Clinical Trials in Nonneovascular Age-Related Macular Degeneration
Benjamin Nicholson MD
Emily Y. Chew MD
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world.1,2 There are two forms of advanced AMD: central geographic atrophy (CGA) and neovascular (wet) AMD. Although new treatments have improved outcomes in neovascular AMD over the last decade, there remains no proven treatment for geographic atrophy (GA). Therapies that focus on prevention by addressing modifiable risk factors such as diet and nutritional status are important approaches to reducing the burden of AMD. Such preventive strategies are especially important as life expectancy in the United States and Europe continues to increase.
Scientific publications on early AMD and GA have greatly increased over the last decade. Some of this scientific interest has resulted in the development of clinical trials for early AMD and GA. This chapter summarizes the key clinical trials of therapies for early and intermediate AMD and GA that have been published to date. None of these trials, with the exception of the Age-Related Eye Disease Study (AREDS), has resulted in a widely adopted new therapy. These trials do, however, inform the design of ongoing and future studies.
Treatment of Early and Intermediate Age-Related Macular Degeneration
Trials of treatment for early and intermediate AMD have largely been designed to target various aspects of AMD pathogenesis. The specifics of AMD pathogenesis remain unknown, but aging, genetic factors, and environmental factors play important roles. Oxidative damage is implicated as an end effector in the pathogenesis of AMD. The retina is uniquely susceptible to oxidative damage given its high metabolic activity and daily exposure to light.3,4 Pathologic examination and proteome analysis of retinas of eyes with AMD reveal more protein adducts resulting from oxidative modification of carbohydrate and lipid than control eyes.5 The increasing incidence of macular degeneration with advancing age may be related to gradual dysfunction and degeneration of retinal tissues as oxidative damage accumulates. A growing body of evidence also implicates inflammatory processes in the pathogenesis and progression of macular degeneration.3
The trials of early and intermediate AMD presented below fall broadly into three groups: nutritional supplements and antioxidants, treatments that affect microcirculation and oxygen delivery, and macular laser. The nutritional supplements investigated to date have been targeted toward the oxidative stresses and inflammation implicated in AMD pathogenesis. Studies of supplements gained momentum with the publication of AREDS in 2001, and many studies since then have looked at related supplements and potential improvements upon the AREDS formula. Trials that have targeted oxygen delivery and the intraocular microcirculatory environment have employed rheopheresis and oxygen ozone therapy. Age-related thinning of the choroid6 and decreased choroidal blood flow in AMD7 underlie the hypotheses that improving blood viscosity and oxygen delivery might help halt the progression of AMD. Finally, macular
laser was proposed by Donald Gass as a potential therapy for early AMD in part because it induces regression of macular drusen.8 These three groups of trials are summarized below.
laser was proposed by Donald Gass as a potential therapy for early AMD in part because it induces regression of macular drusen.8 These three groups of trials are summarized below.
Age-Related Eye Disease Study
Study Design
The AREDS was a multicenter, randomized, placebo-controlled trial designed to study the natural history of AMD and age-related cataract and to assess the impact of antioxidant vitamins and zinc supplementation on these conditions.9 The intervention incorporated antioxidant vitamins and zinc for two main reasons.9 First, several epidemiologic studies and clinical trials at that time had suggested a role for antioxidants in reducing the risk of cancer, cardiovascular disease, and eye disease. A small trial had also suggested that pharmacologic doses of zinc reduced the risk of vision loss in AMD.10 The second reason was the growing use of commercially available antioxidant and zinc supplements among AMD patients, despite a paucity of clinical evidence. A large, randomized trial was needed to evaluate these supplements for AMD.
The AREDS trial randomized 3,640 participants with AMD to antioxidant supplements, zinc, combined antioxidants and zinc, or placebo (Table 8A.1). The combined AREDS supplement contained 15 mg beta-carotene, 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc oxide, and 2 mg of copper as cupric oxide. Participants were stratified into four categories of AMD by clinical appearance:
Category 1: No drusen to few drusen; 0.44% developed advanced AMD by year 5.
TABLE 8A.1 AREDS Treatment Groups | ||||||||||||||||||||||||||||||||||||
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Category 2: Extensive small drusen, pigment abnormalities, or at least one intermediate drusen in at least one eye; 1.3% probability of progression to advanced AMD by year 5.
Category 3: Extensive intermediate drusen, large drusen, or non-CGA in at least one eye; 18% probability of progression to advanced AMD by year 5. Patients within category 3 who had bilateral large drusen or noncentral GA in at least one eye at enrollment were four times more likely to progress to advanced AMD than the remaining participants in category 3 (27% vs. 6% at 5 years).
Category 4: Advanced AMD or vision loss due to nonadvanced AMD in one eye; 43% probability of progression to advanced AMD in 5 years.
Primary Outcome
Progression to advanced AMD 15-letter decrease in visual acuity score
Key Secondary Outcomes
Worsening of AMD classification 30-letter decrease in visual acuity score Loss of acuity to level of 20/100
Major Inclusion Criteria
Age 55 to 80 years 20/32 acuity or better in study eye
Results
The interventional AMD study results were published in 2001.11 The combination of antioxidant vitamins with zinc was protective against the development of advanced AMD (odds ratio [OR] 0.72, 99% confidence
interval [CI] 0.52-0.98). The treatment effect was greater when category 3 and 4 participants were analyzed (OR 0.66, 99% CI 0.47-0.91). Those with category 1 or 2 AMD had a very low risk of progression to advanced AMD, and a much larger sample size and longer follow-up would be required to evaluate for a treatment effect for the AREDS formulation for these patients.
interval [CI] 0.52-0.98). The treatment effect was greater when category 3 and 4 participants were analyzed (OR 0.66, 99% CI 0.47-0.91). Those with category 1 or 2 AMD had a very low risk of progression to advanced AMD, and a much larger sample size and longer follow-up would be required to evaluate for a treatment effect for the AREDS formulation for these patients.
The zinc without antioxidants treatment group in AREDS had a suggestive, but not statistically significant, reduction in risk of progression to advanced disease (OR 0.75, 99% CI 0.55-1.03). When analysis was restricted to category 3 and 4 participants, there was a significant reduction in progression to advanced AMD (OR 0.71, 99% CI 0.52-0.99). For zinc alone, there was no significant reduction in rates of moderate vision loss. Secondary analyses of the AREDS cohort revealed that participants who took zinc had a significantly lower mortality (mean follow-up 6.5 years, relative risk 0.73, 95% CI 0.61-0.89).
The antioxidant vitamin-only group had a nonsignificant reduction in risk (OR 0.80, 99% CI 0.59-1.09). The risk reduction remained statistically nonsignificant when analysis was restricted to category 3 and 4 participants (OR 0.76, 99% CI 0.55-1.05).
The AREDS formulation was shown to be protective against the development of advanced AMD, but subgroup analysis indicates that the supplements reduce the rate of neovascular disease but not CGA. The number of participants who developed CGA in AREDS was not sufficient to rule out a treatment effect, but analysis of all AREDS patients who developed at least moderate GA also did not indicate a benefit.
Safety
In AREDS, patients taking zinc were hospitalized more often for genitourinary complaints than controls (7.5% vs. 4.9%; p = 0.001).11 Those in the zinc arm had a higher self-reported rate of anemia (13.2% vs. 10.2%; p = 0.004), although measured hematocrit did not differ between the two groups. Antioxidant vitamins were associated with skin yellowing. Circulatory adverse experiences (0.3% vs. 0.8%; p = 0.04) and skin conditions (2.2% vs. 1.0%; p = 0.003) were more frequent in the antioxidant vitamin group.
Future Directions
The National Eye Institute has conducted AREDS2, a multicenter, randomized, placebo-controlled trial, to assess the effects of daily oral supplementation of lutein, zeaxanthin, and/or omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid) on the progression to advanced AMD (Table 8A.2). More than 4,000 participants aged 50 to 85 years were enrolled and have been followed for 5 years. At baseline, participants had bilateral large drusen or large drusen in one eye with advanced AMD in the fellow eye. The primary outcome is the development of advanced AMD.
AREDS2 provides an opportunity to further refine the original AREDS formulation by testing the macular carotenoids and a lower dose of zinc. The macular carotenoids may provide additional benefit over beta-carotene, which is not found in the eye but was available for study at the time of the original AREDS study. The full 80 mg of zinc may not be necessary, as recent data suggest that maximal systemic absorption of zinc is about 25 mg/day (Table 8A.3).4
TABLE 8A.2 Treatment Groups in the Primary Randomization in AREDS24 | ||||||||||||||
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TABLE 8A.3 Treatment Groups in the Secondary Randomization in AREDS24 | ||||||||||||||||||||||||||||||||||||||||||
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Oral Zinc in Macular Degeneration
Study Design
The first clinical evidence of a beneficial effect of zinc supplementation in AMD came in 1988 from a small (n = 151), randomized, placebo-controlled trial of 100 mg of oral zinc sulfate for a wide range of AMD patients.10
Primary Outcome
Change in visual acuity at 12 to 24 months
Major Inclusion Criteria
Drusen and pigmentary change on clinical examination
Vision of 20/80 or better in one eye
Results
There was a 2.5× risk reduction for loss of 20 letters of acuity. At the final study visit, 86% of treated patients had lost less than 9 letters of acuity versus 66% in the placebo group.
Safety
Two patients in the treatment group experienced mild gastrointestinal irritation.
Oral Zinc and the Second Eye in Age-Related Macular Degeneration
Study Design
In 1996, Stur and colleagues published a randomized, placebo-controlled trial of 200 mg of oral zinc sulfate over 2 years in patients with unilateral exudative AMD (n = 112).14 Patients were followed for 24 months. The original study design called for 500 participants, but the drug maker stopped recruitment based on interim analyses that did not suggest a treatment effect.
Primary Outcome
Development of choroidal neovascularization (CNV) in the study eye
Major Inclusion Criteria
Unilateral exudative AMD
20/40 or better acuity in study eye (nonexudative disease at baseline)
Macular drusen in the study eye
Results
Just 14 participants developed new neovascularization during the 2-year study, and there was no apparent treatment benefit. Nine eyes in the treatment group developed CNV versus five in the placebo group.
Safety
Six participants withdrew from the study due to gastrointestinal symptoms related to the study medication. Fourteen further participants withdrew from the study for unspecified reasons.
Zinc Monocysteine
Study Design
In 2008, Newsome published a trial (n=80) of zinc monocysteine for dry AMD.15 This compound in theory delivers both a zinc supplement and a cysteine supplement.
Cysteine is a precursor molecule in the glutathione pathway, and the objective of cysteine supplementation in this trial was to boost levels of the antioxidant glutathione. Subjects with early or intermediate AMD were randomized 1:1 to zinc monocysteine 25 mg daily or placebo, and the study drug was administered for 6 months.
Cysteine is a precursor molecule in the glutathione pathway, and the objective of cysteine supplementation in this trial was to boost levels of the antioxidant glutathione. Subjects with early or intermediate AMD were randomized 1:1 to zinc monocysteine 25 mg daily or placebo, and the study drug was administered for 6 months.
Primary Outcome
Tolerability of study supplement
Change in best-corrected visual acuity at 6 months
Change in contrast sensitivity at 6 months
Change in photorecovery time at 6 months
Major Inclusion Criteria
Macular drusen with or without pigment changes
Best-corrected visual acuity between 20/25 and 20/70
Results
The study supplement was well tolerated, and there was a statistically significant improvement in visual acuity (3-4 letter mean improvement, p < 0.0001), contrast sensitivity, and photorecovery time at 6 months.
Safety
One patient in the supplement group developed significant gastrointestinal irritation due to the study intervention. There were no other supplement-related adverse events.
Vitamin E, Cataract, and Age-Related Maculopathy Study
Study Design
The results of the AMD trial within the Vitamin E, Cataract, and Age-Related Maculopathy Study (VECAT) were published in 2002.16 VECAT was a randomized, placebo-controlled trial of 500 IU vitamin E. The study group enrolled 1,204 participants and followed them over 4 years. At baseline, 18% had early or intermediate AMD and 0.5% had advanced AMD.
Primary Outcome
Development of early or intermediate AMD Development of cataract
Key Secondary Outcomes
Progression of early AMD
Development of advanced AMD
Change in visual acuity
Change in visual function
Major Inclusion Criteria
Age 55 to 80 years
Phakic in at least one eye
Results
VECAT showed no effect of vitamin E supplementation on the incidence of early or late AMD.16 In the vitamin E group, 8.6% of participants developed early or intermediate AMD versus 8.1% in the placebo group. For late AMD, the treatment group had a 0.8% rate versus 0.6% for the placebo group. Vitamin E supplementation did not affect the incidence or progression of cataract,17 and there were no significant differences among the secondary outcome measures.
Safety
There were no serious adverse events, and no vitamin E-related adverse effects were identified.
CARMA (Carotenoids with Coantioxidants in Age-Related Maculopathy)
Study Design
The AREDS supplement incorporates the carotenoid beta-carotene, but lutein and zeaxanthin have long been carotenoids of interest for AMD and other macular diseases because, unlike beta-carotene, they occur naturally in the macula. They are thought to protect the outer retina and retinal pigment epithelium (RPE) from damage.18 CARMA was a randomized, controlled trial of a supplement (12 mg lutein, 0.6 mg zeaxanthin, 15 mg vitamin E, 150 mg ascorbic acid, 20 mg zinc oxide, and 0.4 mg copper gluconate [marketed by Bausch and Lomb under the Ocuvite® brand]) versus placebo.19 The 433 participants took the supplement once daily for at least 1 year.
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