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Cognitively Normal Older AdultsPhase 2/3rrADNCT02913664

Risk Reduction for Alzheimer's Disease

A Phase 2/3 study testing Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine), Aerobic Exercise Training and Stretching Exercise in people with Cognitively Normal Older Adults and Hypertension, run by University of Texas Southwestern Medical Center at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 60 to 85 years
What is being tested?
Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine), Aerobic Exercise Training and Stretching Exercise
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
513 participants
Where
4 sitesUnited States
Study dates
2 Feb 2017to 31 Jan 2022
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 60 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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".
  • Allergy to other study drugs or their ingredients; for example, clinical history or self-reported allergy or intolerance to atorvastatin.
  • 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.
  • A medical condition likely to limit survival to less than 3 years.
  • Participant has any condition(s) judged by the study investigator to be medically inappropriate, risky or likely to cause poor study compliance. For example:
  • Plans to move outside the clinic catchment area in the next 2 years;
  • Significant concerns about participation in the study from spouse, significant other, or family members;
  • Lack of support from primary health care provider;
  • 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;
  • Residence in a nursing home; persons residing in an assisted living or retirement community are eligible if they meet the other criteria.
  • 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.
  • Couples or significant partners who live together cannot be enrolled or participate simultaneously in the study.
  • Lack of approval from participant's regular healthcare providers, i.e. a signed letter of agreement for the participants to be enrolled in rrAD.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Pennington Biomedical Research Center

    Baton Rouge, Louisiana, 70808

  • UT Southwestern Medical Center

    Dallas, Texas, 75390

  • University of Kansas Medical Center Research Institute

    Kansas City, Kansas, 66160

  • Washington University in St. Louis

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: Exercise and Intensive Vascular Risk Reduction in Preventing Dementia

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.

Read the detailed description

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).

Being tested
Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine), Aerobic Exercise Training, Usual Care, Stretching Exercise
Keywords
Dementia, Alzheimer's Disease, Cognitive Function, Blood Pressure, Cholesterol, Physical Activity, Exercise, Magnetic Resonance Imaging
Medical subject headings
Hypertension, Dementia, Alzheimer Disease, Motor Activity

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 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)

  • Aerobic Exercise TrainingBehavioural

    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 CareOther

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

  • Stretching ExerciseBehavioural

    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.

Study groups in NCT02913664
Study groupRoleWhat they receive
Aerobic Exercise (Ex)ExperimentalAerobic exercise training; blood and cholesterol management will be standard-care by participant's regular doctor.
Receives: Behavioral: Aerobic Exercise Training; Other: Usual Care
Intensive Reduction of Vascular Risk Factors (IRVR)ExperimentalLowering SBP < 130 mmHg, administration of atorvastatin 80 mg daily, and stretching exercise.
Receives: Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine); Behavioral: Stretching Exercise
IRVR+ExExperimentalA combination of IRVR and aerobic exercise training.
Receives: Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine); Behavioral: Aerobic Exercise Training
Usual CarePlacebo comparatorBlood and cholesterol management will be standard-care by participant's regular doctor, and stretching exercise.
Receives: Other: Usual Care; Behavioral: Stretching Exercise

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 2 Years

Secondary outcomes (9)

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

    Measured: 2 Years

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

    Measured: 2 years

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

    Measured: 2 years

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

    Measured: 2 years

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

    Measured: 2 years

  6. Brain neural network functional connectivity assessed via functional Magnetic Resonance Imaging (MRI).

    Measured: 2 years

  7. Patient-reported outcomes (PRO) of mental and physical health and health-related quality of life assessed by using NIH PROMIS.

    Measured: 2 years

  8. Physical function assessed via the Short Physical Performance Battery (SPPB).

    Measured: 2 years

  9. Dual task performance assessed via distracted and non-distracted 10 meter walk.

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Sep 2016 (estimated)
  2. Study start2 Feb 2017
  3. Primary completion30 Nov 2021
  4. Study completion31 Jan 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Factorial
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
513 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02913664
Sponsor's protocol ID
RZNIA60
Acronym
rrAD
Status last verified
Feb 2022
First submitted
14 Sep 2016
Last updated
15 Feb 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Data from the study will be shared approximately 18-24 months after the primary study publication.

Publications

  • Zhang R, Vidoni E, Vongpatanasin W, Kerwin DR, Cullum CM, Rossetti H, Stowe AM, Billinger SA, Gupta A, Hall T, Scheel N, Zhu DC, Hynan LS, Burns JM, Keller JN, Binder EF. Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial. JAMA Neurol. 2026 May 1;83(5):424-434. doi: 10.1001/jamaneurol.2026.0359.

    PubMed 41870419

  • 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.

    PubMed 35636733

  • 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.

    PubMed 32716358

  • 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.

    PubMed 31710528

  • 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.

    PubMed 30826452

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine), Aerobic Exercise Training and Stretching Exercise in people with Cognitively Normal Older Adults and Hypertension, run by University of Texas Southwestern Medical Center at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in global neurocognitive function (time frame: 2 Years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02913664, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2022.

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