Clinical research
Randomized, double-blind, placebo-controlled study of zeaxanthin and visual function in patients with atrophic age-related macular degeneration: The Zeaxanthin and Visual Function Study (ZVF) FDA IND #78, 973

https://doi.org/10.1016/j.optm.2011.08.008Get rights and content

Abstract

Background

The purpose of this study is to evaluate whether dietary supplementation with the carotenoid zeaxanthin (Zx) raises macula pigment optical density (MPOD) and has unique visual benefits for patients with early atrophic macular degeneration having visual symptoms but lower-risk National Institute of Health/National Eye Institute/Age-Related Eye Disease Study characteristics.

Methods

This was a 1-year, n = 60 (57 men, 3 women), 4-visit, intention-to-treat, prospective, randomized controlled clinical trial of patients (74.9 years, standard deviation [SD] 10) with mild-to-moderate age-related macular degeneration (AMD) randomly assigned to 1 of 2 dietary supplement carotenoid pigment intervention groups: 8 mg Zx (n = 25) and 8 mg Zx plus 9 mg lutein (L) (n = 25) or 9 mg L (“Faux Placebo,” control group, n = 10). Analysis was by Bartlett’s test for equal variance, 3-way repeated factors analysis of variance, independent t test (P < 0.05) for variance and between/within group differences, and post-hoc Scheffé's tests. Estimated foveal heterochromic flicker photometry, 1° macular pigment optical density (MPOD QuantifEye®), low- and high-contrast visual acuity, foveal shape discrimination (Retina Foundation of the Southwest), 10° yellow kinetic visual fields (KVF), glare recovery, contrast sensitivity function (CSF), and 6° blue cone ChromaTest® color thresholds were obtained serially at 4, 8, and 12 months.

Results

Ninety percent of subjects completed ≥ 2 visits with an initial Age-Related Eye Disease Study report #18 retinopathy score of 1.4 (1.0 SD)/4.0 and pill intake compliance of 96% with no adverse effects. There were no intergroup differences in 3 major AMD risk factors: age, smoking, and body mass index as well as disease duration and Visual Function Questionnaire 25 composite score differences. Randomization resulted in equal MPOD variance and MPOD increasing in each of the 3 groups from 0.33 density units (du) (0.17 SD) baseline to 0.51 du (0.18 SD) at 12 m, (P = 0.03), but no between-group differences (Analysis of Variance; P = 0.47). In the Zx group, detailed high-contrast visual acuity improved by 1.5 lines, Retina Foundation of the Southwest shape discrimination sharpened from 0.97 to 0.57 (P = 0.06, 1-tail), and a larger percentage of Zx patients experienced clearing of their KVF central scotomas (P = 0.057). The “Faux Placebo” L group was superior in terms of low-contrast visual acuity, CSF, and glare recovery, whereas Zx showed a trend toward significance.

Conclusion

In older male patients with AMD, Zx-induced foveal MPOD elevation mirrored that of L and provided complementary distinct visual benefits by improving foveal cone-based visual parameters, whereas L enhanced those parameters associated with gross detailed rod-based vision, with considerable overlap between the 2 carotenoids. The equally dosed (atypical dietary ratio) Zx plus L group fared worse in terms of raising MPOD, presumably because of duodenal, hepatic-lipoprotein or retinal carotenoid competition. These results make biological sense based on retinal distribution and Zx foveal predominance.

Section snippets

Methods

The study design was a 1-year, staggered recruitment, prospective, double-blind, intention-to-treat RCT of patients with early and moderate AMD (ICD9 362.51), but not advanced disease. The sample included 60 patients (119 eyes), predominantly male (57 male and 3 female), 74.9 years of age, with an SD of 10 years. Subjects were allocated randomly to 1 of 2 dietary supplement treatment carotenoid pigment arms: 8 mg Zx (n = 25 subjects), a higher-dose 8-mg Zx/9-mg L combination (n = 25), or “Faux

Demographic, dietary, skin carotenoids, confounding lens opacification and NEI Visual Function Questionnaire 25 AMD symptom assessment

Demographic parameters included a query of age, gender, months since AMD diagnosis, smoking in pack years, alcohol consumption in ounces per day, physical activity, and diabetes. Iris color was noted as blue, green, or brown. Physical assessment included body mass index (BMI), hand grip, and body fat percentage measured by bioelectric impedance (Omron Corp, Japan) at the baseline and final 12-month visit, as adipose tissue is a known reservoir for carotenoids.32, 33

Diet was assessed using the

Primary outcome measure—estimated central foveal 1° MPOD and 3-dimensional autofluorescence MPOD distribution

Replicate measures of foveal 1° estimated central MPOD were evaluated with the QuantifEye® MPS 9000 macular pigment screener (ZeaVision, Inc., Chesterfield, Missouri), a modified heterochromic flicker photometer (HFP). (In HFP, the peripheral test may not be reliable, depending on cataract stage and cognitive ability.) It uses alternating blue and green flickering light-emitting diodes and fixation on a 1° target.40 The method has good repeatability (r = 0.97), and the data are comparable with

Retinal lipofuscin autofluorescence imaging

Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases including AMD.46 Retinal autofluorescence is a noninvasive method of imaging the fundus to observe the presence of lipofuscin.47 Baseline and final visit 50° digital retinal and autofluorescent lipofuscin images were taken with a modified Kowa Digital VK2® system, (KOWA Optimed,

Foveal testing

Testing was exclusively monocular, with the best refraction by a single examiner used for subsequent testing at baseline and serial visits. Conventional high-contrast Early Treatment of Diabetic Retinopathy Study (ETDRS) distance visual acuity was assessed to a fractional line (single letter), displayed randomly on a video projection system at 10 feet (M&S Technologies, Smart Systems II, Park Ridge, Illinois). Measurements were converted to LogMAR visual acuity. One-degree foveal function was

Statistical analysis and blinding (masking)

The primary outcome measure was a change in the MPOD by the intervention group using a 3-factor repeated measures analysis of variance (ANOVA). Post-hoc tests were conducted using Scheffe’s test, and the equal variances assumption was ascertained using Bartlett’s test. When Bartlett’s test violated ANOVA’s equal variances assumption, a Welch’s t test for unequal variances was used. Between-group differences were ascertained using a 2-sample t test with equal variances assumption. Based on prior

Results

In ZVF, 90% of subjects completed at least 2 study visits with 96% pill intake compliance gauged by unused pill count, periodic (daily, weekly, then monthly) telephone queries, and measuring the near universal increase in skin carotenoids (see ZVF non-responder section below). One patient in the “Faux Placebo” L group (subject Z46, age 77) died before the 4-month visit, and 1 subject in the Zx group (subject Z31, age 60) died before the 8-month visit. The cause of these deaths were reviewed by

Baseline demographic and clinical characteristics

Table 1 presents population and group baseline demographic data averages, SDs and significance. On average, 60 older, near obese (BMI 29.1, SD 5) AMD subjects, 74.9 (SD 10) years of age, (57 men and 3 women), with brief average AMD duration of 3.5 years from diagnosis, participated in the RCT. There was a minimal current average population smoking history of only 0.2 (SD 0.5) packs per day and alcohol consumption of only 0.8 (SD 1) ounces of alcohol per day. Population diabetes duration was

Visual function reduction in AMD patients at baseline

Table 2 displays baseline ZVF visual function data. The population composite NEI VFQ25 score was 85 of 100 with no subgroup differences. The ETDRS (high-contrast) visual acuity score was 95.2 (SD 8) or 20/25+1 right eyes, 91.0 (SD 16) or 20/30 left eyes, with no subgroup differences. However, the low-contrast Colenbrander near visual acuity score was reduced, more for left eyes 88.7 (SD 13) R eyes, 76.2 (SD 16) L eyes with no subgroup differences. The Smith Kettlewell Institute Low Luminance

Primary outcome and significance

Figure 1A depicts universal increased palm skin carotenoid scores with carotenoid supplementation. The scores were equal at baseline, but differentially increased during the ZVF study, with a lower increase seen in the Zx group (see nonresponder section below) and with a greater effect in the higher-dosed combined carotenoid group (2-sample t test, equal variance, baseline to 12 months; L, P = 0.02; Zx, P = 0.04, and L plus Zx, P = 0.0008; ANOVA, P = 0.03 at 4 months; P = 0.06 for trend at 8

Foveal vision

Figures 2A-C depict the effects of carotenoid supplementation on conventional average eye high-contrast visual acuity, shape discrimination, and kinetic visual fields, which measure central high-resolution cone-predominating foveal function where Zx outperformed L. In Figure 2A, average eye Colenbrander near visual acuity improved at least 1 line in all 3 intervention groups (L, 5.6 letters; Zx plus L, 6.0 letters; P = 0.05), with the greatest 1.5-line/8.5-letter increase with Zx alone, P =

Subjective vision, retinal lipofuscin, and cataract

Composite summed subjective VFQ25 questionnaire answers improved slightly (+2%) over 12 months, but were not statistically significant, with no summed category intergroup differences by ANOVA, except for the driving subscale that showed a near improvement in the Z group (P < 0.057 for trend) in a linear regression model.58 The AREDS report #18 bilateral simplified AREDS score showed a nonsignificant improvement for Zx subjects who had higher (worse) starting baseline AMD retinopathy (P < 0.007,

ZVF nonresponders and AREDS/AREDS II nutrient intake changes

Sixteen of 60 ZVF subjects (27%) did not show a response in terms of > 5,000 unit increase in their skin carotenoid scores, and 75% of these were in the Zx group. The biophotonic skin carotenoid skin scanner is not efficiently tuned to Zx compared with L.59 Five individuals (8.3%) failed to experience greater than a 10% MPOD increase. These individuals included 2 smokers who were of similar age, BMI, percentage of body fat, AREDS retinopathy score, clinical evidence of gallbladder disease

Discussion

Preliminary results of a single-center (n = 53) patient substudy, within AREDS II, suggests that serum and skin carotenoid measurements are not reliable biomarkers for MPOD.61 There are also formidable technical difficulties in reliably measuring MPOD in elderly patients with cataracts; better objective imaging techniques are desperately needed. Nonetheless, the “low-normal” macular pigment values encountered in ZVF are similar to those encountered in our LAST Study, when adjusted for the

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      In research comparing different spectroscopy methods, spectrophotometer measurements tend to be less accurate, at least compared to RRS, due to interference from various color compounds (Meinke et al., 2016). Macular pigment optical density (MPOD) is a biomarker of carotenoid status applied to studies of various diseases that affect visual function (Akuffo et al., 2015; Davey et al., 2020; Huang et al., 2015; Koh et al., 2004; Liu et al., 2015; Ma, Dou, et al., 2012; Ma, Yan, et al., 2012; Richer, Devenport, & Lang, 2007; Richer et al., 2011; Sabour-Pickett et al., 2014; Trieschmann et al., 2007) such as age-related macular degeneration and visual acuity (Beatty, Boulton, Henson, Koh, & Murray, 1999; Davey, Rosen, & Gierhart, 2021; Wooten & Hammond, 2002). MPOD is correlated with concentrations of specific carotenoids in the brain (Johnson et al., 2013; Vishwanathan, Neuringer, Snodderly, Schalch, & Johnson, 2013) and is increasingly employed in studies of cognitive performance and other brain functions (Feeney et al., 2013; Power et al., 2018; Renzi, Bovier, & Hammond, 2013).

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    Disclosure: The primary investigator is a consultant to Stereo Optical Company Inc. (Chicago, Illinois), manufacturer of the Functional Vision Analyzer, and to Annidis Health Systems (Ottawa, Ontario, Canada).

    Richer SP, Stiles WR, Levin MR, et al. The zeaxanthin and visual function study in atrophic age related macular degeneration (ZVF-FDA IND #78, 973) - MP and foveal shape discrimination data, Poster #510. Presented at: The Association for Research in Vision and Ophthalmology Meeting; Ft Lauderdale, Florida; May 2, 2010.

    This material is based on original work supported by the Captain James A. Lovell Federal Health Care Facility, North Chicago, Illinois, and the Department of Veterans Affairs Research Service/CARES (Hines, Illinois). Chrysantis, Inc. (West Chicago, Illinois) is the primary ZVF granting sponsor. Kowa Optimed, Inc. (Torrance, California and Tokyo, Japan), Stereo Optical, Inc. (Chicago, Illinois), Rush Ophthalmics, Inc. (Gold Beach, Oregon), Pharmanex, Inc. (Provo, Utah), ZeaVision, Inc. (Chesterfield, Missouri), Heidelberg Instruments, Inc. (Heidelberg, Germany), and RTVue (Fremont, California) all provided instrumentation as secondary sponsors in support of both ZVF and our Ocular Nutrition Laboratory.

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    Published by Elsevier U.S.A.