Lipoic Acid and Omega-3 Fatty Acids for Alzheimer's Disease

• Sponsor: Oregon Health and Science University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01058941
• Collaborator: (none)
• Enrollment: 67
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study was to see if taking lipoic acid plus omega-3 fatty acids (omega-3s) can slow the Alzheimer's disease (AD) process. To see if the treatment can slow the AD process, the investigators looked at changes in memory and changes in a person's daily activities over 18 months.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Lipoic acid and fish oil concentrate; Drug: Placebo	Phase 1/Phase 2

Detailed Description

Current pharmacological agents for AD have had no impact on disease prevalence and have had limited effects on improving the clinical course of AD. The exponential rise in the prevalence, incidence, and cost of care for AD make finding therapeutic agents that can either prevent AD or delay disease progression an urgent health care need. Since inflammation, lipid dysregulation, and insulin resistance have each been associated with AD pathology, the combination of lipoic acid plus fish oil has the potential to maximize therapeutic benefit by acting on all three mechanisms associated with disease pathology.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Lipoic Acid and Omega-3 Fatty Acids in Alzheimer's Disease
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lipoic acid and Omega-3 fatty acids Three 1-gram fish oil capsules per day (2 capsules in the morning and 1 capsule in the evening) plus two lipoic acid (LA) capsules per day in the morning. Total daily dose of study drug: 675 mg DHA, 975 mg EPA, 600 mg LA.	Drug: Lipoic acid and fish oil concentrate; Lipoic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months; Other Names: alpha lipoic acid thiotic acid fish oil omega-3 fatty acids
Placebo Comparator: Placebo Three placebo oil capsules per day (2 capsules in the morning and 1 capsule in the evening) plus two placebo LA capsules per day in the morning.	Drug: Placebo; Placebo LA and placebo oil capsules for 18 months; Other Names: Placebo for lipoic acid and fish oil concentrate

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Activities of Daily Living (ADL) at 18 Months [Baseline and 18 months]

   The Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) is used to assess activities of daily living in people with AD using a structured interview to ask the AD participant's caregiver/study partner to assess functional ability over a wide range of performance measures. A higher ADL score indicates greater impairment in functional ability; scores range from 0 to 27.

2. Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 18 Months [Baseline and 18 months]

   The ADAS-cog assesses general cognitive function over multiple domains and evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates greater impairment on a range of scores from 0 to 70. A total score of 70 indicates maximum severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 55 years or older

2. Probable AD by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association - NINCDS/ADRDA criteria

3. MMSE between 15-26

4. Caregiver/study partner that can accompany participant to all study visits

5. Stable use of cholinesterase inhibitors and memantine permitted - doses must be stable for 4 months prior to study enrollment

6. Stable doses of over-the-counter antioxidants (e.g. vitamin E, ginkgo biloba) are permitted - dose must be stable for 4 months prior to study enrollment

7. Stable dose of lipid lowering medication - dose must be stable for 4 months prior to study enrollment

8. Geriatric Depression Scale (GDS) - Score of < 5

9. General health status that will not interfere with the participant's ability to complete the study.

10. Screening laboratory values within normal limits or, if abnormal, deemed clinically insignificant by the investigator

11. Sufficient English language skills to complete all testing

Exclusion Criteria:

1. Non-AD dementia

2. Residence in nursing home facility at screening visit (residence in community assisted living and long-term care facilities in which the participant still performs majority of basic activities of daily living will not be an exclusion)

3. History of clinically significant stroke (stroke with neurologic deficits > 6 months after diagnosis)

4. Health conditions such as cancer diagnosed < 5 years prior to enrollment (prostate cancer gleason grade < 3 and non metastatic skin cancers are acceptable), liver disease, history of ventricular fibrillation or ventricular tachycardia, major psychiatric disorder, central nervous system diseases (e.g. brain tumor, seizure disorder)

5. Insulin dependent diabetes or uncontrolled diabetes (diabetes controlled on medications other than insulin are acceptable)

6. Hyperlipidemic (triglycerides >500 mg/dl, LDL > 160 mg/dl, total cholesterol >240 mg/dl). LDL levels between 160 mg/dl and 165 mg/dl will be reviewed by the PI and included if judged to be safe. Patients who have a history or hyperlipidemia, but are not taking lipid-lowering medications due to potential memory impairment side effects will be reviewed on a case-by-case basis by the PI and enrolled in the study if deemed safe by PI and the patient's primary care provider.

7. Fish intake of one 6 ounce serving > once a week less than 4 months prior to enrollment

8. Omega-3 fatty acid supplement intake (e.g. fish oil capsules, cod liver oil, or flaxseed oil) less than 4 months prior to enrollment

9. Lipoic Acid supplementation less than 1 month prior to enrollment

10. Taking systemic corticosteroids, neuroleptics, antiparkinsonian agents, and narcotic analgesics. Certain low dose antipsychotic use will be reviewed by the principle investigator on a case-by-case basis and may be allowed if determined that dose is not strong enough to affect performance on cognitive evaluations. Low dose sinemet and dopamine agonist taken once a day for restless leg syndrome is not an exclusion.

11. Contraindications to MRI (for subjects enrolled at Bend, Medford, and Klamath sites that decide not to undergo MRI, this will not be an exclusion).

12. Enrollment in another study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• Oregon Health and Science University

Investigators

• Principal Investigator: Lynne Shinto, ND, MPH, Oregon Health and Science University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lynne Shinto, Lynne Shinto, ND, MPH, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT01058941
• Other Study ID Numbers: R01AG033613-01A1
• First Posted: Jan 29, 2010
• Last Update Posted: Apr 13, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Lynne Shinto, Lynne Shinto, ND, MPH, Oregon Health and Science University: Alzheimer's disease; fish oil; lipoic acid
• Additional relevant MeSH terms: Alzheimer Disease; Thioctic Acid

Study Results

Participant Flow

Arm/Group Title	Lipoic Acid and Omega-3 Fatty Acids	Placebo
Arm/Group Description	lipoic acid and fish oil concentrate lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months	placebo lipoic acid plus placebo oil lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months
Period Title: Overall Study
STARTED	34	33
COMPLETED	25	22
NOT COMPLETED	9	11

Baseline Characteristics

Arm/Group Title	Lipoic Acid and Omega-3 Fatty Acids	Placebo	Total
Arm/Group Description	lipoic acid and fish oil concentrate lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months	placebo lipoic acid plus placebo oil lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months	Total of all reporting groups
Overall Participants	34	33	67
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 14.7%	4 12.1%	9 13.4%
>=65 years	29 85.3%	29 87.9%	58 86.6%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	73.3	76.2	74.7
Sex: Female, Male (Count of Participants)
Female	18 52.9%	17 51.5%	35 52.2%
Male	16 47.1%	16 48.5%	32 47.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	34 100%	32 97%	66 98.5%
Unknown or Not Reported	0 0%	1 3%	1 1.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 3%	1 1.5%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.9%	1 3%	2 3%
White	33 97.1%	30 90.9%	63 94%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 3%	1 1.5%
Region of Enrollment (participants) [Number]
United States	34 100%	33 100%	67 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Activities of Daily Living (ADL) at 18 Months
Description	The Alzheimer's Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL) is used to assess activities of daily living in people with AD using a structured interview to ask the AD participant's caregiver/study partner to assess functional ability over a wide range of performance measures. A higher ADL score indicates greater impairment in functional ability; scores range from 0 to 27.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description

Twenty participants discontinued from the study prior to completing all study visits. One treatment participant did not complete the final ADL assessment.

Arm/Group Title	Lipoic Acid and Omega-3 Fatty Acids	Placebo
Arm/Group Description	lipoic acid and fish oil concentrate lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months	placebo lipoic acid plus placebo oil lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months
Measure Participants	24	22
Mean (Standard Deviation) [units on a scale]	-11.58 (12.68)	-13.45 (12.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lipoic Acid and Omega-3 Fatty Acids, Placebo
	Comments	The target enrollment was 60 subjects, allowing for up to a 20% drop-out. It was calculated that with 48 subjects (24 per group) we would have 80% power to see differences in ADL scores over 18 months between the treatment and placebo groups with a significance level of 0.025 based on a simple Bonferroni adjustment, since we had two primary outcomes.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments	We used a significance level of p = 0.025 for our measure of ADL changes based on a simple Bonferroni adjustment since we have two primary outcomes.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline outcome, time from baseline, age, education category, BMI, cholinesterase inhibitors, memantine, vitamin E, and Apo-E.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -3.97 to 3.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) at 18 Months
Description	The ADAS-cog assesses general cognitive function over multiple domains and evaluates memory, attention, reasoning, language, orientation, and praxis. A higher score indicates greater impairment on a range of scores from 0 to 70. A total score of 70 indicates maximum severity.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description

Twenty participants discontinued from the study prior to completing all study visits. One placebo and one treatment participant did not complete the final ADAS-cog assessment.

Arm/Group Title	Lipoic Acid and Omega-3 Fatty Acids	Placebo
Arm/Group Description	lipoic acid and fish oil concentrate lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months	placebo lipoic acid plus placebo oil lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months
Measure Participants	24	21
Mean (Standard Deviation) [units on a scale]	6.61 (6.67)	3.40 (4.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lipoic Acid and Omega-3 Fatty Acids, Placebo
	Comments	The target enrollment was 60 subjects, allowing for up to a 20% drop-out. It was calculated that with 48 subjects (24 per group) we would have 80% power to see differences in ADL scores over 18 months between the treatment and placebo groups with a significance level of 0.025 based on a simple Bonferroni adjustment, since we had two primary outcomes.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	We used a significance level of p = 0.025 for our measure of ADAS-cog changes based on a simple Bonferroni adjustment since we have two primary outcomes.
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline outcome, time from baseline, age, education category, BMI, cholinesterase inhibitors, memantine, vitamin E, and Apo-E.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.68
	Confidence Interval	(2-Sided) 95%; -5.90 to -1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were monitored once a month as a part of the clinic visits and monthly by phone. Reported AEs include events that occurred on or after Day 0 and on or before month 18.
Arm/Group Title	Lipoic Acid and Omega-3 Fatty Acids		Placebo
Arm/Group Description	lipoic acid and fish oil concentrate lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months		placebo lipoic acid plus placebo oil lipoic acid and fish oil concentrate: lipic acid (600 milligrams per day) and fish oil concentrate (3 grams per day) for 18 months
All Cause Mortality
	Lipoic Acid and Omega-3 Fatty Acids		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		2/33 (6.1%)
Serious Adverse Events
	Lipoic Acid and Omega-3 Fatty Acids		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/34 (29.4%)		7/33 (21.2%)
Cardiac disorders
Tachycardia	1/34 (2.9%)	1	0/33 (0%)	0
Atrial fibrillation	1/34 (2.9%)	1	0/33 (0%)	0
Gastrointestinal disorders
Gastrointestinal obstruction	1/34 (2.9%)	1	0/33 (0%)	0
Gastric ulcer haemorrhage	1/34 (2.9%)	1	0/33 (0%)	0
General disorders
Medical device complication	1/34 (2.9%)	1	0/33 (0%)	0
Infections and infestations
Pneumonia	1/34 (2.9%)	1	0/33 (0%)	0
Injury, poisoning and procedural complications
Fall	0/34 (0%)	0	1/33 (3%)	1
Head injury	1/34 (2.9%)	1	0/33 (0%)	0
Metabolism and nutrition disorders
Abnormal loss of weight	1/34 (2.9%)	1	0/33 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia	0/34 (0%)	0	1/33 (3%)	1
Laryngeal cancer	0/34 (0%)	0	1/33 (3%)	1
Nervous system disorders
Dementia Alzheimer's Type	2/34 (5.9%)	2	0/33 (0%)	0
Thrombotic cerebral infarction	0/34 (0%)	0	1/33 (3%)	1
Cerebrovascular accident	1/34 (2.9%)	1	1/33 (3%)	1
Psychiatric disorders
Drug-induced delirium	0/34 (0%)	0	1/33 (3%)	1
Renal and urinary disorders
Acute kidney injury	0/34 (0%)	0	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory tract infection	0/34 (0%)	0	1/33 (3%)	1
Pleural effusion	1/34 (2.9%)	1	0/33 (0%)	0
Surgical and medical procedures
Subdural haematoma evacuation	1/34 (2.9%)	1	0/33 (0%)	0
Other (Not Including Serious) Adverse Events
	Lipoic Acid and Omega-3 Fatty Acids		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/34 (85.3%)		27/33 (81.8%)
Blood and lymphatic system disorders
Anemia	2/34 (5.9%)	2	3/33 (9.1%)	3
Gastrointestinal disorders
Nausea	4/34 (11.8%)	6	5/33 (15.2%)	6
Diarrhea	1/34 (2.9%)	1	7/33 (21.2%)	8
Vomiting	3/34 (8.8%)	4	3/33 (9.1%)	4
Abdominal pain	3/34 (8.8%)	3	2/33 (6.1%)	2
General disorders
Fatigue	4/34 (11.8%)	4	1/33 (3%)	1
Immune system disorders
Allergic conditions	4/34 (11.8%)	4	0/33 (0%)	0
Injury, poisoning and procedural complications
Fall	4/34 (11.8%)	4	3/33 (9.1%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	1/34 (2.9%)	1	4/33 (12.1%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer	2/34 (5.9%)	3	3/33 (9.1%)	4
Nervous system disorders
Dizziness	3/34 (8.8%)	3	4/33 (12.1%)	4
Headache/Migraine	5/34 (14.7%)	6	0/33 (0%)	0
Psychiatric disorders
Depression	2/34 (5.9%)	2	3/33 (9.1%)	3
Behavioral and psychiatric symptoms of dementia	4/34 (11.8%)	5	0/33 (0%)	0
Renal and urinary disorders
Urinary tract infection	1/34 (2.9%)	1	2/33 (6.1%)	3
Urinary incontinence	2/34 (5.9%)	2	2/33 (6.1%)	2
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	5/34 (14.7%)	7	7/33 (21.2%)	7
Vascular disorders
Sycope	2/34 (5.9%)	3	1/33 (3%)	1

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.