Hypertension, Intracranial Pulsatility and Brain Amyloid-beta Accumulation in Older Adults (HIPAC Trial) (HIPAC)

The aim of this study is to determine if lowering blood pressure using FDA approved medication (antihypertensive drugs) alters brain pulsatility and reduces brain amyloid beta protein accumulation in older adults. Amyloid beta protein is high in the brain of older adults with Alzheimer's disease. Hypertension may increase brain amyloid beta protein accumulation and affect memory and thinking ability in older adults. However, whether lowering blood pressure reduces brain amyloid beta protein and improves brain function is inconclusive.

The investigators hypothesize that treating high blood pressure alters brain pulsatility, which in turn reduces brain amyloid beta protein accumulation and improves brain structure and function.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension
• Intervention / Treatment: Drug: Standard Care; Drug: Intensive Treatment

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Age 55-79, all races/ethnicities, and both women and men are eligible;
2. Mini-mental state exam (MMSE) > 26 to exclude cognitive impairment or dementia;
3. Healthy normotensive subjects (24-hour ambulatory BP<125/75 mmHg without use of antihypertensive medication);
4. Patients with hypertension defined as 24-hour SBP ≥130 mmHg , patients on BP medications are eligible;
5. Patients with hypertension are willing to be randomized into either treatment group and ability to return to clinic or laboratory for follow-up visits over 12 months;
6. Fluency in English, adequate visual and auditory acuity to allow neuropsychological testing;
7. Screening laboratory tests and ECG without significant abnormalities that might interfere with the study

Exclusion Criteria:

1. History of stroke, transient ischemic attack, traumatic brain injury or severe cerebrovascular disease by clinical diagnosis or past MRI/CT;
2. Diagnosis of AD or other type of dementia and neurodegenerative diseases;
3. Evidence of severe depression or other DSM-V Axis I psychopathology
4. Unstable heart disease based on clinical judgment (heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure), evidence of atrial fibrillation on ECG, or other severe medical conditions;
5. Chronic kidney diseases with GFR < 40 ml/min;
6. Orthostatic hypotension, defined as standing SBP<100 mmHg;
7. History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and polymyalgia rheumatica;
8. History of drug or alcohol abuse within the last 2 years;
9. Diagnosis of uncontrolled diabetes mellitus (fasting blood sugar ≥126 mg/dL or A1C >7.5%)
10. Obstructive sleep apnea;
11. Regularly smoking cigarette within the past year;
12. Severe obesity with BMI ≥ 45;
13. Participants enrolled in another investigational drug or device study within the past 2 months;
14. Carotid stent or sever stenosis (> 50%);
15. Pacemaker or other medical device of metal that precludes performing MRI;
16. History of B12 deficiency or hypothyroidism (stable treatment for at least 3 months is allowable);
17. Any conditions judged by the study investigators to be either medically inappropriate, or risky for participant or likely to have poor study adherence;
18. Claustrophobia;
19. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Care; Subjects in the standard care arm will receive calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs to reduce 24-hour SBP ≤ 130 mmHg. Drug doses will be titrated to reach the BP target.	Drug: Standard Care; Calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs will be used to reduce 24-hour SBP ≤ 130 mmHg.
Experimental: Intensive Treatment; Subjects in the intensive treatment arm will receive calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs to reduce 24-hour SBP ≤ 120 mmHg.	Drug: Intensive Treatment; Calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs will be used to reduce 24-hour SBP ≤ 120 mmHg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in intracranial pulsatility	Changes in intracranial pulsatility will be measured with CINE phase-contrast MRI	Baseline and 12-months

Secondary Outcome Measures

Outcome Measure	Time Frame
Cerebrospinal fluid Amyloid-β and tau	Baseline and 12-months
Global and regional brain perfusion via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Regional brain volume via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Regional cortical thickness via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Brain white matter hyperintensity (WMH) via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Brain white matter microstructural integrity via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Brain neural network functional connectivity via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
NIH-Toolbox neurocognitive function	Baseline, 6-months,12-months
NIH PROMIS patient-reported outcome measures of physical health	Baseline, 6-months, 12-months
NIH PROMIS patient-reported outcome measures of mental health	Baseline, 6-months, 12-months

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: Michigan State University; Texas Health Resources
• Investigators: Principal Investigator: Rong Zhang, PhD, University of Texas Southwestern Medical Center and Texas Health Resources; Principal Investigator: Wanpen Vongpatanasin, MD, University of Texas Southwestern Medical Center; Principal Investigator: David Zhu, PhD, Michigan State University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2018
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): March 30, 2024

Study Registration Dates

• First Submitted: November 15, 2017
• First Submitted That Met QC Criteria: November 21, 2017
• First Posted (Actual): November 27, 2017

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Dementia; Magnetic Resonance Imaging; Blood Pressure; Cognitive Function
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypertension; Intracranial Hypertension
• Other Study ID Numbers: R01AG057571 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared approximately 18-24 months after the primary study publication.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No