STUDY SUBJECTS

Major inclusion criteria:

• Age 55-80 (Age 55-59 AND category 3 or 4)
• Category 2-4 AMD
  • Category 2 (extensive small drusen, 1 intermediate druse, or pigmentary changes in 1 or both eyes)
  • Category 3 (extensive intermediate drusen, 1 large druse, or non central GA in at least 1 eye)
  • Category 4 (advanced AMD or vision loss < 20/32 from non advanced AMD in 1 eye)
• Best corrected visual acuity of at least 20/32 or better in 1 eye
• Clear ocular media for photographs
• At least 1 eye without any eye disease that complicates assessment of AMD progression, lens status, or visual acuity, or history of ocular surgery

Major exclusion criteria:

• Category 1 AMD (few if any drusen)
• Illness or disorders that would make long term follow up or compliance with study protocol difficult (ie. History of cancer with poor 7 year prognosis, major cardiovascular or cerebrovascular events in the past year, hemochromatosis)

RANDOMIZATION SCHEME AND INTERVENTIONS

Randomized 1:1:1:1 to

(a) Placebo

(b) Antioxidant vitamins (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg);

(c) Zinc (Zinc oxide 80 mg, and copper 2 mg as cupric oxide)

(d) Antioxidants plus Zinc

PRIMARY OUTCOMES

1. Progression to Advanced AMD in study eye at 5 years- determined by fundus photography
   • Advanced AMD Definition: photocoagulation or other treatment for choroidal neovascularization (based on clinical center reports), or photographic documentation of any of the following (based on reading center reports): GA involving the center of the macula, non-drusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and/or sub-retinal fibrosis.
2. Vision Loss of at least 15 letters or greater at 5 years- determined by ETDRS

SECONDARY OUTCOMES

• Development of neovascular AMD, incidence of GA (center or non-center), progression to advanced AMD with an associated 15 letter VA drop, and worsening of AMD classifications in Category 2 to Category 3 or 4 during follow up.
• Decrease in BCVA of 30 or more letters from baseline
• Progression to VA score < 20/100 in 1 or both eyes

Ophthalmic examinations were performed every 6 months. Stereoscopic Fundus Photographs were taken annually starting at 2 years and graded a reading center or if visual acuity first dropped by 10 letters from baseline.

RESULTS

Study population

• 3640 patients overall
• Study completion was 90% at 5 years (13.6% of participants withdrew from their study medication in era of reports of lung cancer and beta carotene were announced)

PRIMARY OUTCOME RESULTS

PROGRESSION TO ADVANCED AMD AT 5 YEARS

By AMD Category (ie. placebo group): Absolute risk at 5 years

• Category 2 AMD: 1.3%
• Category 3 AMD: 18% (range: 6% for extensive intermediate druse and no non-central GA patients, and 27% for those with large druse and non-central GA)
• Category 4 AMD: 43%

By Treatment Group

• Antioxidants plus zinc resulted in significantly reduced risk of AMD progression by ~25%: (OR 0.72; 99% CI, 0.52-0.98) ->Absolute risk rate (28% placebo vs 20% antioxidants plus zinc)
• For Category 3 or 4 AMD patients only: Greater significant reduction in AMD progression for both zinc and zinc plus antioxidants groups (zinc plus antioxidants 0.66; 99% CI 0.47-0.91)

VISUAL ACUITY LOSS OF 15 OR MORE LETTERS AT 5 YEARS:

• No statistical difference in all treatment arms
• For Category 3 or 4 AMD patients only: significant risk reduction of VA loss in the zinc plus antioxidants groups (zinc plus antioxidants 0.73; 99% CI, 0.54-0.99)

NOTABLE SECONDARY OUTCOMES

1. Risk of VA Loss of 15 or more letters PLUS Development of Advanced AMD:
   Category 3 and 4 AMD: Significant reduction in zinc plus antioxidant group (OR 0.63; 99% CI, 0.44-0.92); Mainly significant for the Category 4 AMD subset
2. Risk of VA Loss of 15 or more letters in nonstudy eyes with Advanced AMD at Baseline: significant reduction in all treatment groups
3. Development of Neovascular AMD: significant reduction in the zinc plus antioxidant group for cat 3 and 4 (0.62; 99% CI 0.43-0.90
4. Development of GA: no statistical difference in treatment groups vs placebo

Adverse Events:

• Antioxidant arms: more frequently reported yellow skin (8.3% vs 6.0%; P=.008)
• Zinc arms: showed an excess of self-reported anemia (13.2% vs 10.2%; P=.004), genitourinary hospitalizations
• No difference in mortality rates among smokers
• No significant effects of antioxidants on mortality
• Results of 2 other randomized trials suggested an increased mortality among smokers supplementing with beta carotene, so safety committee suggested stopping treatment in smokers

CONCLUSION

• Zinc alone or in combination with antioxidant supplementation reduces risk of progression to advanced AMD in patients with Category 3 or 4 AMD (extensive intermediate druse, large druse, or non central GA in 1 or both eyes, or advanced AMD in 1 eye and at least 20/32 or better in fellow eye)
• There was a 25% risk reduction of AMD progression in those taking the combined zinc plus antioxidant supplement
• Benefits of supplementation could not be assessed for Category 2 AMD subset only because of the low event rate to begin with. There was no difference in progression to more severe druse pathology (ie. Advancement to Category 3 or 4 AMD)