Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, Cerebrospinal fluid, brain blood flow, cognition, icosapent ethyl, Vascepa, omega-3 fatty acids, eicosapentaenoic acid
Brief summary
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.
Detailed description
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.
Interventions
Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo
OTHERgel cap placebo
Participants will be randomized in a 1:1 ratio to receive icosapent ethyl 4 g daily vs. matching gel cap placebo
Sponsors
University of Wisconsin, Madison
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
1:1 randomization of icosapent ethyl 4 g daily vs matching placebo
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* United States Veteran eligible for VA care * Age 50-75 years, inclusive * Cognitively healthy
Exclusion criteria
* Dementia or mild cognitive impairment on screening evaluation * Current use of fish oil supplements (requires 3 month wash-out period) * Active liver disease with AST or ALT greater than twice the upper limit of normal * Elevated creatine kinase greater than twice the upper limit of normal * Prior adverse reaction to statins or fish oil * Pregnant, nursing, or pregnancy planned * Use of medications that interact with icosapent ethyl * Current use of anticoagulants * Known hypersensitivity to fish and/or shellfish * Current use of other investigational drug * History of significant atherosclerotic cardiovascular disease or diabetes mellitus * Low-density lipoprotein (LDL) cholesterol \> or =190 mg/dL or \<80 mg/dL * Triglycerides \> or = 500 mg/dL * Creatinine \>1.8 mg/dL * Previous lumbar surgery with contraindication to lumbar puncture * Claustrophobia requiring sedation for MRI * Pacemaker or other contraindication for MRI * Consumption of \>200 mg per day omega-3 fatty acids in diet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI | 18 month study visit | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | 18 month study visit | 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. |
| Cognitive Performance | 18 month study visit | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 63 |
| 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 | 68 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 11 | 8 |
Baseline characteristics
| Characteristic | Icosapent Ethyl (IPE) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65.9 years STANDARD_DEVIATION 7.06 | 65.4 years STANDARD_DEVIATION 7 | 65.5 years STANDARD_DEVIATION 7 |
| APOE risk allele Carrier | 11 Participants | 19 Participants | 30 Participants |
| APOE risk allele Non-Carrier | 52 Participants | 49 Participants | 101 Participants |
| Education 2-year college degree (AA or equivalent) | 14 Participants | 8 Participants | 22 Participants |
| Education 4-year college degree (Bachelor's) | 11 Participants | 17 Participants | 28 Participants |
| Education Did not graduate from high school | 0 Participants | 1 Participants | 1 Participants |
| Education GED or ABE certificate | 1 Participants | 2 Participants | 3 Participants |
| Education High school diploma | 8 Participants | 10 Participants | 18 Participants |
| Education Master's degree | 8 Participants | 12 Participants | 20 Participants |
| Education Some college but not a 2- or 4-year degree | 12 Participants | 15 Participants | 27 Participants |
| Education Trade or technical school graduate | 8 Participants | 3 Participants | 11 Participants |
| Education Unknown | 1 Participants | 0 Participants | 1 Participants |
| Parental history of Alzheimer's disease No | 33 Participants | 36 Participants | 69 Participants |
| Parental history of Alzheimer's disease Unknown | 1 Participants | 0 Participants | 1 Participants |
| Parental history of Alzheimer's disease Yes | 29 Participants | 32 Participants | 61 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 61 Participants | 65 Participants | 126 Participants |
| Sex/Gender, Customized Female | 9 Participants | 8 Participants | 17 Participants |
| Sex/Gender, Customized Male | 52 Participants | 60 Participants | 112 Participants |
| Sex/Gender, Customized Unknown | 2 Participants | 0 Participants | 2 Participants |
| Systolic blood pressure | 136.2 mm/Hg STANDARD_DEVIATION 16.4 | 136.1 mm/Hg STANDARD_DEVIATION 16.5 | 136.1 mm/Hg STANDARD_DEVIATION 16.4 |
| Total Cholesterol | 173.2 mg/dL STANDARD_DEVIATION 41.4 | 168.3 mg/dL STANDARD_DEVIATION 45.2 | 170.6 mg/dL STANDARD_DEVIATION 43.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 1 / 68 |
| other Total, other adverse events | 13 / 63 | 19 / 68 |
| serious Total, serious adverse events | 9 / 63 | 7 / 68 |
Outcome results
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.
Time frame: 18 month study visit
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Icosapent Ethyl (IPE) | Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI | 55.7 mL/g/min | Standard Deviation 14.6 |
| Placebo | Regional Cerebral Blood Flow Using Arterial Spin-labeling MRI | 54.5 mL/g/min | Standard Deviation 14.1 |
Comparison: The proposed study aims to investigate the effects of 18 months of IPE vs. placebo on regional cerebral blood flow in the bilateral posterior cingulate gyrus as measured by arterial spin-labeling MRI . IPE was hypothesized to improve regional cerebral blood flow over placebo after 18 months.p-value: 0.1795% CI: [-5.36, 0.99]Regression, Linear
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.
Time frame: 18 month study visit
Population: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Icosapent Ethyl (IPE) | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | beta-amyloid(1-42) | 1281.7 pg/mL | Standard Deviation 558.5 |
| Icosapent Ethyl (IPE) | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | phosphorylated tau(181) | 20.2 pg/mL | Standard Deviation 8.13 |
| Icosapent Ethyl (IPE) | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | Total tau | 218.2 pg/mL | Standard Deviation 83.6 |
| Placebo | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | beta-amyloid(1-42) | 1244.6 pg/mL | Standard Deviation 607.7 |
| Placebo | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | phosphorylated tau(181) | 18.8 pg/mL | Standard Deviation 5.56 |
| Placebo | Cerebrospinal Fluid (CSF) Biomarkers of Alzheimer's Disease | Total tau | 208.0 pg/mL | Standard Deviation 63.7 |
Comparison: Beta-amyloid(1-42) concentration in CSF was log-transformed prior to analysis to approximate a normal distribution.p-value: 0.1295% CI: [-0.04, 0.25]Regression, Linear
Comparison: Phosphorylated tau (pTau181) measured in CSF was log-transformed prior to analysis to approximate a normal distribution.p-value: 0.0595% CI: [0.004, 0.061]Regression, Linear
Comparison: Total tau was log-transformed prior to analysis to better approximate a normal distribution.p-value: 0.0795% CI: [-0.0008, 0.106]Regression, Linear
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.
Time frame: 18 month study visit
Population: Analyses were conducted on an intent-to-treat basis. 19 participants dropped out prior to month 18 study visit (n=11 IPE, n=8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Icosapent Ethyl (IPE) | Cognitive Performance | 0.455 Z-score | Standard Deviation 1.22 |
| Placebo | Cognitive Performance | 0.611 Z-score | Standard Deviation 1.1 |
Comparison: Four cognitive tests were standardized (baseline mean and standard deviation) prior to averaging to create the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC) score. The final composite score was standardized again using baseline mean and standard deviation (range -3.15 to 3.10). Higher scores indicate better cognitive performance. A linear mixed effects model was used to determine if change in ADCS-PACC composite scores was modified by treatment group.p-value: 0.4895% CI: [-0.009, 0.023]Linear Mixed Effects model