Alzheimer's Disease
Conditions
Keywords
fish oil, omega-3 fatty acids, EPA
Brief summary
The purpose of this study is to determine whether chronic DHA (Docosahexaenoic Acid) supplementation slows the progression of cognitive and functional decline in mild to moderate Alzheimer's disease (AD).
Detailed description
Preliminary studies have shown a reduced risk of Alzheimer's disease (AD) in people consuming increased amounts of fish in their diets. Many of the health benefits of fish are attributed to the abundance of omega 3 fatty acids. Docosahexaenoic Acid (DHA) is the most abundant omega 3 fatty acid in the brain. Data from several animal models supports the hypothesis that DHA may be an effective treatment for AD by means of anti-amyloid, antioxidant, and neuroprotectant mechanisms. In this study, 400 individuals with mild to moderate AD will participate at approximately 53 study sites throughout the US for 18 months. Participants will be randomized so that 60% will receive approximately 2 grams of DHA, divided into 4 capsules, 2 capsules taken twice a day, while 40% receive an identical placebo. Potential participants will go to their study site for a screening visit, where eligibility is determined, and if accepted, for a baseline visit where cognitive status, behavioral status, functional status, and global severity of dementia will be assessed. Vital signs and biomarker labs will also be obtained. Subsequent visits will occur every three months for medication checks and, every 6 months, further assessments, physical exams, and labs. Some participants will also take part in MRI (magnetic resonance imaging) and/or CSF (cerebrospinal fluid) sub-studies. For the MRI sub-study, scans will be done prior to beginning the study medication, and again after 18 months. Likewise, for the CSF sub-study, a lumbar puncture will be done prior to beginning the study medication, and again after 18 months. Enrollment is restricted to individuals who consume no more than 200 mg of DHA per day, which is almost 300% of the average daily intake in an American diet. Individuals who take fish oil or omega 3 fatty acid supplements are also not eligible. Each visit will include completion of a very brief food frequency questionnaire to monitor dietary DHA levels.
Interventions
950 mg soft-gel capsules which contain approximately 510 mg DHA, 2 capsules twice a day for 18 months
DRUGPlacebo
2 placebo capsules twice a day for 18 months
Sponsors
National Institute on Aging (NIA)
DSM Nutritional Products, Inc.
Alzheimer's Disease Cooperative Study (ADCS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female * 50 years of age or older * Residing in the community at baseline (includes assisted living facilities, but excludes long-term care nursing facilities) * MMSE (Mini-Mental State Examination) at screen of 14-26 (inclusive) * No medical contraindications to study participation * Fluent in English or Spanish * Corrected vision and hearing sufficient for compliance with testing procedures * Supervision available for study medication * Caregiver/study partner to accompany participant to all visits * Study partner must have direct contact with the participant more than 2 days/week * Able to ingest oral medication * Daily DHA consumption less than or equal to 200 mg/day in prior two months estimated by an abbreviated DHA food frequency questionnaire * Neuroimaging consistent with the diagnosis of AD at some time after the onset of the memory decline * Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator * Stable use of cholinesterase inhibitors and memantine is permitted if doses are stable for 4 months prior to enrollment
Exclusion criteria
* Non-AD dementia * Residence in a long-term care facility at baseline * History of clinically significant stroke * Modified Hachinski Ischemia score ≥ 4 * Current evidence or history in past two years of epilepsy, seizure, focal brain lesion, head injury with loss of consciousness or DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse * Sensory impairment which would prevent subject from participating in or cooperating with the protocol * Use of another investigational agent within two months * Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational new drug including clinically significant or unstable hematologic, hepatic, cardiovascular (including history of ventricular fibrillation or ventricular tachycardia), pulmonary, gastrointestinal, endocrine, metabolic, renal, or other systemic disease or laboratory abnormality * Active neoplastic disease (skin tumors other than melanoma may be included; participants with stable prostate cancer may be included at the discretion of the Project Director)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change on the ADAS-Cog 11. | Baseline, 6, 12, 18 months | ADAS-cog 11 = Alzheimer's Disease Assessment Scale, cognitive sub-scale in points per year. This is a psychometric measure sensitive to change in mild to moderate AD. The range of this instrument is 0 to 70 with higher numbers indicating greater impairment. |
| Rate of Change on CDR-SOB | 18 months | CDR-SOB = Clinical Dementia Rating, Sum of Boxes. This is a global rating of dementia severity based on the clinician's interpretation of the history and examination. The range of this instrument is 0 to 18 with higher numbers indicating greater impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ADCS-ADL | 18 months | ADCS-ADL = Alzheimer's Disease Cooperative Study Activities of Daily Living Score. This is a structured questionnaire about activities of daily living, administered to the subject's caregiver/study partner. The range of this instrument is 0 to 6 with lower numbers indicating greater impairment. |
| Neuropsychiatric Inventory (NPI) | 18 months | The Neuropsychiatric Inventory quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at 51 sites in the United States between February and November 2007.
Pre-assignment details
Out of 555 subjects screened, 402 met the study criteria and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Dosing of 2 grams of placebo administered in a divided dose twice daily with food. | 164 |
| Docosahexaenoic Acid (DHA) Dosing of 2 grams of DHA administered in a divided dose twice daily with food. | 238 |
| Total | 402 |
Baseline characteristics
| Characteristic | Placebo | Docosahexaenoic Acid (DHA) | Total |
|---|---|---|---|
| Age, Continuous | 76 years STANDARD_DEVIATION 9.3 | 76 years STANDARD_DEVIATION 7.8 | 76 years STANDARD_DEVIATION 8.7 |
| Region of Enrollment United States | 164 participants | 238 participants | 402 participants |
| Sex: Female, Male Female | 98 Participants | 112 Participants | 210 Participants |
| Sex: Female, Male Male | 66 Participants | 126 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 144 / 164 | 214 / 238 |
| serious Total, serious adverse events | 50 / 164 | 76 / 238 |
Outcome results
Primary
Rate of Change on CDR-SOB
CDR-SOB = Clinical Dementia Rating, Sum of Boxes. This is a global rating of dementia severity based on the clinician's interpretation of the history and examination. The range of this instrument is 0 to 18 with higher numbers indicating greater impairment.
Time frame: 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rate of Change on CDR-SOB | 2.87 Units on a scale | Standard Deviation 2.93 |
| Docosahexaenoic Acid (DHA) | Rate of Change on CDR-SOB | 2.93 Units on a scale | Standard Deviation 2.83 |
Primary
Rate of Change on the ADAS-Cog 11.
ADAS-cog 11 = Alzheimer's Disease Assessment Scale, cognitive sub-scale in points per year. This is a psychometric measure sensitive to change in mild to moderate AD. The range of this instrument is 0 to 70 with higher numbers indicating greater impairment.
Time frame: Baseline, 6, 12, 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rate of Change on the ADAS-Cog 11. | 7.98 ADAS points per year | Standard Deviation 9.84 |
| Docosahexaenoic Acid (DHA) | Rate of Change on the ADAS-Cog 11. | 8.27 ADAS points per year | Standard Deviation 8.9 |
Secondary
ADCS-ADL
ADCS-ADL = Alzheimer's Disease Cooperative Study Activities of Daily Living Score. This is a structured questionnaire about activities of daily living, administered to the subject's caregiver/study partner. The range of this instrument is 0 to 6 with lower numbers indicating greater impairment.
Time frame: 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | ADCS-ADL | 10.43 Units on a scale | Standard Deviation 11.74 |
| Docosahexaenoic Acid (DHA) | ADCS-ADL | 11.51 Units on a scale | Standard Deviation 13.23 |
Secondary
Neuropsychiatric Inventory (NPI)
The Neuropsychiatric Inventory quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment.
Time frame: 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Neuropsychiatric Inventory (NPI) | 2.93 Units on a scale | Standard Deviation 13.62 |
| Docosahexaenoic Acid (DHA) | Neuropsychiatric Inventory (NPI) | 5.09 Units on a scale | Standard Deviation 15.08 |