Health Evaluation in African Americans Using RAS Therapy (HEART)

• ClinicalTrials.gov Identifier: NCT02471833
• Recruitment Status: Completed
• First Posted: June 15, 2015
• Last Update Posted: April 27, 2023
• Sponsor: Emory University
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Whitney Wharton, Emory University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: Telmisartan 20mg; Drug: Telmisartan 40mg; Drug: Placebo	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Health Evaluation in African Americans Using RAS Therapy
• Actual Study Start Date: April 2015
• Actual Primary Completion Date: April 15, 2022
• Actual Study Completion Date: April 15, 2022

Arms and Interventions

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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Change in Concentration of Angiotensin Converting Enzyme (ACE 1) [ Time Frame: Baseline, Month 8 ]
   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.
2. Change in Concentration of Angiotensin Converting Enzyme 2 (ACE 2) [ Time Frame: Baseline, Month 8 ]
   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.
3. Change in Levels of Cerebrospinal Fluid Amyloid β40 [ Time Frame: Baseline, Month 8 ]
   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.
4. Change in Levels of Cerebrospinal Fluid Amyloid β42 [ Time Frame: Baseline, Month 8 ]
   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.
5. Change in Levels of Cerebrospinal Fluid T-tau [ Time Frame: Baseline, Month 8 ]
   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.
6. Change in Levels of Cerebrospinal Fluid P-tau [ Time Frame: Baseline, Month 8 ]
   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.

Secondary Outcome Measures :

1. Change in Interleukin (IL) Frequency [ Time Frame: Baseline, Month 8 ]
   Interleukin CSF inflammatory markers will be examined in CSF.
2. Change in Monocyte Chemoattractant Protein 1 (MCP-1) Frequency [ Time Frame: Baseline, Month 8 ]
   Monocyte chemoattractant protein 1 inflammatory markers will be examined in CSF.
3. Change in Macrophage derived protein 1 (MDC-1) Frequency [ Time Frame: Baseline, Month 8 ]
   Macrophage derived protein 1 inflammatory markers will be examined in CSF.
4. Change in Transforming Growth Factor Alpha (TGF-α) Frequency [ Time Frame: Baseline, Month 8 ]
   Transforming growth factor alpha inflammatory markers will be examined in CSF.
5. Change in Tumor Necrosis Factor Alpha (TNF-α) Frequency [ Time Frame: Baseline, Month 8 ]
   Tumor necrosis factor alpha inflammatory markers will be examined in CSF.
6. Change in Intercellular Adhesion Molecule 1 (ICAM-1) Frequency [ Time Frame: Baseline, Month 8 ]
   Intercellular adhesion molecule 1 inflammatory markers will be examined in CSF.
7. Change in Vascular Cell Adhesion Molecule 1 (VCAM-1) Frequency [ Time Frame: Baseline, Month 8 ]
   Vascular cell adhesion molecule 1 inflammatory markers will be examined in CSF.
8. Change in Matrix Metalloproteinase (MMP) Frequency [ Time Frame: Baseline, Month 8 ]
   Matrix metalloproteinase inflammatory markers will be examined in CSF.
9. Change in Tissue Inhibitor of Metalloproteinase (TIMP) Frequency [ Time Frame: Baseline, Month 8 ]
   Tissue inhibitor of metalloproteinase inflammatory markers will be examined in CSF.
10. Change in Arterial Spin Labeling-Magnetic Resonance Imaging [ Time Frame: Baseline, Month 8 ]
    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.
11. Change in Structural Magnetic Resonance Imaging and White Matter Hyperintensities [ Time Frame: Baseline, Month 8 ]
    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.
12. Change in CSF-Soluble Platelet-Derived Growth Factor Receptor Beta (sPDGFRβ) [ Time Frame: Baseline, Month 8 ]
    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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

Sponsors and Collaborators

Emory University

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Whitney Whitney, PhD; Emory University

  Study Documents (Full-Text)

Documents provided by Whitney Wharton, Emory University:

Informed Consent Form  [PDF] January 13, 2021

More Information

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.

• Responsible Party: Whitney Wharton, Assistant Professor, Emory University
• ClinicalTrials.gov Identifier: NCT02471833
• Other Study ID Numbers: IRB00080192; 1RF1AG051514 ( U.S. NIH Grant/Contract )
• First Posted: June 15, 2015
• Last Update Posted: April 27, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Whitney Wharton, Emory University:

hypertension; prevention; family history; inflammation; blood brain barrier; amyloid

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Telmisartan; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Molecular Mechanisms of Pharmacological Action