Risk Reduction for Alzheimer's Disease

NCT02913664 | Completed Phase 2 DMC

• 1 other identifier: RZNIA60
• Study Type: interventional
• Target: 513
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

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

Keywords

Dementia; Alzheimer's Disease; Cognitive Function; Blood Pressure; Cholesterol; Physical Activity; Exercise; Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (1)

• Change in global neurocognitive function

  Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC) and NIH Toolbox (NIH-TB) Cognition Battery will be used to assess changes in neurocognitive function. The composite z-score for global cognition will be obtained by conversion of individual test scores to the standardized z-scores, then averaged to obtain a composite score.

  2 Years

Secondary Outcomes (9)

• Domain-specific neurocognitive function assessed by using the tests included in the ADCS-PACC and NIH-TB Cognition.

  2 Years

• Whole brain and hippocampal volume assessed via Magnetic Resonance Imaging (MRI).

  2 years

• Global and regional brain perfusion assessed via Magnetic Resonance Imaging (MRI).

  2 years

• Brain white matter hyperintensity (WMH) assessed via Magnetic Resonance Imaging (MRI).

  2 years

• Brain white matter microstructural integrity assessed via Magnetic Resonance Imaging (MRI).

  2 years

Study Arms (4)

Aerobic Exercise (Ex)

EXPERIMENTAL

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

Behavioral: Aerobic Exercise Training; Other: Usual Care

Intensive Reduction of Vascular Risk Factors (IRVR)

EXPERIMENTAL

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

Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine); Behavioral: Stretching Exercise

IRVR+Ex

EXPERIMENTAL

A combination of IRVR and aerobic exercise training.

Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine); Behavioral: Aerobic Exercise Training

Usual Care

PLACEBO COMPARATOR

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

Other: Usual Care; Behavioral: Stretching Exercise

Interventions

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

IRVR+Ex; Intensive Reduction of Vascular Risk Factors (IRVR)

Aerobic Exercise Training 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.

Aerobic Exercise (Ex); IRVR+Ex

Usual Care OTHER

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

Aerobic Exercise (Ex); Usual Care

Stretching Exercise 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.

Intensive Reduction of Vascular Risk Factors (IRVR); Usual Care

Eligibility Criteria

• Age: 60 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 60-85, all races/ethnicities, and both sexes are eligible.
• 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.
• Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia.
• 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.
• 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).
• Willingness to be randomized into the treatment groups and ability to return to clinic for follow-up visits over 24 months.
• Fluency in English, adequate visual and auditory acuity to allow neuropsychological testing.
• Participants must have a regular healthcare provider.
• Physical ability to undergo exercise training; able to walk 10 minutes without pain.

You may not qualify if:

• 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.
• 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.
• 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.
• 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.
• 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.
• Systolic BP equal or greater than 180 mmHg and/or diastolic BP equal or greater than 110 mmHg, may be rescreened in 1 week.
• Orthostatic hypotension, defined as the third standing SBP \< 100mmHg, may be rescreened after 2 weeks.
• History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis, or polymyalgia rheumatic.
• Significant history of alcoholism or drug abuse within the last five years.
• Uncontrolled diabetes mellitus, defined as hemoglobin A1C \> 7.5%, or requiring insulin treatment.
• Regularly smoking cigarette within the past year.
• Women with a potential for pregnancy, lactation/child bearing (2 year post- menopausal or surgically sterile to be considered not child bearing potential).
• Participant enrolled in another investigational drug or device study, either currently or within the past 2 months.
• Severe obesity with BMI ≥ 45; clinical judgment should be applied in all cases to assess patient safety and anticipated compliance.
• Allergy to angiotensin receptor blockers (ARBs), i.e., drugs that have a suffix "-sartan".

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• Texas Health Resources: collaborator
• University of Kansas Medical Center: collaborator
• Washington University School of Medicine: collaborator
• Pennington Biomedical Research Center: collaborator
• Michigan State University: collaborator

Study Sites (4)

University of Kansas Medical Center Research Institute

Kansas City, Kansas, 66160, United States

Location

Pennington Biomedical Research Center

Baton Rouge, Louisiana, 70808, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Related Publications (4)

• 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.

  PMID: 35636733 DERIVED

• 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.

  PMID: 32716358 DERIVED

• 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.

  PMID: 31710528 DERIVED

• 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.

  PMID: 30826452 DERIVED

Related Links

• Study Website

MeSH Terms

Conditions

Hypertension; Dementia; Alzheimer Disease; Motor Activity

Interventions

Angiotensin Receptor Antagonists; Losartan; Calcium Channel Blockers; Amlodipine; Muscle Stretching Exercises

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Tauopathies; Neurodegenerative Diseases; Behavior

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Cardiovascular Agents; Therapeutic Uses; Dihydropyridines; Pyridines; Exercise Therapy; Rehabilitation; Aftercare; Continuity of Patient Care; Patient Care; Therapeutics; Physical Therapy Modalities; Exercise; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Rong Zhang, PhD

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

• Jeffrey Keller, PhD

  Pennington Biomedical Research Center

  PRINCIPAL INVESTIGATOR

• Jeffrey Burns, MD

  University of Kansas Medical Center

  PRINCIPAL INVESTIGATOR

• Ellen Binder, MD

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

• Munro Cullum, PhD

  UT Southwestern

  PRINCIPAL INVESTIGATOR

• Diana Kerwin, MD

  Texas Health Resources

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: September 14, 2016
• First Posted: September 26, 2016
• Study Start: February 2, 2017
• Primary Completion: November 30, 2021
• Study Completion: January 31, 2022
• Last Updated: February 15, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will share

Locations

US (4)