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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00345176
Recruitment Status : Completed
First Posted : June 27, 2006
Results First Posted : December 24, 2013
Last Update Posted : May 5, 2015
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Office of Dietary Supplements (ODS)
National Center for Complementary and Integrative Health (NCCIH)
Information provided by (Responsible Party):
National Eye Institute (NEI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Age-related Macular Degeneration
Cataract
Interventions Dietary Supplement: Lutein/zeaxanthin
Dietary Supplement: DHA/EPA
Drug: Lutein/zeaxanthin and DHA/EPA
Enrollment 4203
Recruitment Details Between October 2006 and September 2008 a total of 4,203 participants aged 50 - 85 years were randomized at 82 clinical sites.
Pre-assignment Details Prior to randomization, participants had to complete the Qualification phase. They could only be randomized if they took at least 75% of the run-in medication.
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Hide Arm/Group Description Considered control because all participants received the AREDS formulation lutein (10mg)/zeaxanthin (2 mg) DHA (350 mg)/EPA (650 mg) lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
Period Title: Overall Study
Started 1012 1044 1068 1079
Completed 1007 1038 1062 1069
Not Completed 5 6 6 10
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA Total
Hide Arm/Group Description Considered control because all participants received the AREDS formulation lutein (10mg)/zeaxanthin (2 mg) DHA (350 mg)/EPA (650 mg) lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg) Total of all reporting groups
Overall Number of Baseline Participants 1012 1044 1068 1079 4203
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Participants
Number Analyzed 1012 participants 1044 participants 1068 participants 1079 participants 4203 participants
74
(68 to 79)
74
(68 to 79)
74
(68 to 79)
75
(68 to 79)
74
(68 to 79)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1012 participants 1044 participants 1068 participants 1079 participants 4203 participants
Female
548
  54.2%
596
  57.1%
603
  56.5%
641
  59.4%
2388
  56.8%
Male
464
  45.8%
448
  42.9%
465
  43.5%
438
  40.6%
1815
  43.2%
1.Primary Outcome
Title Development of Advanced AMD in People at Moderate to High Risk for Progression.
Hide Description 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.
Time Frame 5 years of follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Intention to Treat. Participants lost to follow-up during the course of the study were censored at the time of last contact.
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Hide Arm/Group Description:
Considered control because all participants received the AREDS formulation
lutein (10mg)/zeaxanthin (2 mg)
DHA (350 mg)/EPA (650 mg)
lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
Overall Number of Participants Analyzed 1007 1038 1062 1069
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
 1691 1709 1749 1742
Measure Type: Number
Unit of Measure: Eyes
493 468 507 472
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin
Comments Each of the 3 active arms was compared to the placebo/control arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.013
Comments Adjusted for 3 treatment versus placebo comparisons and interim analyses
Method Regression, Cox
Comments Adjusted for baseline AMD status
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.90
Confidence Interval (2-Sided) 98.7%
0.76 to 1.07
Estimation Comments The reference group is placebo.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo/Control, DHA/EPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.013
Comments Adjusted for multiple comparisons
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.97
Confidence Interval (2-Sided) 98.7%
0.82 to 1.16
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin + DHA/EPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.013
Comments [Not Specified]
Method Regression, Cox
Comments Adjusted for multiple comparisons
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.89
Confidence Interval (2-Sided) 98.7%
0.75 to 1.06
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Progression to Moderate Vision Loss
Hide Description Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization
Time Frame 5 years of follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Hide Arm/Group Description:
Considered control because all participants received the AREDS formulation
lutein (10mg)/zeaxanthin (2 mg)
DHA (350 mg)/EPA (650 mg)
lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
Overall Number of Participants Analyzed 1007 1038 1062 1069
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
 1630 1660 1694 1672
Measure Type: Number
Unit of Measure: Eyes
515 509 519 506
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.84 to 1.08
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo/Control, DHA/EPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.84 to 1.09
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin + DHA/EPA
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.83 to 1.07
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Adverse Events
Hide Description Safety outcomes included serious adverse events and mortality.
Time Frame 5 years of follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Number of deaths in 5 years
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Hide Arm/Group Description:
Considered control because all participants received the AREDS formulation
lutein (10mg)/zeaxanthin (2 mg)
DHA (350 mg)/EPA (650 mg)
lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
Overall Number of Participants Analyzed 1012 1044 1068 1079
Measure Type: Number
Unit of Measure: Participants
Mortality 81 87 96 104
Serious Adverse Events 479 484 505 519
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin
Comments Comparison of Lutein/Zeaxantin versus Control for mortality
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
0.77 to 1.40
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo/Control, DHA/EPA
Comments Comparison of DHA/EPA versus Placebo for mortality
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
0.84 to 1.52
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo/Control, Lutein/Zeaxanthin + DHA/EPA
Comments Comparison of Lutein/Zeaxanthin + DHA/EPA versus Placebo for Mortality
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.23
Confidence Interval (2-Sided) 95%
0.92 to 1.65
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Progression to Cataract Surgery
Hide Description 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.
Time Frame 5 years of follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Includes participants who were phakic in at least 1 eye at baseline
Arm/Group Title No Lutein/Zeaxanthin Lutein/Zeaxanthin
Hide Arm/Group Description:
Lutein main effect - includes participants who did not receive Lutein/Zeaxanthin
Lutein main effect - includes all participants who received Lutein/Zeaxanthin
Overall Number of Participants Analyzed 1577 1578
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
 3022 3005
Measure Type: Number
Unit of Measure: Eyes
708 681
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection No Lutein/Zeaxanthin, Lutein/Zeaxanthin
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.84 to 1.10
Estimation Comments [Not Specified]
5.Other Pre-specified Outcome
Title Incident Cardiovascular Disease
Hide Description Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease
Time Frame 5 years of follow-up
Outcome Measure Data Not Reported
6.Other Pre-specified Outcome
Title Cognition as Measured by a Telephone Battery
Hide Description Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function
Time Frame 5 years of follow-up
Outcome Measure Data Not Reported
7.Other Pre-specified Outcome
Title Prevalence of Peripheral Changes as Measured Using OPTOS Imaging
Hide Description Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina
Time Frame 5 years of follow-up
Outcome Measure Data Not Reported
8.Other Pre-specified Outcome
Title Genetics for the Association of AMD and Cataract
Hide Description [Not Specified]
Time Frame 5 years of follow-up
Outcome Measure Data Not Reported
9.Other Pre-specified Outcome
Title Genetics for the Progression of AMD and Cataract
Hide Description [Not Specified]
Time Frame 5 years of follow-up
Outcome Measure Data Not Reported
Time Frame 5 years
Adverse Event Reporting Description Adverse events reported by System Organ Class
 
Arm/Group Title Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Hide Arm/Group Description Considered control because all participants received the AREDS formulation lutein (10mg)/zeaxanthin (2 mg) DHA (350 mg)/EPA (650 mg) lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
All-Cause Mortality
Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   479/1012 (47.33%)      484/1044 (46.36%)      505/1068 (47.28%)      519/1079 (48.10%)    
Blood and lymphatic system disorders         
Blood and lymphatic system disorders * 1  12/1012 (1.19%)  14 11/1044 (1.05%)  11 9/1068 (0.84%)  10 7/1079 (0.65%)  7
Cardiac disorders         
Cardiac Disorders * 1  96/1012 (9.49%)  122 110/1044 (10.54%)  138 119/1068 (11.14%)  144 103/1079 (9.55%)  133
Congenital, familial and genetic disorders         
Congenital, familian and genetic disorders * 1  3/1012 (0.30%)  3 1/1044 (0.10%)  1 0/1068 (0.00%)  0 0/1079 (0.00%)  0
Ear and labyrinth disorders         
Ear and labyrinth disorders * 1  7/1012 (0.69%)  7 3/1044 (0.29%)  3 4/1068 (0.37%)  4 1/1079 (0.09%)  1
Endocrine disorders         
Endocrine disorders * 1  2/1012 (0.20%)  2 3/1044 (0.29%)  3 3/1068 (0.28%)  3 0/1079 (0.00%)  0
Eye disorders         
Eye disorders * 1  3/1012 (0.30%)  3 11/1044 (1.05%)  13 4/1068 (0.37%)  6 0/1079 (0.00%)  0
Gastrointestinal disorders         
Gastrointestinal disorders * 1  76/1012 (7.51%)  101 69/1044 (6.61%)  81 58/1068 (5.43%)  72 61/1079 (5.65%)  71
General disorders         
General disorders and administration site conditions * 1  54/1012 (5.34%)  60 50/1044 (4.79%)  54 51/1068 (4.78%)  58 46/1079 (4.26%)  50
Hepatobiliary disorders         
Hepatobiliary disorders * 1  8/1012 (0.79%)  8 16/1044 (1.53%)  16 16/1068 (1.50%)  16 17/1079 (1.58%)  18
Immune system disorders         
Immune system disorders * 1  2/1012 (0.20%)  2 1/1044 (0.10%)  1 2/1068 (0.19%)  2 2/1079 (0.19%)  2
Infections and infestations         
Infections and infestations * 1  90/1012 (8.89%)  109 102/1044 (9.77%)  139 103/1068 (9.64%)  144 99/1079 (9.18%)  127
Injury, poisoning and procedural complications         
Injury, poisoning and procedural complications * 1  76/1012 (7.51%)  90 62/1044 (5.94%)  72 74/1068 (6.93%)  90 66/1079 (6.12%)  84
Investigations         
Investigations * 1  14/1012 (1.38%)  14 19/1044 (1.82%)  20 13/1068 (1.22%)  15 12/1079 (1.11%)  12
Metabolism and nutrition disorders         
Metabolism and nutrition disorders * 1  21/1012 (2.08%)  22 16/1044 (1.53%)  18 13/1068 (1.22%)  13 23/1079 (2.13%)  25
Musculoskeletal and connective tissue disorders         
Musculoskeletal and connective tissue disorders * 1  66/1012 (6.52%)  77 74/1044 (7.09%)  91 71/1068 (6.65%)  85 85/1079 (7.88%)  101
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Neoplasms benign, malignant and unspecified (incl cysts and polyps) * 1  80/1012 (7.91%)  103 88/1044 (8.43%)  111 83/1068 (7.77%)  100 92/1079 (8.53%)  112
Nervous system disorders         
Nervous system disorders * 1  66/1012 (6.52%)  73 74/1044 (7.09%)  93 72/1068 (6.74%)  87 73/1079 (6.77%)  86
Psychiatric disorders         
Psychiatric disorders * 1  4/1012 (0.40%)  4 5/1044 (0.48%)  5 5/1068 (0.47%)  5 9/1079 (0.83%)  11
Renal and urinary disorders         
Renal and urinary disorders * 1  19/1012 (1.88%)  20 25/1044 (2.39%)  26 24/1068 (2.25%)  25 25/1079 (2.32%)  29
Reproductive system and breast disorders         
Reproductive system and breast disorders * 1  9/1012 (0.89%)  11 8/1044 (0.77%)  8 12/1068 (1.12%)  13 11/1079 (1.02%)  11
Respiratory, thoracic and mediastinal disorders         
Respioratory, thoracic and mediastinal disorders * 1  44/1012 (4.35%)  59 43/1044 (4.12%)  52 37/1068 (3.46%)  50 46/1079 (4.26%)  51
Skin and subcutaneous tissue disorders         
Skin and subcutaneous tissue disorders * 1  1/1012 (0.10%)  1 6/1044 (0.57%)  7 3/1068 (0.28%)  3 5/1079 (0.46%)  5
Surgical and medical procedures         
Surgical and medical procedures * 1  32/1012 (3.16%)  32 29/1044 (2.78%)  31 27/1068 (2.53%)  30 32/1079 (2.97%)  32
Vascular disorders         
Vascular disorders * 1  41/1012 (4.05%)  45 40/1044 (3.83%)  42 42/1068 (3.93%)  45 42/1079 (3.89%)  46
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (10.0)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo/Control Lutein/Zeaxanthin DHA/EPA Lutein/Zeaxanthin + DHA/EPA
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   717/1012 (70.85%)      791/1044 (75.77%)      759/1068 (71.07%)      791/1079 (73.31%)    
Eye disorders         
Dry eye † 1  55/1012 (5.43%)  62 39/1044 (3.74%)  40 64/1068 (5.99%)  70 62/1079 (5.75%)  70
Eye disorder † 1  67/1012 (6.62%)  100 67/1044 (6.42%)  96 62/1068 (5.81%)  98 82/1079 (7.60%)  152
Visual disturbance † 1  88/1012 (8.70%)  118 110/1044 (10.54%)  139 84/1068 (7.87%)  116 88/1079 (8.16%)  119
Vitreous disorder † 1  133/1012 (13.14%)  208 154/1044 (14.75%)  213 165/1068 (15.45%)  228 162/1079 (15.01%)  208
Gastrointestinal disorders         
Change in bowel habit † 1  57/1012 (5.63%)  69 67/1044 (6.42%)  77 48/1068 (4.49%)  58 57/1079 (5.28%)  60
Infections and infestations         
Bronchitis † 1  62/1012 (6.13%)  72 69/1044 (6.61%)  83 57/1068 (5.34%)  80 56/1079 (5.19%)  66
Upper respiratory tract infection † 1  139/1012 (13.74%)  175 150/1044 (14.37%)  190 139/1068 (13.01%)  179 138/1079 (12.79%)  173
Urinary tract infection † 1  57/1012 (5.63%)  82 75/1044 (7.18%)  103 71/1068 (6.65%)  108 73/1079 (6.77%)  96
Vascular disorders         
Hypertension † 1  59/1012 (5.83%)  66 60/1044 (5.75%)  62 69/1068 (6.46%)  72 73/1079 (6.77%)  73
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (10.0)
[Not Specified]
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Traci Clemons, PhD
Organization: The EMMES Corporation
Phone: 301-251-1161 ext 212
EMail: tclemons@emmes.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: National Eye Institute (NEI)
ClinicalTrials.gov Identifier: NCT00345176    
Obsolete Identifiers: NCT00409513
Other Study ID Numbers: NEI-120
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 )
First Submitted: June 14, 2006
First Posted: June 27, 2006
Results First Submitted: November 1, 2013
Results First Posted: December 24, 2013
Last Update Posted: May 5, 2015