Clinical trial NCT02814526: Exercise in Adults With Mild Memory Problems
Official title: Therapeutic Effects of Exercise in Adults With Amnestic Mild Cognitive Impairment (MCI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mild Cognitive Impairment
Cognitive Decline
Memory Impairment
Keywords: exercise
Lead sponsor: Alzheimer's Disease Cooperative Study (ADCS)
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Wake Forest University Health Sciences
First posted: 2016-06-27
Enrollment: 296
Sex: ALL
Minimum age (years): 65
Maximum age (years): 89
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the effects of physical exercise on cognition, functional status, brain atrophy and blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease in adults with a mild memory impairment.

Half of participants will participate in a stretching-balance-range of motion exercise program, while the other half will participate in a moderate/high aerobic training program.

Detailed description: Overall Study Design:

The EXERT trial was a multicenter phase 3 randomized, single-blind study that examined the effects of aerobic exercise on cognition, functional status, whole and regional cerebral blood flow, and cerebrospinal fluid biomarkers of Alzheimer's disease in approximately 300 adults with amnestic MCI. EXERT included an 18-month behavioral intervention trial, with a 12-month supervised exercise intervention phase with its primary endpoints, followed by a 6-month unsupervised exercised phase.

Subject Populations and Group Assignments:

The study population included male and female subjects aged 65 to 89 diagnosed with test scores and clinical ratings consistent with amnestic Mild Cognitive Impairment (MCI).

Assignment to study groups:

involved randomization to either treatment or active control, and study staff performing assessments were blinded to intervention assignment to maintain the single-blind structure of the trial.

Participants were to complete EXERT interventions at participating YMCAs located near the selected clinic sites across the U.S. The YMCA provided 18-month memberships at no cost to participants. In the first 12 months, a study-certified YMCA Trainer supervised all participants for the first 8 exercise sessions completed (weeks 1 and 2), and for 2 of 4 weekly sessions thereafter through Month 12. At Month 12, participants transitioned to independent exercise and were instructed to continue their assigned exercise programs for the final 6 months of the study without supervision. To encourage adherence and optimize cost efficiency, Trainers provided supervision to small groups of participants (2-4 individuals) randomized to the same intervention whenever possible. Compliance was evaluated using multiple mechanisms including heart rate monitoring, participant ratings of perceived exertion, entries in participants' Physical Activity Logs, Trainer assessment of effort, and weekly data review by the YMCA-Project Manager (Y-PM) and the Intervention Oversight Team (includes the Project Directors, Wake Forest team of exercise trial specialists, and Y-USA). These mechanisms provided multiple and regular opportunities to discuss participant progress, identify and resolve barriers, and encourage high levels of adherence to study protocols. The Intervention Oversight Team had the necessary expertise to successfully accomplish this objective in EXERT.

Eligibility criteria: Inclusion Criteria

1. Age between 65 and 89 years old, inclusive
2. MMSE: ≥24 for participants with 13 or more years of education; ≥22 for participants with 12 or fewer years of education
3. Global CDR score of 0.5 with a memory score of at least 0.5
4. Profile of test scores and clinical ratings is consistent with amnestic mild cognitive impairment
5. Speaks English fluently
6. Visual and auditory acuity adequate for cognitive testing
7. Completed at least 6 years of formal education or work history sufficient to exclude mental retardation
8. Has an informant who knows the participant well, has regular contact, and is available to accompany the participant to clinic visits or complete study partner assessments remotely.
9. Sedentary or underactive, determined by responses to the staff-administered EXERT Telephone Assessment of Physical Activity (TAPA) survey
10. Willing to be randomized to either intervention group and to complete the assigned activities as specified for 18 months
11. Willing and able to reliably travel to the identified YMCA, 4 times per week for 18 months
12. Ability to safely participate in either intervention and complete the 400 m Walk Test within 15 min without sitting or use of any assistance
13. Plans to reside in the area for at least 18 months
14. For planned travel, total time away must be no more than 2 months over the course of the study, and no more than 1 month at any one time; participants must be willing to continue the assigned exercise program if travelling out of the area for more than 1 week
15. In overall good general health with no disease or planned surgery that could interfere with study participation
16. Modified Hachinski ≤4
17. Stable use of cholinesterase inhibitors, memantine, vitamin E, estrogens, aspirin (81 300 mg daily), beta-blockers, or cholesterol-lowering agents for 12 weeks prior to screening (important for biomarker analyses)
18. Stable use of antidepressants lacking significant anticholinergic side effects for 4 weeks prior to screening as long as the participant does not meet DSM V criteria for major depression currently or in the last 12 months; GDS scores are to be used to inform clinical decisions but there is no specified cut-off score for inclusion
19. When applicable, willing to complete 4-week washout of psychoactive medications, including disallowed antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, and willing to avoid these medications for the duration of the trial
20. Able to complete all baseline assessments

Exclusion Criteria

1. Any significant neurologic disease, other than MCI, including any form of dementia, Parkinsons disease, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma with persistent neurologic sequelae or known structural brain abnormalities
2. Sensory or musculoskeletal impairment sufficient to preclude successful and safe completion of the intervention or assessment protocols; must be able to walk safely and unassisted on a treadmill
3. Contraindications for MRI studies, including claustrophobia, metal (ferromagnetic) implants, or cardiac pacemaker
4. Brain MRI at screening shows evidence of infection, infarction, or other clinically significant focal lesions, including multiple lacunes in prefrontal or critical memory regions; inconclusive findings may be subject to review by the ADCS Imaging Core
5. History of major depression or bipolar disorder (DSM V criteria), psychotic features, agitation or behavioral problems within the last 12 months
6. History of schizophrenia, as per DSM V criteria
7. History of alcohol or substance abuse or dependence within the past 2 years, as per DSM V criteria
8. Currently consumes more than 3 alcoholic drinks per day
9. Clinically significant or unstable medical condition, including uncontrolled hypertension or significant cardiac, pulmonary, hematologic, renal, hepatic, gastrointestinal, endocrine, metabolic or other systemic disease in the opinion of clinic medical personnel that may put the participant at increased risk, influence the results or compromise the participants ability to participate in the study (treated atrial fibrillation for more than 1 year or occasional premature ventricular contractions on ECG are not exclusions)
10. History in the last 6 months of myocardial infarction, coronary artery angioplasty, bypass grafting, or STENT placement
11. History in the last 3 months of transient ischemic attack or small vessel stroke (if more than 3 months, small vessel stroke with no residual effects are permitted)
12. Expected joint replacement surgery within the next 18 months
13. History within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen posttreatment
14. Hemoglobin A1c \>7.0
15. Clinically significant abnormalities in screening laboratory blood tests: low B12 is exclusionary, unless follow-up labs (homocysteine \[HCY\] and methylmalonic acid \[MMA\]) indicate that it is not physiologically significant
16. Current or past use of insulin to treat type 2 diabetes (other diabetes medications are acceptable if hemoglobin A1c ≤7)
17. Current use (within 60 days of screening) of psychoactive medications including tricyclic antidepressants, antipsychotics, mood-stabilizing psychotropic agents (e.g. lithium salts), psychostimulants, opiate analgesics, antiparkinsonian medications, anticonvulsant medications (except gabapentin and pregabalin for non-seizure indications), systemic corticosteroids, or medications with significant central anticholinergic activity. Limited use of antipsychotics (quetiapine ≤ 50mg/day or risperidone ≤ 0.5mg/day), and non-chronic use of opiate analgesics on an as needed basis is permitted; such medications must be avoided for 8 hours before clinic assessments
18. Chronic use of anxiolytics or sedative hypnotics except as follows: use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing of anxiolytics is permitted; medications must be avoided for 8 hours before clinic assessments
19. Previous or current treatment involving active immunization against amyloid
20. Previous treatment with approved or investigational agents with anti-amyloid properties or passive immunization against amyloid are prohibited 12 months prior to screening and for the duration of the trial; treatment with other investigational agents are prohibited 3 months prior to screening and for the duration of the trial
21. For LP, current use of anticoagulants such as Coumadin, Plavix, or high dose Vitamin E
22. For LP, current blood clotting or bleeding disorder, or significantly abnormal prothrombin time (PT) or partial thromboplastin time (PTT) at screening
23. For LP, presence of physical distortions due to spinal surgery, severe degenerative joint disease or deformity, or obesity that could interfere with CSF collection (as per investigator judgment)
24. Participants whom the PI deems otherwise ineligible

Primary outcomes:
measure: ADAS-Cog-Exec Global Composite
timeFrame: Baseline to mean (Mo 6, Mo 12)
Secondary outcomes:
measure: ADAS-Cog-Exec Global Composite in Subset Population
timeFrame: Baseline to mean (Mo 6, Mo 12)
measure: Executive Function Composite Score
timeFrame: Baseline to mean (Mo 6, Mo 12)
measure: Episodic Memory Composite Score
timeFrame: Baseline to mean (Mo 6, Mo 12)
measure: Volumetric Magnetic Resonance Imaging (MRI) of Hippocampus
timeFrame: 12 Months
measure: Volumetric Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region
timeFrame: 12 Months
measure: Volumetric Magnetic Resonance Imaging (MRI) of AD Signature Composite Region
timeFrame: 12 Months
measure: Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Hippocampus
timeFrame: Baseline to 12 Months
measure: Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of Prefrontal Composite Region
timeFrame: Baseline to 12 Months
measure: Arterial Spin Labeling (ASL) Magnetic Resonance Imaging (MRI) of AD Signature Composite Region
timeFrame: Baseline to 12 Months
measure: Ratio of AD Biomarkers in Blood
timeFrame: 12 Months
measure: AD Biomarkers in CSF (ab42/ab40)
timeFrame: 12 Months
measure: AD Biomarkers in CSF (ab42/Tau)
timeFrame: 12 Months
measure: AD Biomarkers in CSF (ab42/P-tau)
timeFrame: 12 Months
Other outcomes:
measure: Intervention Effects on Secondary Outcomes in a Subset of Participants Who Completed 12 Months of the Study Prior to the COVID-19 Pandemic.
timeFrame: 12 months
measure: Exploratory Magnetic Resonance Imaging (MRI) Volumes and Perfusion and Individual AD Biomarkers in CSF and Blood Measures
timeFrame: 12 Months
measure: Clinical Dementia Rating Scale-Sum of Boxes (CDR) and Alzheimers Disease Assessment Scale-Cognitive 13-item (ADAS-Cog13)
timeFrame: 12 Months
measure: Measures of Cognitive Function and Well-being Including (1) ADCS-ADL-MCI); (2) BRIEF-A; (3) GDS; (4) NPI; SF-36; EuroQol: 5-Item Health Questionnaire; (5) CCI: Cognitive Change Index); and (6) Study Partner Self-Assessment
timeFrame: 12 Months
measure: ADAS-Cog-Exec, Executive Function, and Episodic Memory Composites
timeFrame: 18 Months
measure: Subgroup Treatment Responder Analyses
timeFrame: 12 Months
Locations:
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Palo Alto
country: United States
facility: VAPAHCS / Stanford University School of Medicine
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Great Lakes Clinical Trials (Andersonville)
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health
state: Nevada
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Alzheimer's Disease Cooperative Study (ADCS)
name: Howard Feldman, MDCM FRCP(C)
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, Plymate SR, Fishel MA, Watson GS, Cholerton BA, Duncan GE, Mehta PD, Craft S. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010 Jan;67(1):71-9. doi: 10.1001/archneurol.2009.307.
citation: Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37. doi: 10.1001/jama.300.9.1027.
citation: Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1166-70. doi: 10.1093/gerona/61.11.1166.
citation: Voss MW, Prakash RS, Erickson KI, Basak C, Chaddock L, Kim JS, Alves H, Heo S, Szabo AN, White SM, Wojcicki TR, Mailey EL, Gothe N, Olson EA, McAuley E, Kramer AF. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci. 2010 Aug 26;2:32. doi: 10.3389/fnagi.2010.00032. eCollection 2010.
citation: Colcombe SJ, Erickson KI, Raz N, Webb AG, Cohen NJ, McAuley E, Kramer AF. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci. 2003 Feb;58(2):176-80. doi: 10.1093/gerona/58.2.m176.
citation: Burns JM, Cronk BB, Anderson HS, Donnelly JE, Thomas GP, Harsha A, Brooks WM, Swerdlow RH. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology. 2008 Jul 15;71(3):210-6. doi: 10.1212/01.wnl.0000317094.86209.cb.
citation: Nichol KE, Poon WW, Parachikova AI, Cribbs DH, Glabe CG, Cotman CW. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J Neuroinflammation. 2008 Apr 9;5:13. doi: 10.1186/1742-2094-5-13.