Risk Reduction for Alzheimer's Disease

NCT ID: NCT02913664

Last Updated: 2022-02-15

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

513 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-02-02

Study Completion Date

2022-01-31

Brief Summary

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Physical inactivity, high blood pressure and dyslipidemia are risk factors for Alzheimer's disease (AD) and vascular dementia. Importantly, these risk factors are modifiable with lifestyle changes, pharmacological treatment, or both. The rrAD study will determine effects of aerobic exercise training and intensive vascular risk reduction on cognitive performance in older adults who have high risk for AD.

Detailed Description

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Numerous lines of evidence suggest that interventions that confer therapeutic benefits for cardiovascular health are also associated with improvements in, or preservation of, cognitive function. Many believe "What's good for the heart is good for the brain." However, stronge scientific evidence is needed to prove this hypothesis. The rrAD study is a 4-arm, multicenter, randomized trial to assess the effects of aerobic exercise training and intensive pharmacological reduction of vascular risk factors on cognitive performance in older adults who have high risk for AD, that is, those who have high blood pressure, family history of dementia or subjective memory complaints. Furthermore, rrAD will examine effects of exercise and vascular risk reduction on brain volume, perfusion, and neural network connectivity using magnetic resonance imaging (MRI).

Conditions

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Cognitively Normal Older Adults Hypertension Subjective Cognitive Decline Family History of Alzheimer's Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

PREVENTION

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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Aerobic Exercise (Ex)

Aerobic exercise training; blood and cholesterol management will be standard-care by participant's regular doctor.

Group Type EXPERIMENTAL

Aerobic Exercise Training

Intervention Type BEHAVIORAL

Participants will take part in a supervised, moderate to vigorous aerobic exercise training program for approximately 24 months. This program consists of exercising 3 times per week for about 30 minutes per session at the beginning, and will increase to 4-5 times per week, 40-50 minutes per session over a period of 4-5 months. Exercise frequency, intensity and duration will be maintained at this level during the rest of the study period.

Usual Care

Intervention Type OTHER

Participants will follow their regular doctor's recommendations for blood pressure and lipid control.

Intensive Reduction of Vascular Risk Factors (IRVR)

Lowering SBP \< 130 mmHg, administration of atorvastatin 80 mg daily, and stretching exercise.

Group Type EXPERIMENTAL

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)

Intervention Type DRUG

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP\<130 mmHg; atorvastatin 80 mg daily will be administered to reduce blood lipid level. Additional antihypertensives may be used if needed.

Intensive Reduction of Vascular Risk Factors (IRVR)

Stretching Exercise

Intervention Type BEHAVIORAL

Participants will perform home-based stretching exercise 3 times per week, gradually increased to 4-5 times per week over a period of 4-5 months, and maintained at this level during the rest of the study period. They will be encouraged to attend monthly stretching exercise classes, which will be led by study staff or exercise trainers.

IRVR+Ex

A combination of IRVR and aerobic exercise training.

Group Type EXPERIMENTAL

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)

Intervention Type DRUG

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP\<130 mmHg; atorvastatin 80 mg daily will be administered to reduce blood lipid level. Additional antihypertensives may be used if needed.

Intensive Reduction of Vascular Risk Factors (IRVR)

Aerobic Exercise Training

Intervention Type BEHAVIORAL

Participants will take part in a supervised, moderate to vigorous aerobic exercise training program for approximately 24 months. This program consists of exercising 3 times per week for about 30 minutes per session at the beginning, and will increase to 4-5 times per week, 40-50 minutes per session over a period of 4-5 months. Exercise frequency, intensity and duration will be maintained at this level during the rest of the study period.

Usual Care

Blood and cholesterol management will be standard-care by participant's regular doctor, and stretching exercise.

Group Type PLACEBO_COMPARATOR

Usual Care

Intervention Type OTHER

Participants will follow their regular doctor's recommendations for blood pressure and lipid control.

Stretching Exercise

Intervention Type BEHAVIORAL

Participants will perform home-based stretching exercise 3 times per week, gradually increased to 4-5 times per week over a period of 4-5 months, and maintained at this level during the rest of the study period. They will be encouraged to attend monthly stretching exercise classes, which will be led by study staff or exercise trainers.

Interventions

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Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)

Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine) will be used to reduce SBP\<130 mmHg; atorvastatin 80 mg daily will be administered to reduce blood lipid level. Additional antihypertensives may be used if needed.

Intensive Reduction of Vascular Risk Factors (IRVR)

Intervention Type DRUG

Aerobic Exercise Training

Participants will take part in a supervised, moderate to vigorous aerobic exercise training program for approximately 24 months. This program consists of exercising 3 times per week for about 30 minutes per session at the beginning, and will increase to 4-5 times per week, 40-50 minutes per session over a period of 4-5 months. Exercise frequency, intensity and duration will be maintained at this level during the rest of the study period.

Intervention Type BEHAVIORAL

Usual Care

Participants will follow their regular doctor's recommendations for blood pressure and lipid control.

Intervention Type OTHER

Stretching Exercise

Participants will perform home-based stretching exercise 3 times per week, gradually increased to 4-5 times per week over a period of 4-5 months, and maintained at this level during the rest of the study period. They will be encouraged to attend monthly stretching exercise classes, which will be led by study staff or exercise trainers.

Intervention Type BEHAVIORAL

Eligibility Criteria

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Inclusion Criteria

1. Age 60-85, all races/ethnicities, and both sexes are eligible.
2. a) A positive family history of dementia defined as having at least one first-degree relative with a history of AD or other type of dementia,or b) having subjective cognitive decline.
3. Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia.
4. Must lead a sedentary lifestyle defined by not having an "active" rating on Rapid Assessment of Physical Activity (RAPA), i.e., score below 6 on RAPA.
5. a) Individuals treated for HTN with 110 ≤ SBP ≤ 130 mmHg; or b) Individuals with SBP \> 130 and SBP \< 180 (If an individual, not treated for HTN, has a SBP ≥ 125 mmHg, consider rescreening after 24 hours).
6. Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months.
7. Fluency in English, adequate visual and auditory acuity to allow neuropsychological testing.
8. Participants must have a regular healthcare provider.
9. Physical ability to undergo exercise training; able to walk 10 minutes without pain.

Exclusion Criteria

1. Clinically documented history of stroke, focal neurological signs or other major cerebrovascular diseases based on clinical judgment or MRI/CT scans such as evidence of infection, infarction or other brain lesions.
2. Diagnosis of AD or other type of dementia, or significant neurologic diseases such as Parkinson's disease, seizure disorder, multiple sclerosis, history of severe head trauma or normal pressure hydrocephalus.
3. Evidence of severe major depression (GDS \> 12, may be rescreened after 12 weeks or longer if evidence of reactive depression or temporary mood disturbances) or clinically significant psychopathology(e.g. psychosis and schizophrenia); if hospitalized in past year, can be rescreened in 6 months; or presence of a major psychiatric disorder that in the investigator's opinion, could interfere with adherence to research assessments or procedures.
4. Unstable heart disease based on clinical judgment (e.g., heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure),or other severe medical conditions.
5. History of atrial fibrillation and evidence on ECG with any of the following: active symptoms of persistent palpitation, dizziness, history of syncope, chest pain, dyspnea, orthopnea, shortness of breath at rest, or paroxysmal nocturnal dyspnea within the past 6 months; resting heart rate of \< 30 or \> 110 bpm; taking class I or III anti-arrhythmic drugs including flecanide, propafenone, dronedarone, sotalol, dofetilide, and amiodarone; or clinical concerns for safely participating in exercise and lowering blood pressure.
6. Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.
7. Orthostatic hypotension, defined as the third standing SBP \< 100mmHg, may be rescreened after 2 weeks.
8. History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, or polymyalgia rheumatic.
9. Significant history of alcoholism or drug abuse within the last five years.
10. Uncontrolled diabetes mellitus, defined as hemoglobin A1C \> 7.5%, or requiring insulin treatment.
11. Regularly smoking cigarette within the past year.
12. Women with a potential for pregnancy, lactation/child bearing (2 year post- menopausal or surgically sterile to be considered not child bearing potential).
13. Participant enrolled in another investigational drug or device study, either currently or within the past 2 months.
14. Severe obesity with BMI ≥ 45; clinical judgment should be applied in all cases to assess patient safety and anticipated compliance.
15. Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan".
16. Allergy to other study drugs or their ingredients; for example, clinical history or self-reported allergy or intolerance to atorvastatin.
17. Abnormal screening laboratory tests (e.g., liver ALT and AST \> 3 x ULN, CK \> 3 x ULN, GFR \< 30 or Hct \< 28%); may be rescreened after 2 weeks or longer.
18. A medical condition likely to limit survival to less than 3 years.
19. Participant has any condition(s) judged by the study investigator to be medically inappropriate, risky or likely to cause poor study compliance. For example:

1. Plans to move outside the clinic catchment area in the next 2 years;
2. Significant concerns about participation in the study from spouse, significant other, or family members;
3. Lack of support from primary health care provider;
4. Residence too far from the study clinic site such that transportation is a barrier including persons who require transportation assistance provided by the study clinic funds for screening or randomization visits;
5. Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria.
6. Other medical, psychiatric, or behavioral factors that, in the judgment of the site PI or clinician, may interfere with study participation or the ability to follow the study Protocol.
7. Couples or significant partners who live together cannot be enrolled or participate simultaneously in the study.
20. Lack of approval from participant's regular healthcare providers, i.e. a signed letter of agreement for the participants to be enrolled in rrAD.
Minimum Eligible Age

60 Years

Maximum Eligible Age

85 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Texas Health Resources

OTHER

Sponsor Role collaborator

University of Kansas Medical Center

OTHER

Sponsor Role collaborator

Washington University School of Medicine

OTHER

Sponsor Role collaborator

Pennington Biomedical Research Center

OTHER

Sponsor Role collaborator

Michigan State University

OTHER

Sponsor Role collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Rong Zhang

Professor of Neurology

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Rong Zhang, PhD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern Medical Center

Jeffrey Keller, PhD

Role: PRINCIPAL_INVESTIGATOR

Pennington Biomedical Research Center

Jeffrey Burns, MD

Role: PRINCIPAL_INVESTIGATOR

University of Kansas Medical Center

Ellen Binder, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Munro Cullum, PhD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern

Diana Kerwin, MD

Role: PRINCIPAL_INVESTIGATOR

Texas Health Resources

Locations

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University of Kansas Medical Center Research Institute

Kansas City, Kansas, United States

Site Status

Pennington Biomedical Research Center

Baton Rouge, Louisiana, United States

Site Status

Washington University in St. Louis

St Louis, Missouri, United States

Site Status

UT Southwestern Medical Center

Dallas, Texas, United States

Site Status

Countries

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United States

References

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Szabo-Reed A, Clutton J, White S, Van Sciver A, White D, Morris J, Martin L, Lepping R, Shaw A, Puchalt JP, Montgomery R, Mahnken J, Washburn R, Burns J, Vidoni ED. COMbined Exercise Trial (COMET) to improve cognition in older adults: Rationale and methods. Contemp Clin Trials. 2022 Jul;118:106805. doi: 10.1016/j.cct.2022.106805. Epub 2022 May 27.

Reference Type DERIVED
PMID: 35636733 (View on PubMed)

Vidoni ED, Kamat A, Gahan WP, Ourso V, Woodard K, Kerwin DR, Binder EF, Burns JM, Cullum M, Hynan LS, Vongpatanasin W, Zhu DC, Zhang R, Keller JN. Baseline Prevalence of Polypharmacy in Older Hypertensive Study Subjects with Elevated Dementia Risk: Findings from the Risk Reduction for Alzheimer's Disease Study (rrAD). J Alzheimers Dis. 2020;77(1):175-182. doi: 10.3233/JAD-200122.

Reference Type DERIVED
PMID: 32716358 (View on PubMed)

Gottesman RF. To INFINITY and Beyond: What Have We Learned and What Is Still Unknown About Blood Pressure Lowering and Cognition? Circulation. 2019 Nov 12;140(20):1636-1638. doi: 10.1161/CIRCULATIONAHA.119.042827. Epub 2019 Nov 11. No abstract available.

Reference Type DERIVED
PMID: 31710528 (View on PubMed)

Szabo-Reed AN, Vidoni E, Binder EF, Burns J, Cullum CM, Gahan WP, Gupta A, Hynan LS, Kerwin DR, Rossetti H, Stowe AM, Vongpatanasin W, Zhu DC, Zhang R, Keller JN. Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study). Contemp Clin Trials. 2019 Apr;79:44-54. doi: 10.1016/j.cct.2019.02.007. Epub 2019 Mar 1.

Reference Type DERIVED
PMID: 30826452 (View on PubMed)

Related Links

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Other Identifiers

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RZNIA60

Identifier Type: -

Identifier Source: org_study_id

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