DHA (Docosahexaenoic Acid), an Omega 3 Fatty Acid, in Slowing the Progression of Alzheimer's Disease

• Sponsor: Alzheimer's Disease Cooperative Study (ADCS) (Other)
• Overall Status: Completed
• CT.gov ID: NCT00440050
• Collaborator: National Institute on Aging (NIA) (NIH), DSM Nutritional Products, Inc. (Industry)
• Enrollment: 402
• Locations: 51
• Arms: 2
• Duration (Months): 26.9
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: DHA (Docosahexaenoic Acid); Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 402 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Placebo-Controlled Trial Of The Effects Of Docosahexaenoic Acid (DHA) In Slowing The Progression Of Alzheimer's Disease
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: May 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1. DHA	Drug: DHA (Docosahexaenoic Acid); 950 mg soft-gel capsules which contain approximately 510 mg DHA, 2 capsules twice a day for 18 months; Other Names: Neuromins
Placebo Comparator: 2. Placebo	Drug: Placebo; 2 placebo capsules twice a day for 18 months

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35294
2	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
3	Sun Health Research Institute/Arizona Consortium	Sun City	Arizona	United States	85351
4	University of California Irvine	Irvine	California	United States	92697
5	UCSD Shiley-Marcos Alzheimer's Research Center	La Jolla	California	United States	92037
6	University of Southern California Psychiatry and Behavioral Sciences	Los Angeles	California	United States	90033
7	UCLA Neurology	Los Angeles	California	United States	90095
8	Palo Alto Institute for Research & Education	Palo Alto	California	United States	94304
9	UC-Davis Alzheimer's Disease Center	Sacramento	California	United States	95817
10	Pacific Research Network	San Diego	California	United States	92103
11	Yale University School of Medicine	New Haven	Connecticut	United States	06510
12	Georgetown University Medical Center, Dept. of Neurology	Washington	District of Columbia	United States	20057
13	Howard University College of Medicine	Washington	District of Columbia	United States	20060
14	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32224
15	Wien Center	Miami Beach	Florida	United States	33140
16	University of South Florida Suncoast Alzheimer's and Gerontology Center	Tampa	Florida	United States	33617
17	Byrd Alzheimer's Institute	Tampa	Florida	United States	33647
18	Emory University Dept. of Psychiatry	Atlanta	Georgia	United States	30322
19	Northwestern University Cognitive Neurology and Alzheimer Disease Center	Chicago	Illinois	United States	60611
20	Rush Alzheimer's Disease Center	Chicago	Illinois	United States	60612
21	Indiana University	Indianapolis	Indiana	United States	46202
22	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
23	University of Kentucky, Lexington, Sanders-Brown Center on Aging/Neurology	Lexington	Kentucky	United States	40536
24	Johns Hopkins University Division of Cognitive Neuroscience	Baltimore	Maryland	United States	20205
25	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
26	Boston University Alzheimer's Disease Clinical and Research Program	Boston	Massachusetts	United States	02118
27	University of Michigan Dept. of Neurology	Ann Arbor	Michigan	United States	48105
28	Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
29	Mayo Clinic Rochester, Alzheimer's Disease Research Center	Rochester	Minnesota	United States	55905
30	Saint Louis University, Department of Psychiatry	St. Louis	Missouri	United States	63104
31	Washington University ADRC-Memory and Aging Project	St. Louis	Missouri	United States	63108
32	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
33	Albany Medical College	Albany	New York	United States	12208
34	Dent Neurological Institute	Amherst	New York	United States	14226
35	Mount Sinai School of Medicine	Bronx	New York	United States	10468
36	New York University Medical Center	New York	New York	United States	10016
37	Columbia University	New York	New York	United States	10032
38	University of Rochester Medical Center	Rochester	New York	United States	14620
39	Wake Forest University Health Services	Winston-Salem	North Carolina	United States	27157
40	Case Western Reserve University Memory and Aging Center	Cleveland	Ohio	United States	44120
41	The Ohio State University	Columbus	Ohio	United States	43210
42	Oregon Health and Science University Neurology	Portland	Oregon	United States	97239
43	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
44	Rhode Island Hospital Neurology	Providence	Rhode Island	United States	02903
45	Medical University of South Carolina	North Charleston	South Carolina	United States	29406
46	Meharry Medical College	Nashville	Tennessee	United States	37208
47	University of Texas Southwestern-Memory Research Unit	Dallas	Texas	United States	75390
48	Baylor University Department of Neurology	Houston	Texas	United States	77030
49	The Memory Clinic	Bennington	Vermont	United States	05201
50	University of Washington/Seattle Institute for Biomedical & Clinical Research	Seattle	Washington	United States	98108
51	University of Wisconsin Department of Medicine	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Alzheimer's Disease Cooperative Study (ADCS)
• National Institute on Aging (NIA)
• DSM Nutritional Products, Inc.

Investigators

• Principal Investigator: Joseph Quinn, MD, Oregon Health and Science University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N Jr, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45.
• Horrocks LA, Farooqui AA. Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):361-72. Review.
• Kalmijn S, van Boxtel MP, Ocké M, Verschuren WM, Kromhout D, Launer LJ. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology. 2004 Jan 27;62(2):275-80.
• Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005 Mar 23;25(12):3032-40.
• Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003 Jul;60(7):940-6.
• Suzuki H, Morikawa Y, Takahashi H. Effect of DHA oil supplementation on intelligence and visual acuity in the elderly. World Rev Nutr Diet. 2001;88:68-71.

• Responsible Party: Alzheimer's Disease Cooperative Study (ADCS)
• ClinicalTrials.gov Identifier: NCT00440050
• Other Study ID Numbers: IA0099; 1RC2AG036535; ADC-027-DHA
• First Posted: Feb 26, 2007
• Last Update Posted: Sep 25, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Alzheimer's Disease Cooperative Study (ADCS): fish oil; omega-3 fatty acids; EPA
• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	Subjects were recruited at 51 sites in the United States between February and November 2007.
Pre-assignment Detail	Out of 555 subjects screened, 402 met the study criteria and were randomized.

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
Period Title: Overall Study
STARTED	164	238
COMPLETED	124	171
NOT COMPLETED	40	67

Baseline Characteristics

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)	Total
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.	Total of all reporting groups
Overall Participants	164	238	402
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	76 (9.3)	76 (7.8)	76 (8.7)
Sex: Female, Male (Count of Participants)
Female	98 59.8%	112 47.1%	210 52.2%
Male	66 40.2%	126 52.9%	192 47.8%
Region of Enrollment (participants) [Number]
United States	164 100%	238 100%	402 100%

Outcome Measures

1. Primary Outcome

Title	Rate of Change on the ADAS-Cog 11.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
Measure Participants	164	238
Mean (Standard Deviation) [ADAS points per year]	7.98 (9.84)	8.27 (8.9)

2. Primary Outcome

Title	Rate of Change on CDR-SOB
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
Measure Participants	164	238
Mean (Standard Deviation) [Units on a scale]	2.87 (2.93)	2.93 (2.83)

3. Secondary Outcome

Title	ADCS-ADL
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
Measure Participants	164	238
Mean (Standard Deviation) [Units on a scale]	10.43 (11.74)	11.51 (13.23)

4. Secondary Outcome

Title	Neuropsychiatric Inventory (NPI)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.	Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
Measure Participants	164	238
Mean (Standard Deviation) [Units on a scale]	2.93 (13.62)	5.09 (15.08)

Adverse Events

Arm/Group Title	Placebo		Docosahexaenoic Acid (DHA)
Arm/Group Description	Dosing of 2 grams of placebo administered in a divided dose twice daily with food.		Dosing of 2 grams of DHA administered in a divided dose twice daily with food.
All Cause Mortality
	Placebo		Docosahexaenoic Acid (DHA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Docosahexaenoic Acid (DHA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/164 (30.5%)		76/238 (31.9%)
Blood and lymphatic system disorders
deep venous thrombosis/pulmonary embolus	2/164 (1.2%)	2	8/214 (3.7%)	8
General disorders
death	4/164 (2.4%)	4	11/214 (5.1%)	11
other	44/164 (26.8%)	44	57/214 (26.6%)	57
Other (Not Including Serious) Adverse Events
	Placebo		Docosahexaenoic Acid (DHA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	144/164 (87.8%)		214/238 (89.9%)
Gastrointestinal disorders
diarrhea	10/164 (6.1%)	10	18/238 (7.6%)	18
General disorders
dizziness	9/164 (5.5%)	9	12/238 (5%)	12
other	88/164 (53.7%)	88	119/238 (50%)	119
Injury, poisoning and procedural complications
fall	33/164 (20.1%)	33	42/238 (17.6%)	42
Psychiatric disorders
agitation	12/164 (7.3%)	12	24/238 (10.1%)	24
Renal and urinary disorders
urinary tract infection	12/164 (7.3%)	12	23/238 (9.7%)	23

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.