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| ID | Type | Description | Link |
|---|---|---|---|
| CX001261 | Other Grant/Funding Number | VA Merit |
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| Name | Class |
|---|---|
| University of Wisconsin, Madison | OTHER |
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The number of Americans diagnosed with Alzheimer's disease (AD) is expected to triple by 2050. Compared to the general population, Veterans have a greater risk of AD, likely in part due to their increased incidence of traumatic brain injury, post-traumatic stress disorder, depression, and other vascular-related health issues. Based on available data, 423,000 new cases of AD are anticipated in Veterans by 2020. Thus, the discovery of effective therapies to prevent or delay the onset of AD in Veterans is critical. The goal of this study is to evaluate the efficacy of a purified form of the omega-3 fatty acid eicosapentaenoic acid (EPA) called icosapent ethyl (IPE), on improving brain blood flow, spinal fluid markers of AD pathology, and cognitive performance in middle-aged, cognitively-healthy Veterans with increased risk of AD. If IPE delays the onset of AD by even 5 years, the incidence of AD would be reduced by 50% in this population and could have a profound effect on Veteran quality of life and healthcare costs.
The proposed study is a proof-of-concept, randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of 18 months of icosapent ethyl (IPE) therapy on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in 150 cognitively-healthy Veterans ages 50-75 years. The overarching goal of this trial is to assess whether icosapent ethyl beneficially affects intermediate physiological measures associated with onset of AD in order to evaluate whether larger, multi-site, longer-duration Alzheimer's prevention trials are warranted to assess more definitive clinical outcomes. The proposed study aims to: 1) investigate the effects of 18 months of IPE vs. placebo on regional cerebral blood flow as measured by arterial spin-labeling MRI; 2) determine the impact of 18 months of IPE vs. placebo on CSF biomarkers of AD pathology; and 3) evaluate the effects of 18 months of IPE vs. placebo on cognitive performance.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| icosapent ethyl (IPE) | Experimental | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
|
| placebo | Placebo Comparator | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| icosapent ethyl (IPE) | Drug | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
|
| Measure | Description | Time Frame |
|---|---|---|
| Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI | For the primary outcome we chose an anatomical region, posterior cingulate gyrus, that aligned with statistical region of interest sensitive to changes in cerebral blood flow in cognitively-unimpaired adults at risk for Alzheimer's disease. Brain blood flow was averaged across the right and left posterior cingulate gyrus. | 18 month study visit |
| Measure | Description | Time Frame |
|---|---|---|
| Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | CSF beta-amyloid-42, total tau, and phosphorylated tau-181 (Roche Cobas Elecsys e611). Lower CSF beta-amyloid-42 and higher phosphorylated tau-181 or total tau are associated with risk for Alzheimer's disease. | 18 month study visit |
| Cognitive Performance |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cynthia M. Carlsson, MD MS | William S. Middleton Memorial Veterans Hospital, Madison, WI | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| William S. Middleton Memorial Veterans Hospital, Madison, WI | Madison | Wisconsin | 53705-2254 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Icosapent Ethyl (IPE) | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo icosapent ethyl (IPE): Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
| FG001 | Placebo | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo gel cap placebo: Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Icosapent Ethyl (IPE) | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo icosapent ethyl (IPE): Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI | For the primary outcome we chose an anatomical region, posterior cingulate gyrus, that aligned with statistical region of interest sensitive to changes in cerebral blood flow in cognitively-unimpaired adults at risk for Alzheimer's disease. Brain blood flow was averaged across the right and left posterior cingulate gyrus. | Analysis sample is intent-to-treat (ITT), ASL values were imputed from baseline values for 23 participants (n=14 IPE and n=9 placebo); 17 participants lacked baseline ASL values (n=9 IPE, n=8 placebo) and could not be included in analyses. | Posted | Mean | Standard Deviation | mL/g/min | 18 month study visit |
|
18 months
Participants were assessed for adverse events at months 1, 3, 6, 9, 12, 15, and 18.
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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 | Icosapent Ethyl (IPE) | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo icosapent ethyl (IPE): Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mortatilty | General disorders | SNOMED CT | Systematic Assessment | Participant passed away after falling down a staircase. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Injury, poisoning and procedural complications | SNOMED CT | Systematic Assessment | Participant reported headache following an LP |
Study sample lacked racial, ethnic and gender diversity. The study was on-going during COVID-19 closures which impacted participants' ability to take part in in-person study procedures.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cynthia Carlsson, MD, MS; Professor of Medicine (Geriatrics) | Madison Veterans Affairs Geriatrics Research, Education & Clinical Center (GRECC) | 608-280-7000 | cynthia.carlsson@va.gov |
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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 | Sep 13, 2024 | Sep 13, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C035276 | eicosapentaenoic acid ethyl ester |
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1:1 randomization of icosapent ethyl 4 g daily vs matching placebo
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| gel cap placebo | Other | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
|
|
Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (ADCS-PACC). Composite scores at each time point are standardize to baseline values such that at baseline the mean=0 and the standard deviation = 1. Standardized scores range from -3.15 to 3.09. Higher scores indicate better cognition. |
| 18 month study visit |
Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo gel cap placebo: Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Education | Count of Participants | Participants |
|
| APOE risk allele | Apolipoprotein e4 risk allele carriership. | Count of Participants | Participants |
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| Parental history of Alzheimer's disease | Count of Participants | Participants |
|
| Systolic blood pressure | Mean | Standard Deviation | mm/Hg |
|
| Total Cholesterol | Mean | Standard Deviation | mg/dL |
|
| OG001 | Placebo | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo gel cap placebo: Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo |
|
|
|
| Secondary | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | CSF beta-amyloid-42, total tau, and phosphorylated tau-181 (Roche Cobas Elecsys e611). Lower CSF beta-amyloid-42 and higher phosphorylated tau-181 or total tau are associated with risk for Alzheimer's disease. | Analysis is based on an intent-to-treat, n=19 participants dropped out prior to receiving an 18 month lumbar puncture (n=11 IPE, n=8 placebo); 26 participants opted out of the lumbar puncture procedure (n=11 IPE, n=15 placebo) | Posted | Mean | Standard Deviation | pg/mL | 18 month study visit |
|
|
|
|
| Secondary | Cognitive Performance | Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite (ADCS-PACC). Composite scores at each time point are standardize to baseline values such that at baseline the mean=0 and the standard deviation = 1. Standardized scores range from -3.15 to 3.09. Higher scores indicate better cognition. | Analyses were conducted on an intent-to-treat basis. 19 participants dropped out prior to month 18 study visit (n=11 IPE, n=8) | Posted | Mean | Standard Deviation | Z-score | 18 month study visit |
|
|
|
|
| 0 |
| 63 |
| 9 |
| 63 |
| 13 |
| 63 |
| EG001 | Placebo | Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo gel cap placebo: Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo | 1 | 68 | 7 | 68 | 19 | 68 |
|
| COPD | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Systematic Assessment | Participant was hospitalized after COPD attack |
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| Chest pain or tightness | Cardiac disorders | SNOMED CT | Systematic Assessment | Participant was admitted to hospital after presenting chest tightness |
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| Laparoscopic prostatectomy | Surgical and medical procedures | SNOMED CT | Systematic Assessment | Participant had planned surgery for prostate cancer. |
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| Surgery | Cardiac disorders | SNOMED CT | Systematic Assessment | Participant underwent bypass surgery |
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| Sinus bradycardia | Cardiac disorders | SNOMED CT | Systematic Assessment | Participant admitted after presenting to hospital with heart palpitations. |
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| Aortic aneurysm | Cardiac disorders | SNOMED CT | Systematic Assessment | Participant admitted to hospital after an aortic aneurysm |
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| non-ST elevated myocardial infarction | Cardiac disorders | SNOMED CT | Systematic Assessment | Participant hospitalized after a NSTEMI. |
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| Pneumothorax | Respiratory, thoracic and mediastinal disorders | SNOMED CT | Systematic Assessment | Participant hospitalized after developing spontaneous pneumothorax. |
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| Throat infection | General disorders | SNOMED CT | Systematic Assessment | Participant hospitalized after presenting with neck pain and inability to swallow. |
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| Dehydration | General disorders | SNOMED CT | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | SNOMED CT | Systematic Assessment | Participant presented to the hospital after a fall. |
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| Urinary tract infection | Renal and urinary disorders | SNOMED CT | Systematic Assessment | Participant was admitted to hospital after developing a UTI. |
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| Hypertension | Vascular disorders | SNOMED CT | Systematic Assessment | Participant hospitalized after presenting with high blood pressure. |
|
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| Accident | Injury, poisoning and procedural complications | SNOMED CT | Systematic Assessment | Participant suffered an accidental injury, resolved. |
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| Muscle pain | Musculoskeletal and connective tissue disorders | SNOMED CT | Systematic Assessment |
|
| Synovial cyst | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | SNOMED CT | Systematic Assessment | Participant had a synovial cyst removed from spine (L4/L5). |
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| Itching | Skin and subcutaneous tissue disorders | SNOMED CT | Systematic Assessment | Participant reported sweating and itching after starting study drug. |
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| Abscess | Skin and subcutaneous tissue disorders | SNOMED CT | Systematic Assessment | Resolved. |
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| Distended bladder | Renal and urinary disorders | SNOMED CT | Systematic Assessment | Resolved. |
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| Hematoma | Renal and urinary disorders | SNOMED CT | Systematic Assessment | Hematoma following orchiectomy was resolved. |
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| Atrial fibrillation | Cardiac disorders | SNOMED CT | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | SNOMED CT | Systematic Assessment | Participant fell after feeling light-headed. |
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| Diarrhea | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
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| Bloating | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
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| Cellulitus, eye | Infections and infestations | SNOMED CT | Systematic Assessment |
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| COVID19 | Infections and infestations | SNOMED CT | Systematic Assessment |
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| Hemorrhoids | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
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| Cancer | Reproductive system and breast disorders | SNOMED CT | Systematic Assessment | Prostate cancer |
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| Cancer | Gastrointestinal disorders | SNOMED CT | Systematic Assessment | Positive Colorectal screening |
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| Sinus infection | Infections and infestations | SNOMED CT | Systematic Assessment | Participant experienced breathing issues related to sinus infection. |
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| orthopedic | Surgical and medical procedures | SNOMED CT | Systematic Assessment | wrist pain following surgery |
|
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| Total tau |
|
| Phosphorylated tau (pTau181) measured in CSF was log-transformed prior to analysis to approximate a normal distribution. | Regression, Linear | log-transformed 18 month pTau181 was regressed on group (IPE vs placebo) and covariates age at baseline and log-transformed ptau181at baseline visit. | 0.05 | Slope | 0.045 | 2-Sided | 95 | 0.004 | 0.061 | Placebo group is the reference group. | Superiority |
| Total tau was log-transformed prior to analysis to better approximate a normal distribution. | Regression, Linear | .07 | 18 months total Tau was regressed on Group (IPE vs placebo) and covariates age at baseline and total Tau at baseline. | Slope | 0.046 | 2-Sided | 95 | -0.0008 | 0.106 | Placebo group was the reference group. | Superiority |
| Superiority |