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| ID | Type | Description | Link |
|---|---|---|---|
| H-2009-0036 | Other Identifier | UW Madison IRB | |
| A534255 | Other Identifier | UW, Madison | |
| SMPH/MEDICINE/GER-AD DEV | Other Identifier | UW, Madison |
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Angiotensin converting enzyme inhibitors (ACE-I) are a group of blood pressure-lowering medicines. Some studies suggest that ACE-I, such as ramipril, may help prevent Alzheimer's disease (AD). The purpose of the research is to see how ramipril affects a substance in the body called beta-amyloid. Beta-amyloid is found in the brain and in the liquid around the brain and spinal cord. High amounts of beta-amyloid may be associated with a greater risk of getting Alzheimer's disease. This study will see if ramipril can lower the amount of beta-amyloid in the spinal fluid. This study will also see if ramipril affects blood vessel function and memory and thinking. The investigators hope that future studies will show whether ramipril might prevent memory loss and decrease the chance of developing Alzheimer's disease.
High blood pressure (BP) in midlife is predictive of Alzheimer's disease (AD) in later life. Similarly, reductions in BP are associated with protection against AD. Treatment with antihypertensive medications, specifically angiotensin converting enzyme inhibitors (ACE-I) such as ramipril, is associated with up to a 55% reduction in the prevalence of AD, suggesting a potentially promising role for ACE-I in the prevention of AD. It is unknown however 1) whether ACE-Is will have the same effect on Cerebrospinal fluid (CSF) Aβ levels in humans as in animal models 2) whether ACE-Is induce changes associated with vascular function (i.e. levels of CSF angiotensin converting enzyme (ACE) and peripheral endothelial function) and 3) whether there are interactions between ACE-I-induced changes in CSF Aβ, CSF ACE and indices of vascular function.
One mechanism by which antihypertensives may protect against AD is via Aβ neuropathology. In order to better understand the mechanisms through which ACE-I may modify CSF Aβ and possibly AD risk, we propose a randomized, double-blind, placebo-controlled pilot clinical trial, enrolling 20 middle-aged (age range 40 - 65 years), mildly hypertensive (between 130 - 160 mmHg mean systolic and between 85 - 100 mmHg mean diastolic) participants, who are adult children of an individual with AD. The main objective of this trial is to examine the effects of the ACE-I, ramipril, on 1) CSF Aβ levels 2) CSF ACE levels and 3) peripheral endothelial function as measured by brachial artery flow-mediated vasodilation (FMD) and aortic augmentation index (AAIx), in middle-aged adults with mildly elevated BP, who are at increased risk of developing AD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Matching Placebo |
|
| Active | Experimental | Ramipril 5mg/day |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ramipril | Drug | Ramipril 5 mg/day |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | CSF Aβ42 levels will be measured from the cerebrospinal fluid taken from subjects on ramipril or placebo at the baseline visit and month 4 and will be measured by Dr. Henrik Zetterberg's laboratory. | Baseline to 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | CSF ACE levels will be measured from the cerebrospinal fluid taken from subjects on Ramipril or placebo at the baseline visit and month 4 and will be measured by ARUP® laboratories by spectrophotometric enzymatic assay. | Baseline to 4 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cynthia M Carlsson, MD, MS | University of Wisconsin, Madison | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wisconisn Alzheimer's Disease Research Center | Madison | Wisconsin | 53705 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22776970 | Background | Wharton W, Stein JH, Korcarz C, Sachs J, Olson SR, Zetterberg H, Dowling M, Ye S, Gleason CE, Underbakke G, Jacobson LE, Johnson SC, Sager MA, Asthana S, Carlsson CM. The effects of ramipril in individuals at risk for Alzheimer's disease: results of a pilot clinical trial. J Alzheimers Dis. 2012;32(1):147-56. doi: 10.3233/JAD-2012-120763. |
| Label | URL |
|---|---|
| Related Info | View source |
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Participants were recruited from the Wisconsin Alzheimer's Disease Research Center (ADRC) registry and from the community for the clinical trial, Studying the Effects of Antihypertensives in Individuals at Risk for Alzheimer's (SEAIRA).
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Matching Placebo Placebo: Matching Placebo |
| FG001 | Active | Ramipril 5mg/day Ramipril: Ramipril 5 mg/day |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Matching Placebo Placebo: Matching Placebo |
| BG001 | Active | Ramipril 5mg/day Ramipril: Ramipril 5 mg/day |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Cerebrospinal Fluid (CSF) Amyloid Beta-42 (Aβ42) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | CSF Aβ42 levels will be measured from the cerebrospinal fluid taken from subjects on ramipril or placebo at the baseline visit and month 4 and will be measured by Dr. Henrik Zetterberg's laboratory. | Posted | Mean | Standard Deviation | pg/ml | Baseline to 4 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Matching Placebo Placebo: Matching Placebo |
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Limitations included small sample size, short duration of trial, and lack of A-beta neuropathology.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cynthia M. Carlsson, MD, MS | University of Wisconsin School of Medicine and Public Health | 608-256-1901 | 11691 | cmc@medicine.wisc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 5, 2014 | Aug 13, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D017257 | Ramipril |
| ID | Term |
|---|---|
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Placebo |
| Drug |
Matching Placebo |
|
| Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | FMD is calculated as the ratio of brachial artery diameter after reactive hyperemia to baseline diameter, expressed as percentage change. FMD for each subject (ramipril v placebo) will be measured at baseline and month 4, observing any differences. | Baseline to 4 months |
| Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Pulse wave velocity was measured using an AtCor SphymoCor Px tonometry system. A small pressure transducer was placed on the skin at the point the arterial pulsation of the right common carotid and right radial arteries. A Millar micromanometer is in the tip of the probe. Using a generalized transfer function, the distance between these pressure points, and the peripheral arterial waveforms, a central aortic pressure signal is derived, from which aortic augmentation index is determined. | Baseline to 4 months |
| The Effects of Ramipril in Individuals at Risk for Alzheimer's Disease: Results of a Pilot Clinical Trial | View source |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | Change in CSF Angiotensin Converting Enzyme (ACE) Levels Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | CSF ACE levels will be measured from the cerebrospinal fluid taken from subjects on Ramipril or placebo at the baseline visit and month 4 and will be measured by ARUP® laboratories by spectrophotometric enzymatic assay. | Posted | Mean | Standard Deviation | U/L | Baseline to 4 months |
|
|
|
|
| Secondary | Change in Flow-mediated Vasodilation (FMD) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | FMD is calculated as the ratio of brachial artery diameter after reactive hyperemia to baseline diameter, expressed as percentage change. FMD for each subject (ramipril v placebo) will be measured at baseline and month 4, observing any differences. | Posted | Mean | Standard Deviation | Percentage change | Baseline to 4 months |
|
|
|
|
| Secondary | Change in Augmentation Index (%) Between Baseline and Month 4 in Subjects Taking Ramipril vs Subjects on Placebo | Pulse wave velocity was measured using an AtCor SphymoCor Px tonometry system. A small pressure transducer was placed on the skin at the point the arterial pulsation of the right common carotid and right radial arteries. A Millar micromanometer is in the tip of the probe. Using a generalized transfer function, the distance between these pressure points, and the peripheral arterial waveforms, a central aortic pressure signal is derived, from which aortic augmentation index is determined. | Posted | Mean | Standard Deviation | Percentage change | Baseline to 4 months |
|
|
|
|
| 0 |
| 6 |
| 0 |
| 6 |
| EG001 | Active | Ramipril 5mg/day Ramipril: Ramipril 5 mg/day | 0 | 8 | 0 | 8 |
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| 0.009 |
| Mean Difference (Final Values) |
| -0.63 |
| Standard Deviation |
| 0.32 |
| 2-Sided |
| Other |
Mann-Whitney Test |
| 0.755 |
| Mean Difference (Final Values) |
| -0.29 |
| Standard Deviation |
| 1.23 |
| 2-Sided |
| Other |
Mann-Whitney test |
| 0.491 |
| Mean Difference (Final Values) |
| -1.8 |
| Standard Deviation |
| 2.2 |
| 2-Sided |
| Other |
Mann-Whitney test |