the normatively derived scaled scores for all of the tests in that domain.	Baseline to 6 months	No
Secondary	Change in Insulin Resistance	Change in whole body glucose disposal rate (mg/kg/min) calculated during a single-stage (40 mU/m2/min), 3-hour hyperinsulinemic, euglycemic clamp	Baseline to 6 months	No
Secondary	Change in Peak Oxygen Uptake (VO2 Peak)	Peak oxygen consumption (VO2 peak, ml/kg/min) was determined by open circuit spirometry during a standard treadmill stress test (modified Balke protocol).	Baseline to 6 months	No

External Links

•   Poem Full Protocol
•   POEM Statistical Analysis Plan