Age-Related Eye Disease Study 2 (AREDS2) | NCT00345176

ID	Type	Description
N01-EY-5-0007	Other Grant/Funding Number	NIH
HHS-N-260-2005-00007-C	Other Grant/Funding Number	HHS
CC-070025	Other Identifier	NIH Clinical Center
07-EI-0025	Other Identifier	National Eye Institute

Status Module

Name	Class
National Heart, Lung, and Blood Institute (NHLBI)	NIH
Office of Dietary Supplements (ODS)	NIH
National Center for Complementary and Integrative Health (NCCIH)	NIH

Description Module

Detailed Description

AREDS2 was a randomized, double-masked, placebo-controlled, 2x2 factorial trial evaluating the risks and benefits of adding lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), or both to the AREDS formulation, which consisted of vitamins C (500 mg), vitamin E (400 international units), beta carotene (15 mg), zinc (80 mg as zinc oxide), and copper (2 mg as cupric oxide) for the treatment of progression to advanced AMD. The study enrolled 4,203 participants aged 50 to 85 years, with sufficiently clear ocular media to allow accurate assessment of AMD from fundus photographs. Subjects were enrolled on the basis of the AREDS Simplified Severity Scale for defining risk categories for development of advanced age-related macular degeneration. All participants were offered additional treatment with the original AREDS formulation (now considered standard of care) and 3 variations of this formula. These are: (1) no beta-carotene; (2) lower amount of zinc (25 mg); and (3) no beta-carotene and lower amount of zinc (25 mg). Eligible participants were followed for a minimum of five years.

Multiple ancillary studies were conducted using the parent study (AREDS2) data to explore:

Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function
1. Outcome is measured with a battery of tests administered over the telephone at baseline, and at years 2 and 4 of the study.
2. Primary outcome is the change in the composite score for the results of the cognitive function testing from baseline over time.
Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease

a. Primary measure of cardiovascular morbidity and mortality
Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina

a. Primary outcome is the development of peripheral drusen, geographic atrophy, reticular pigmentary changes, and pseudoreticular drusen.
Association of genotype polymorphisms with age-related macular degeneration and cataract

a. Whole genome sequencing will be completed. Evaluation of association genetic associations with disease will be conducted using AREDS controls.
Association of genotype polymorphisms with progression of age-related macular degeneration

a. Whole genome sequencing is conducted. Progression from early to late and severe stages of AMD will be examined with the genotype data to evaluate the risks of progression associated with the genotype polymorphisms.
Association of genotype polymorphisms with dietary intake a. Whole genome sequencing is conducted. Progression from early to late and severe stages of AMD will be examined regarding potential interaction of the dietary intake with the genotype data to evaluate the risks of progression.
Association of genotype polymorphisms with AREDS2 supplements a. Interaction of genetic polymorphisms with AREDS2 supplements for progression to late AMD will be evaluated using the data from the whole genome sequencing project.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Lutein/Zeaxanthin	Active Comparator	lutein (10mg)/zeaxanthin (2 mg)	Dietary Supplement: Lutein/zeaxanthin
DHA/EPA	Active Comparator	DHA (350 mg)/EPA (650 mg)	Dietary Supplement: DHA/EPA
Lutein/Zeaxanthin + DHA/EPA	Active Comparator	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)	Drug: Lutein/zeaxanthin and DHA/EPA
Placebo/Control	Placebo Comparator	Considered control because all participants received the AREDS formulation

Name	Type	Description	Arm Group Labels	Other Names
Lutein/zeaxanthin	Dietary Supplement	10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules)	Lutein/Zeaxanthin

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Development of Advanced AMD in People at Moderate to High Risk for Progression.	Defined as central geographic atrophy or retinal features of choroidal neovascularization detected on central grading of the stereoscopic fundus photographs or a history of treatment for advanced AMD after study enrollment.	5 years of follow-up

Secondary Outcomes

Measure	Description	Time Frame
Progression to Moderate Vision Loss	Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization	5 years of follow-up
Adverse Events	Safety outcomes included serious adverse events and mortality.

Other Outcomes

Measure	Description	Time Frame
Incident Cardiovascular Disease	Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease	5 years of follow-up
Cognition as Measured by a Telephone Battery

Name	Affiliation	Role
Emily Y Chew, MD	National Eye Institute, National Institutes of Health	Study Chair
John Paul SanGiovanni, Sc.D.	National Eye Institute, National Institutes of Health	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
University of Alabama at Birmingham		Birmingham	Alabama	35294	United States
Jones Eye Institute - UAMS

PubMed Identifier	Type	Citation	Retractions
37702300	Derived	Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2023 Sep 13;9(9):CD000254. doi: 10.1002/14651858.CD000254.pub5.
34793832	Derived	Bhandari S, Vitale S, Agron E, Clemons TE, Chew EY; Age-Related Eye Disease Study 2 Research Group. Cataract Surgery and the Risk of Developing Late Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 Report Number 27. Ophthalmology. 2022 Apr;129(4):414-420. doi: 10.1016/j.ophtha.2021.11.014. Epub 2021 Nov 16.

Label	URL
NEI Website: Age-Related Eye Disease Study 2	View source

Results Section

Participant Flow Module

ID	Title	Description
FG000	Placebo/Control	Considered control because all participants received the AREDS formulation
FG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

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

Development of Advanced AMD in People at Moderate to High Risk for Progression.

Defined as central geographic atrophy or retinal features of choroidal neovascularization detected on central grading of the stereoscopic fundus photographs or a history of treatment for advanced AMD after study enrollment.

Intention to Treat. Participants lost to follow-up during the course of the study were censored at the time of last contact.

Posted

Number

Eyes

5 years of follow-up

Eyes

Participants

ID	Title	Description
OG000	Placebo/Control	Considered control because all participants received the AREDS formulation
OG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)
OG002	DHA/EPA	DHA (350 mg)/EPA (650 mg)
OG003	Lutein/Zeaxanthin + DHA/EPA	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)

Units	Counts
Participants	OG0001007 OG0011038 OG0021062 OG003

Title

Denominators

Categories

Title	Measurements
	OG000493 OG001468 OG002507 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Each of the 3 active arms was compared to the placebo/control arm.	Regression, Cox	Adjusted for baseline AMD status	<0.013	Adjusted for 3 treatment versus placebo comparisons and interim analyses	Hazard Ratio (HR)	0.90			2-Sided	98.7	0.76	1.07			The reference group is placebo.	No	Superiority or Other

Secondary

Progression to Moderate Vision Loss

Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization

Posted

Number

Eyes

5 years of follow-up

Eyes

Participants

ID	Title	Description
OG000	Placebo/Control	Considered control because all participants received the AREDS formulation
OG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)
OG002	DHA/EPA	DHA (350 mg)/EPA (650 mg)
OG003	Lutein/Zeaxanthin + DHA/EPA	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)

Units	Counts
Participants

Secondary

Adverse Events

Safety outcomes included serious adverse events and mortality.

Number of deaths in 5 years

Posted

Number

Participants

5 years of follow-up

ID	Title	Description
OG000	Placebo/Control	Considered control because all participants received the AREDS formulation
OG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)
OG002	DHA/EPA	DHA (350 mg)/EPA (650 mg)
OG003	Lutein/Zeaxanthin + DHA/EPA	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)

Units	Counts
Participants

Secondary

Progression to Cataract Surgery

The study examined the effects of lutein/zeaxanthin on progression to cataract surgery with data collected during regular telephone contacts and the annual study visits.

Includes participants who were phakic in at least 1 eye at baseline

Posted

Number

Eyes

5 years of follow-up

Eyes

Participants

ID	Title	Description
OG000	No Lutein/Zeaxanthin	Lutein main effect - includes participants who did not receive Lutein/Zeaxanthin
OG001	Lutein/Zeaxanthin	Lutein main effect - includes all participants who received Lutein/Zeaxanthin

Units	Counts
Participants	OG000

Other Pre-specified

Incident Cardiovascular Disease

Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease

Not Posted

5 years of follow-up

Other Pre-specified

Cognition as Measured by a Telephone Battery

Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function

Not Posted

5 years of follow-up

Other Pre-specified

Prevalence of Peripheral Changes as Measured Using OPTOS Imaging

Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina

Not Posted

5 years of follow-up

Other Pre-specified

Genetics for the Association of AMD and Cataract

Not Posted

5 years of follow-up

Other Pre-specified

Genetics for the Progression of AMD and Cataract

Not Posted

5 years of follow-up

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Cardiac Disorders	Cardiac disorders	MedDRA (10.0)	Non-systematic Assessment	EG000122 events96 affected1,012 at risk EG001138 events110 affected1,044 at risk EG002144 events119 affected1,068 at risk EG003133 events103 affected1,079 at risk
Gastrointestinal disorders	Gastrointestinal disorders	MedDRA (10.0)	Non-systematic Assessment	EG000101 events76 affected1,012 at risk EG00181 events69 affected1,044 at risk EG00272 events58 affected1,068 at risk EG003
Blood and lymphatic system disorders	Blood and lymphatic system disorders	MedDRA (10.0)	Non-systematic Assessment	EG00014 events12 affected1,012 at risk EG00111 events11 affected1,044 at risk EG00210 events9 affected1,068 at risk EG003
Ear and labyrinth disorders	Ear and labyrinth disorders	MedDRA (10.0)	Non-systematic Assessment	EG0007 events7 affected1,012 at risk EG0013 events3 affected1,044 at risk EG0024 events4 affected1,068 at risk EG003
Congenital, familian and genetic disorders	Congenital, familial and genetic disorders	MedDRA (10.0)	Non-systematic Assessment	EG0003 events3 affected1,012 at risk EG0011 events1 affected1,044 at risk EG0020 events0 affected1,068 at risk EG003
Endocrine disorders	Endocrine disorders	MedDRA (10.0)	Non-systematic Assessment	EG0002 events2 affected1,012 at risk EG0013 events3 affected1,044 at risk EG0023 events3 affected1,068 at risk EG003
Eye disorders	Eye disorders	MedDRA (10.0)	Non-systematic Assessment	EG0003 events3 affected1,012 at risk EG00113 events11 affected1,044 at risk EG0026 events4 affected1,068 at risk EG003
General disorders and administration site conditions	General disorders	MedDRA (10.0)	Non-systematic Assessment	EG00060 events54 affected1,012 at risk EG00154 events50 affected1,044 at risk EG00258 events51 affected1,068 at risk EG003
Hepatobiliary disorders	Hepatobiliary disorders	MedDRA (10.0)	Non-systematic Assessment	EG0008 events8 affected1,012 at risk EG00116 events16 affected1,044 at risk EG00216 events16 affected1,068 at risk EG003
Immune system disorders	Immune system disorders	MedDRA (10.0)	Non-systematic Assessment	EG0002 events2 affected1,012 at risk EG0011 events1 affected1,044 at risk EG0022 events2 affected1,068 at risk EG003
Infections and infestations	Infections and infestations	MedDRA (10.0)	Non-systematic Assessment	EG000109 events90 affected1,012 at risk EG001139 events102 affected1,044 at risk EG002144 events103 affected1,068 at risk EG003
Injury, poisoning and procedural complications	Injury, poisoning and procedural complications	MedDRA (10.0)	Non-systematic Assessment	EG00090 events76 affected1,012 at risk EG00172 events62 affected1,044 at risk EG00290 events74 affected1,068 at risk EG003
Investigations	Investigations	MedDRA (10.0)	Non-systematic Assessment	EG00014 events14 affected1,012 at risk EG00120 events19 affected1,044 at risk EG00215 events13 affected1,068 at risk EG003
Metabolism and nutrition disorders	Metabolism and nutrition disorders	MedDRA (10.0)	Non-systematic Assessment	EG00022 events21 affected1,012 at risk EG00118 events16 affected1,044 at risk EG00213 events13 affected1,068 at risk EG003
Musculoskeletal and connective tissue disorders	Musculoskeletal and connective tissue disorders	MedDRA (10.0)	Non-systematic Assessment	EG00077 events66 affected1,012 at risk EG00191 events74 affected1,044 at risk EG00285 events71 affected1,068 at risk EG003
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (10.0)	Non-systematic Assessment	EG000103 events80 affected1,012 at risk EG001111 events88 affected1,044 at risk EG002100 events83 affected1,068 at risk EG003
Nervous system disorders	Nervous system disorders	MedDRA (10.0)	Non-systematic Assessment	EG00073 events66 affected1,012 at risk EG00193 events74 affected1,044 at risk EG00287 events72 affected1,068 at risk EG003
Psychiatric disorders	Psychiatric disorders	MedDRA (10.0)	Non-systematic Assessment	EG0004 events4 affected1,012 at risk EG0015 events5 affected1,044 at risk EG0025 events5 affected1,068 at risk EG003
Renal and urinary disorders	Renal and urinary disorders	MedDRA (10.0)	Non-systematic Assessment	EG00020 events19 affected1,012 at risk EG00126 events25 affected1,044 at risk EG00225 events24 affected1,068 at risk EG003
Reproductive system and breast disorders	Reproductive system and breast disorders	MedDRA (10.0)	Non-systematic Assessment	EG00011 events9 affected1,012 at risk EG0018 events8 affected1,044 at risk EG00213 events12 affected1,068 at risk EG003
Respioratory, thoracic and mediastinal disorders	Respiratory, thoracic and mediastinal disorders	MedDRA (10.0)	Non-systematic Assessment	EG00059 events44 affected1,012 at risk EG00152 events43 affected1,044 at risk EG00250 events37 affected1,068 at risk EG003
Skin and subcutaneous tissue disorders	Skin and subcutaneous tissue disorders	MedDRA (10.0)	Non-systematic Assessment	EG0001 events1 affected1,012 at risk EG0017 events6 affected1,044 at risk EG0023 events3 affected1,068 at risk EG003
Surgical and medical procedures	Surgical and medical procedures	MedDRA (10.0)	Non-systematic Assessment	EG00032 events32 affected1,012 at risk EG00131 events29 affected1,044 at risk EG00230 events27 affected1,068 at risk EG003
Vascular disorders	Vascular disorders	MedDRA (10.0)	Non-systematic Assessment	EG00045 events41 affected1,012 at risk EG00142 events40 affected1,044 at risk EG00245 events42 affected1,068 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Dry eye	Eye disorders	MedDRA (10.0)	Systematic Assessment	EG00062 events55 affected1,012 at risk EG00140 events39 affected1,044 at risk EG00270 events64 affected1,068 at risk EG00370 events62 affected1,079 at risk
Eye disorder	Eye disorders	MedDRA (10.0)	Systematic Assessment	EG000100 events67 affected1,012 at risk EG00196 events67 affected1,044 at risk EG00298 events62 affected1,068 at risk EG003
Visual disturbance	Eye disorders	MedDRA (10.0)	Systematic Assessment	EG000118 events88 affected1,012 at risk EG001139 events110 affected1,044 at risk EG002116 events84 affected1,068 at risk EG003
Vitreous disorder	Eye disorders	MedDRA (10.0)	Systematic Assessment	EG000208 events133 affected1,012 at risk EG001213 events154 affected1,044 at risk EG002228 events165 affected1,068 at risk EG003
Change in bowel habit	Gastrointestinal disorders	MedDRA (10.0)	Systematic Assessment	EG00069 events57 affected1,012 at risk EG00177 events67 affected1,044 at risk EG00258 events48 affected1,068 at risk EG003
Bronchitis	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG00072 events62 affected1,012 at risk EG00183 events69 affected1,044 at risk EG00280 events57 affected1,068 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG000175 events139 affected1,012 at risk EG001190 events150 affected1,044 at risk EG002179 events139 affected1,068 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (10.0)	Systematic Assessment	EG00082 events57 affected1,012 at risk EG001103 events75 affected1,044 at risk EG002108 events71 affected1,068 at risk EG003
Hypertension	Vascular disorders	MedDRA (10.0)	Systematic Assessment	EG00066 events59 affected1,012 at risk EG00162 events60 affected1,044 at risk EG00272 events69 affected1,068 at risk EG003

ID	Term
D012162	Retinal Degeneration
D012164	Retinal Diseases
D005128	Eye Diseases
D007905	Lens Diseases

ID	Term
D014975	Lutein
D065146	Zeaxanthins
D004281	Docosahexaenoic Acids
D015118	Eicosapentaenoic Acid

ID	Term
D024341	Xanthophylls
D002338	Carotenoids
D011090	Polyenes
D000475	Alkenes
D006839	Hydrocarbons, Acyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D053138	Cyclohexenes
D003510	Cyclohexanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic
D006844	Hydrocarbons, Cyclic
D013729	Terpenes
D010860	Pigments, Biological
D001685	Biological Factors
D015525	Fatty Acids, Omega-3
D004042	Dietary Fats, Unsaturated
D004041	Dietary Fats
D005223	Fats
D008055	Lipids
D005231	Fatty Acids, Unsaturated
D005227	Fatty Acids
D005395	Fish Oils
D009821	Oils
D015777	Eicosanoids

ID	Title	Description
BG000	Placebo/Control	Considered control because all participants received the AREDS formulation
BG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)
BG002	DHA/EPA	DHA (350 mg)/EPA (650 mg)
BG003	Lutein/Zeaxanthin + DHA/EPA	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
BG004	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo/Control	Considered control because all participants received the AREDS formulation	479	1,012	717	1,012
EG001	Lutein/Zeaxanthin	lutein (10mg)/zeaxanthin (2 mg)	484	1,044	791	1,044
EG002	DHA/EPA	DHA (350 mg)/EPA (650 mg)	505	1,068	759	1,068
EG003	Lutein/Zeaxanthin + DHA/EPA	lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)	519	1,079	791	1,079