Impact of Intensive Treatment of SBP on Brain Perfusion, Amyloid, and Tau (IPAT Study) (IPAT)

• ClinicalTrials.gov Identifier: NCT05331144
• Recruitment Status: Recruiting
• First Posted: April 15, 2022
• Last Update Posted: December 2, 2022
• Sponsor: Rong Zhang
• Collaborators: National Institute on Aging (NIA); Texas Health Resources; Michigan State University
• Information provided by (Responsible Party): Rong Zhang, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

The purpose of this study is to determine if intensive lowering of systolic blood pressure (SBP), using FDA approved medications (antihypertensive), reduces Alzheimer's Disease pathology (i.e., excessive brain amyloid and tau protein deposition) in older adults at high risk for memory decline or dementia.

Condition or disease	Intervention/treatment	Phase
Cognitively Normal Older Adults; Hypertension; Subjective Cognitive Decline; Family History of Dementia	Drug: Angiotensin II Receptor Blockers (ARBs, losartan) and Calcium Channel Blockers (CCB, amlodipine); Other: PCP	Phase 2

Detailed Description:

The IPAT study is a 2-arm open-label randomized controlled trial to assess the effects of intensive pharmacological reduction of high blood pressure (SBP) on brain amyloid and tau protein deposition (Alzheimer's Disease pathology) in older adults who are at high risk for AD and related dementias, that is, those who have high blood pressure, family history of dementia, or subjective memory complaints. Furthermore, IPAT will examine effects of intensive blood pressure lowering on brain volume, perfusion, and neural network connectivity using magnetic resonance imaging (MRI) and cognitive performance.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid, and Tau in Older Adults (IPAT Study)
• Actual Study Start Date: October 25, 2022
• Estimated Primary Completion Date: June 1, 2027
• Estimated Study Completion Date: June 1, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intensive Treatment (IT); Lowering SBP < 120 mmHG	Drug: Angiotensin II Receptor Blockers (ARBs, losartan) and Calcium Channel Blockers (CCB, amlodipine); Angiotensin II Receptor Blockers (ARBs, losartan) and Calcium Channel Blockers (CCB, amlodipine) will be used to treat high blood pressure. Additional antihypertensive medications may be used if needed.
Active Comparator: Usual Care (UC); Participants will follow their PCP's recommendations for BP control	Other: PCP; Participants will follow their PCP's recommendations for BP control.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Brain Fibrillar Beta-Amyloid Protein (Aβ) [ Time Frame: Baseline, 24 months ]
   Brain Aβ will be measured by annual change of amyloid mean cortical standardized uptake value ratio (SUVR) with positron emission tomography (PET).

Secondary Outcome Measures :

1. Change From Baseline in Brain Tau Deposition [ Time Frame: Baseline, 24 months ]
   Brain Tau Deposition will be measured by tau temporal meta-ROI composite with positron emission tomography (PET).
2. Change From Baseline in regional Cerebral Blood Flow (CBF) [ Time Frame: Baseline, 12 months, 24 months ]
   Regional CBF will be measured by MRI using arterial spin labeling.
3. Change From Baseline in global Cerebral Blood Flow (CBF) [ Time Frame: Baseline, 12 months, 24 months ]
   Global CBF will be measured by PC-MRI and 2D color-coded duplex ultrasonography.
4. Change From Baseline in Arterial Stiffness [ Time Frame: Baseline, 12months, 4 months ]
   Central arterial stiffness (pulse wave velocity and carotid β-stiffness index) will be measured by artery applanation tonometry.
5. Change From Baseline in Amplitude of Low Frequency Fluctuations of Blood-Oxygen-Level-Dependent Signal (BOLD ALFF) [ Time Frame: Baseline, 12 months, 24 months ]
   BOLD ALFF will be measured by resting state functional MRI (rs-fMRI).
6. Change From Baseline in White Matter Hyperintensity Volume [ Time Frame: Baseline, 12 months, 24 months ]
   White matter hyperintensity volume will be measured by MRI using 3D T2 FLAIR sequence .
7. Change From Baseline in Brain Neural Network Connectivity [ Time Frame: Baseline, 12 months, 24 months ]
   Brain neural network connectivity will be measured by rs-fMRI.
8. Change From Baseline in Neurocognitive Function [ Time Frame: Baseline, 12 months, 24 months ]
   A composite z score will be obtained by conversion of individual test scores of the Preclinical Alzheimer Cognitive Composite (PACC) and the NIH Toolbox Cognition Battery to standardized z scores, then averaged to assess changes in global cognitive function. Domain-specific z scores will be used to assess specific domains of cognitive function (i.e., memory, executive function, language etc.).

Eligibility Criteria

• Ages Eligible for Study: 60 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age 60-80, 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 memory complaints defined as a positive answer to BOTH of the following questions:

  1. "Are you worried about your memory or thinking abilities?

     a) Not at all, b) A little bit, c) A lot"; B and C - includes

  2. "Do you feel you have difficulty with your memory or thinking that is worse than in the past?" b) Yes or No; Yes - includes
• Mini-Mental State Exam (MMSE) ≥ 26 to exclude gross dementia; based on clinical judgment, may be rescreened in ≥ 7 days;
• Individuals with SBP ≥ 130 and SBP ≤ 180; Those on antihypertensives are eligible. 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 or Spanish or both, adequate visual and auditory acuity to allow neuropsychological testing;
• Participants must have a regular healthcare provider.

Exclusion Criteria:

• 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 antiarrhythmic drugs including flecainide, propafenone, dronedarone, sotalol, dofetilide, and amiodarone; or clinical concerns for safely participating in 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 rheumatica;
• Significant history of alcoholism or drug abuse within the last five years;
• Uncontrolled diabetes mellitus, defined as hemoglobin A1C > 6.5%, or requiring insulin treatment;
• Clinically diagnosed and untreated sleep apnea;
• Regularly smoking cigarettes within the past year;
• Pacemaker or other medical device of metal that precludes performing MRI;
• Women with a potential for pregnancy, lactation/childbearing (2 year post-menopausal or surgically sterile to be considered not childbearing potential);
• Participant enrolled in another investigational drug or device study, either currently or within the past 2 months;
• Severe obesity with BMI > 40 ; 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 amlodipine;
• Abnormal screening laboratory tests (e.g., liver ALT and AST > 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:

  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.

Contacts and Locations

Contacts

Contact: Tristyn Hall-Curtis, MBA; 2143454245; TristynHall@texashealth.org

Locations

United States, Texas

University of Texas Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75390

Contact: Tristyn Hall-Curtis, MBA 214-345-4245 TristynHall@texashealth.org

Principal Investigator: Rong Zhang, PhD

Principal Investigator: Wanpen Vongpatanasin, MD

Sponsors and Collaborators

Rong Zhang

National Institute on Aging (NIA)

Texas Health Resources

Michigan State University

Investigators

• Principal Investigator: Rong Zhang, PhD; University of Texas Southwestern Medical Center
• Principal Investigator: Wanpen Vongpatanasin, MD; University of Texas Southwestern Medical Center
• Principal Investigator: David Zhu, PhD; Michigan State University

More Information

• Responsible Party: Rong Zhang, Professor of Medicine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT05331144
• Other Study ID Numbers: STU-2021-1210; 1R01AG076660-01 ( U.S. NIH Grant/Contract )
• First Posted: April 15, 2022
• Last Update Posted: December 2, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All of the individual participant data collected during the trial, after deidentification.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: At the time of publication of the primary results or within 9 months of the database lock whichever comes first.
• Access Criteria: The Study Steering Committee (SC) will review and approve the Data and Resource Sharing (DRS) requests from qualified investigators. A Material Transfer Agreement (MTA) and Data Use Agreement (DUA) will be in place with any academic group or scientists before any transfer of bio-samples or other data. Investigators receiving the data and/or samples will be required to abide by the conditions of these agreements. We will make the data and associated documentation available to other investigators only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate technology; and (3) a commitment to destroying or returning the data after analyses are completed.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rong Zhang, University of Texas Southwestern Medical Center:

Dementia; Alzheimer's Disease; Cognitive Function; Blood Pressure; Amyloid; Tau

Additional relevant MeSH terms:

Dementia; Cognitive Dysfunction; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Losartan; Amlodipine; Calcium Channel Blockers; Angiotensin II; Giapreza; Calcium; Angiotensin Receptor Antagonists; Angiotensinogen; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Antihypertensive Agents; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Anti-Arrhythmia Agents; Angiotensin II Type 1 Receptor Blockers; Vasoconstrictor Agents; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors