Health Evaluation in African Americans Using RAS Therapy (HEART)

The purpose of this study is to determine if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease prevention in African Americans, who are at high risk for Alzheimer's disease.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Telmisartan 20mg; Drug: Telmisartan 40mg; Drug: Placebo

Detailed Description

This study will assess if telmisartan, an FDA approved blood pressure medication, may also have beneficial effects on Alzheimer's disease (AD) prevention in African Americans, who are at high risk for Alzheimer's disease. Blood pressure medications known as angiotensin-receptor blockers have been associated with reduced risk of Alzheimer's in Caucasians because they act on the renin-angiotensin system (RAS), a key regulator of blood pressure in the body and the brain. The drugs appear to slow the progression of the disease by affecting flow of blood and the amount of plaque in the brain, but these benefits have not been tested in African Americans. The investigator will evaluate if telmisartan is able to influence the renin-angiotensin system in the brain and produce favorable effects on brain blood flow and enzymes that cause the brain plaques in Alzheimer's disease.The investigator will assess the mechanism by which telmisartan modifies the brain renin angiotensin system, cerebrospinal fluid amyloid-β, cerebral blood flow (CBF) and inflammatory markers in hypertensive African Americans.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Mean resting systolic blood pressure ≥ 110 mmHg and ≤ 170 mmHg
• Family history of Alzheimer's disease
• African American

Exclusion Criteria:

• Currently in another investigational drug study
• Potassium >5.0 meq/dL at baseline
• Creatinine >1.99 mg/dL at baseline
• History of stroke or transient ischemic attack (TIA)
• Dementia
• Current use of a RAS acting medication
• Contraindication for lumbar puncture or magnetic resonance imaging
• Heart failure
• Diabetes Types I and II
• Pregnant or nursing women

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Telmisartan 20mg; African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive telmisartan 20mg once a day orally.	Drug: Telmisartan 20mg; Participants will be given 20 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.; Other Names: Micardis
Experimental: Telmisartan 40mg; African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive telmisartan 40mg once a day orally.	Drug: Telmisartan 40mg; Participants will be given 40 mg of telmisartan to be taken orally once a day before bedtime, for a duration of 8 months.; Other Names: Micardis
Placebo Comparator: Placebo; African American participants with and without hypertension and at high risk for Alzheimer's disease randomly assigned to receive a placebo to match telmisartan once a day orally.	Drug: Placebo; Participants will be given placebo to be taken orally once a day before bedtime, for a duration of 8 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Concentration of Angiotensin Converting Enzyme (ACE 1)	The cerebrospinal fluid renin-angiotensin system (RAS) will be assessed by measuring levels of angiotensin metabolites sample 1ml of cerebrospinal fluid (CSF). ACE 1 helps to regulate blood pressure by converting angiotensin I to angiotensin II. Normal values for ACE are below 40 micrograms/L.	Baseline, Month 8
Change in Concentration of Angiotensin Converting Enzyme 2 (ACE 2)	The cerebrospinal fluid renin-angiotensin system (RAS) will be assessed by measuring levels of angiotensin metabolites sample 1ml of cerebrospinal fluid (CSF). ACE 2 regulates levels of circulating angiotensin II. ACE 2 increases during illness and with Alzheimer's disease.	Baseline, Month 8
Change in Levels of Cerebrospinal Fluid Amyloid β40	Levels of amyloid β40 (Aβ40) in the cerebrospinal fluid will be measured using LUMIPULSE® technology. The relationship between Aβ40 is non-linear with moderate levels showing the highest risk of future cognitive decline in some studies.	Baseline, Month 8
Change in Levels of Cerebrospinal Fluid Amyloid β42	Levels of amyloid β42 (Aβ42) in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Decrease in concentrations of amyloid β42 are indicative of a decrease in cognitive function.	Baseline, Month 8
Change in Levels of Cerebrospinal Fluid T-tau	Levels of T-tau in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Increase in concentrations of T-tau are indicative of a decrease in cognitive function.	Baseline, Month 8
Change in Levels of Cerebrospinal Fluid P-tau	Levels of P-tau in the cerebrospinal fluid will be measured using LUMIPULSE® technology. Increase in concentrations of P-tau are indicative of a decrease in cognitive function.	Baseline, Month 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Interleukin (IL) Frequency	Interleukin CSF inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Monocyte Chemoattractant Protein 1 (MCP-1) Frequency	Monocyte chemoattractant protein 1 inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Macrophage derived protein 1 (MDC-1) Frequency	Macrophage derived protein 1 inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Transforming Growth Factor Alpha (TGF-α) Frequency	Transforming growth factor alpha inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Tumor Necrosis Factor Alpha (TNF-α) Frequency	Tumor necrosis factor alpha inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Intercellular Adhesion Molecule 1 (ICAM-1) Frequency	Intercellular adhesion molecule 1 inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency	Vascular cell adhesion molecule 1 inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Matrix Metalloproteinase (MMP) Frequency	Matrix metalloproteinase inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Tissue Inhibitor of Metalloproteinase (TIMP) Frequency	Tissue inhibitor of metalloproteinase inflammatory markers will be examined in CSF.	Baseline, Month 8
Change in Arterial Spin Labeling-Magnetic Resonance Imaging	Echoplanar T1 mapping scans will be used for image registration and a scout image of the head will be obtained in order to choose the appropriate location for spin labeling and flow imaging. Arterial Spin Labeling images will be acquired using a custom 3D stack of interleaved spirals fast spin echo sequences and will be averaged in order to improve the signal-to-noise ratio. Images will be interpolated and smoothed in a panel by using a 0.5-pixel, full-width, half-maximum Gaussian kernel. Regional perfusion will be quantified in each hemisphere and maps of cerebral vasoreactivity will be obtained by co-registration of perfusion and anatomical images.	Baseline, Month 8
Change in Structural Magnetic Resonance Imaging and White Matter Hyperintensities	High-resolution anatomical images will be acquired using a 3D-Fast Spoiled Gradient Recalled Echo (FSPGR) Sequence. White Matter Hyperintensities (WMH) will be identified by a 3D T2 Fluid Attenuated Inversion Recovery (FLAIR) Fast Spin Echo sequence. The images will be co-registered using a within-subject inter-modal alignment between structural and perfusion images. T1-weighted Spoiled Gradient Recalled (SPGR) images will be used to identify cerebrospinal fluid and white and gray matter. Increased volumes of white matter hyperintensities indicate impaired cognitive function.	Baseline, Month 8
Change in CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ)	Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) is a marker of breakdown in the blood brain barrier. Increased levels of sPDGFRβ indicate cognitive dysfunction.	Baseline, Month 8

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Whitney Whitney, PhD, Emory University

Publications and helpful links

General Publications

• Wharton W, Goldstein FC, Tansey MG, Brown AL, Tharwani SD, Verble DD, Cintron A, Kehoe PG. Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. J Alzheimers Dis. 2018;61(2):815-824. doi: 10.3233/JAD-161198.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): April 15, 2022
• Study Completion (Actual): April 15, 2022

Study Registration Dates

• First Submitted: June 10, 2015
• First Submitted That Met QC Criteria: June 11, 2015
• First Posted (Estimate): June 15, 2015

Study Record Updates

• Last Update Posted (Actual): April 27, 2023
• Last Update Submitted That Met QC Criteria: April 11, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: amyloid; hypertension; prevention; blood brain barrier; inflammation; family history
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Telmisartan
• Other Study ID Numbers: IRB00080192; 1RF1AG051514 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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