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Risk Reduction for Alzheimer's Disease (rrAD)

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ClinicalTrials.gov Identifier: NCT02913664
Recruitment Status : Recruiting
First Posted : September 26, 2016
Last Update Posted : February 15, 2019
Sponsor:
Collaborators:
Texas Health Resources
University of Kansas Medical Center
Washington University School of Medicine
Pennington Biomedical Research Center
Michigan State University
Information provided by (Responsible Party):
Rong Zhang, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE September 14, 2016
First Posted Date  ICMJE September 26, 2016
Last Update Posted Date February 15, 2019
Study Start Date  ICMJE September 2016
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2016)
Change in global neurocognitive function [ Time Frame: 2 Years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02913664 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2016)
  • Domain-specific neurocognitive function assessed by using the tests included in the ADCS-PACC and NIH-TB Cognition. [ Time Frame: 2 Years ]
  • Whole brain and hippocampal volume assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  • Global and regional brain perfusion assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  • Brain white matter hyperintensity (WMH) assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  • Brain white matter microstructural integrity assessed via Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  • Brain neural network functional connectivity assessed via functional Magnetic Resonance Imaging (MRI). [ Time Frame: 2 years ]
  • Patient-reported outcomes (PRO) of mental and physical health and health-related quality of life assessed by using NIH PROMIS. [ Time Frame: 2 years ]
  • Physical function assessed via the Short Physical Performance Battery (SPPB). [ Time Frame: 2 years ]
  • Dual task performance assessed via distracted and non-distracted 10 meter walk. [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Risk Reduction for Alzheimer's Disease
Official Title  ICMJE Exercise and Intensive Vascular Risk Reduction in Preventing Dementia
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.
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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Cognitively Normal Older Adults
  • Hypertension
  • Subjective Cognitive Decline
  • Family History of Alzheimer's Disease
Intervention  ICMJE
  • Drug: 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)

  • Behavioral: 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.
  • Other: Usual Care
    Participants will follow their regular doctor's recommendations for blood pressure and lipid control.
  • Behavioral: 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.
  • Drug: Atorvastatin
Study Arms  ICMJE
  • Experimental: Aerobic Exercise (Ex)
    Aerobic exercise training; blood and cholesterol management will be standard-care by participant's regular doctor.
    Interventions:
    • Behavioral: Aerobic Exercise Training
    • Other: Usual Care
  • Experimental: Intensive Reduction of Vascular Risk Factors (IRVR)
    Lowering SBP < 130 mmHg, administration of atorvastatin 80 mg daily, and stretching exercise.
    Interventions:
    • Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)
    • Behavioral: Stretching Exercise
    • Drug: Atorvastatin
  • Experimental: IRVR+Ex
    A combination of IRVR and aerobic exercise training.
    Interventions:
    • Drug: Angiotensin II receptor blocker (ARB, losartan) and calcium channel blocker (CCB, amlodipine)
    • Behavioral: Aerobic Exercise Training
  • Placebo Comparator: Usual Care
    Blood and cholesterol management will be standard-care by participant's regular doctor, and stretching exercise.
    Interventions:
    • Other: Usual Care
    • Behavioral: Stretching Exercise
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 23, 2016)
640
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lauren Braunfeld, BS 214-345-7134 LaurenBraunfeld@TexasHealth.org
Contact: Ann Jacob, BSN 214-345-4665 AnnJacob@TexasHealth.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02913664
Other Study ID Numbers  ICMJE RZNIA60
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data from the study will be shared approximately 18-24 months after the primary study publication.
Responsible Party Rong Zhang, University of Texas Southwestern Medical Center
Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Collaborators  ICMJE
  • Texas Health Resources
  • University of Kansas Medical Center
  • Washington University School of Medicine
  • Pennington Biomedical Research Center
  • Michigan State University
Investigators  ICMJE
Principal Investigator: Rong Zhang, PhD UT 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
PRS Account University of Texas Southwestern Medical Center
Verification Date February 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP