Table 5.
A summary of the eligible randomized clinical trials reporting on AMD.
| Authors (Year) | Study | Participants | Duration | Interventions | MPOD | Main Findings |
|---|---|---|---|---|---|---|
| Richer (2004) [225] | LAST | 90 patients with atrophic AMD; aged (74.7 ± 7.4) years in USA | 12 months | 10 mg L; 10 mg L * (multivitamin); placebo | HFP | Significant benefit in MPOD (p < 0.001), BCVA (p < 0.01) and CS at low/middle spatial frequencies (p < 0.05 for all) |
| Bartlett (2007) [209] | - | 25 patients with atrophic AMD; aged (69.2 ± 7.8) years in USA | 9 months | 6 mg L; placebo | - | Non-significant trend towards improvement in CS reported |
| Cangemi (2007) [212] | TOZAL | 37 patients with atrophic AMD; aged (76.3 ± 7.8) years in USA | 6 months | 8 mg L and 0.4 mg Z * (multivitamin) | - | Modest improvements observed in BCVA (p = 0.045) |
| Trieschmann (2007) [119] | LUNA | 100 patients with AMD; aged (71.5 ± 7.1) years in Germany | 6 months | 12 mg L and 1 mg Z * (multivitamin);placebo | Fundus AFI | Mean increase of +15.9% in MPOD measured at 0.5° eccentricity (p < 0.001) compared to control |
| Parisi (2008) [223] | CARMIS | 27 patients with atrophic AMD; aged (65.5 ± 5.1) years in Italy | 12 months | 10 mg L + 1 mg Z * (multivitamin); placebo | - | Enhanced improvement in central retinal function measures on mfERG (ring 1 and ring 2; p < 0.01 for both) |
| Connolly (2010) [213] | MOST | 5 patients with early AMD; aged (72.0 ± 11.0) years in Ireland | 2 months | 7.3 mg MZ, 3.7 mg L and 0.8 mg Z | cHFP | Significant increase in MPOD measured at 0.25° and 1° eccentricity with respect to time (p < 0.05 for all) |
| Richer (2011) [226] | ZVF | 60 patients with early/intermediate AMD; aged (74.9 ± 10.0) years in USA | 12 months | 8 mg Z; 8 mg and 9 mg L; 9 mg L | HFP | Central (1°) MPOD increased in all three groups (p < 0.03 for all); significant improvement in measures of foveal vision greater in Z-only group, while benefits in parafoveal vision were greater in L-only group |
| Weigert (2011) [120] | LISA | 126 patients with early/intermediate AMD; aged (71.6 ± 8.6) years in Austria | 6 months | 20 mg L for 3 months, then 10 mg L for 3 months; placebo | Reflectometry | Average increase of +27.9% in MPOD (p < 0.001); trend toward improvement in BCVA did not reach statistical significance |
| Ma (2012) [117] | - | 108 patients with early AMD; aged 50–81 years in China | 48 weeks | 10 mg L; 20 mg L; 10 mg L and 10 mg Z; placebo | Fundus AFI | Significant dose-response effect with increased MPOD (p < 0.01) positively related to benefits in CS (p < 0.05) and central retina function on mfERG (p < 0.01) |
| Piermarocchi (2012) [224] | CARMIS | 145 patients with atrophic AMD; aged (72.5 ± 7.0) years in Italy | 24 months | 10 mg L + 1 mg Z * (multivitamin); placebo | - | Reported significant benefits in BCVA and CS at 6-, 12-, and 24 months (p < 0.01 for all) compared to placebo |
| AREDS2 Research Group (2013) [50] | AREDS2 | 4203 patients with intermediate or late AMD; aged (73.1 ± 7.7) years in USA | 5 years | 10 mg L and 2 mg Z * (multivitamin); 10 mg L, 2 mg Z and omega-3 fatty acids * (multivitamin); “placebo” | - | Reduced hazard ratios of 0.82 (95% CI:0.69–0.96; p = 0.02) for late AMD and 0.76 (95% CI: 0.64–0.94; p = 0.01) for neovascular AMD compared to β-carotene in formulation † |
| Arnold (2013) [206] | - | 20 patients with atrophic AMD; aged (66.0 ± 8.0) years in Germany | 4 weeks | 10 mg L and 3 mg Z, in oleaginous kale extract | Reflectometry | Enhanced augmentation of macular pigment parameters including volume, area and maxOD (p < 0.001 for all) |
| Beatty (2013) [210] | CARMA | 433 patients with early AMD; aged (73.9 ± 8.1) years in Ireland | 12 months | 12 mg L and 0.6 mg Z * (multivitamin); placebo |
Raman spectroscopy | Statistically significant increase in MPOD with a positive linear trend during trial period (p < 0.01 for all) |
| Berrow (2013) [211] | - | 14 patients with early AMD; aged (67.6 ± 8.4) years in UK | 40 weeks | 12 mg L and 0.6 mg Z * (multivitamin); placebo |
- | Remarkable benefits in mfERG N1P1 response amplitude densities in ring 3 (p = 0.027); no differential changes observed in BCVA and CS |
| Dawczynski (2013) [215] | LUTEGA | 145 patients with atrophic AMD; aged (70.0 ± 10.0) years in Germany | 12 months | 10 mg L and 1 mg Z * (multivitamin); 20 mg L and 2 mg Z * (multivitamin); placebo | Reflectometry | Significant improvements observed for MPOD parameters (volume, area, maxOD and mean OD) and BCVA (p < 0.001 for all) in both treatment groups |
| García-Layana (2013) [216] | - | 44 patients with early AMD; aged (68.5 ± 8.5) years in Spain | 12 months | 12 mg L and 0.6 mg Z * (multivitamin); placebo |
HFP | Considerable rise in MPOD (+0.162 ODU; p < 0.01); however, no significant changes seen in BCVA and CS |
| Murray (2013) [222] | CLEAR | 72 patients with early AMD; aged (70.5 ± 8.7) years in United Kingdom | 12 months | 10 mg L; placebo | cHFP | Highly statistically significant increase in MPOD (+39.5%; p < 0.001) when compared to placebo |
| Sabour-Pickett (2014) [228] | MOST | 52 patients with early AMD; aged (66.0 ± 8.0) years in Ireland | 12 months | 20 mg L and 2 mg Z; 10 mg L, 2 mg Z and 10 mg MZ; 3 mg L, 2 mg Z and 17 mg MZ | cHFP | Robust improvements in MPOD spatial profile observed in those supplemented all three carotenoids in formulation (Group 2, p < 0.005; Group 3, p < 0.05) |
| Akuffo (2015) [205] | MOST | 52 patients with early AMD; aged (66.0 ± 8.0) years in Ireland | 3 years | 20 mg L and 2 mg Z; 10 mg L, 2 mg Z and 10 mg MZ; 3 mg L, 2 mg Z and 17 mg MZ | cHFP | Clinically meaningful CS benefits were seen in all three groups (p < 0.05 for all): Group 1 (15.15 cpd), Group 2 (1.2-, 6- and 9.6 cpd) and Group 3 (6-, 9.6- and 15.15 cpd) |
| Huang (2015) [115] | - | 112 patients with early AMD; aged (69.1 ± 7.4) years in China | 24 months | 10 mg L; 20 mg L; 10 mg L and 10 mg Z; placebo | Fundus AFI | Highly significant time x treatment interaction (p < 0.001) between changes in MPOD and central retinal function improvements (mfERG and MRS; p < 0.05 for both) |
| Thurnham (2015) [230] | - | 32 patients with early AMD; aged (66.0 ± 9.0) years in Ireland | 8 weeks | 20 mg L, 2 mg Z and 0.3 mg MZ; 10 mg L, 2 mg Z and 10 mg MZ; 3 mg L, 2 mg Z and 17 mg MZ | cHFP | Significant increase in all three groups (p < 0.05); Group 2 formulation (10 mg L, 2 mg Z and 10 mg MZ) may offer greater improvement to macular pigment spatial profile |
| Wolf-Schnurrbusch (2015) [231] | - | 79 patients with early/intermediate AMD; aged between 55–88 years in Switzerland | 6 months | 10 mg L and 1 mg Z * (multivitamin); 10 mg L, 1 mg Z and omega-3 fatty acids * (multivitamin); placebo | Fundus AFI | Demonstrable benefits in MPOD (p < 0.005) and CS scores (p < 0.01) observed in Group 1 only (carotenoid treatment without omega-3 fatty acids in formulation) |
| Akuffo (2017) [204] | CREST | 121 patients with early/intermediate AMD; aged (64.7 ± 9.0) years in Ireland | 24 months | 10 mg L, 2 mg Z and 10 mg MZ * (AREDS2 multivitamin); 10 mg L and 10 mg Z * (AREDS2 multivitamin) | cHFP | Augmentation of MPOD (p < 0.001) with clinically meaningful benefits in visual function (CS and GD under mesopic and photopic conditions, photostress recovery, and mean/max reading speed; p < 0.05 for all) |
| Azar (2017) [208] | - | 79 patients with neovascular AMD; aged (75.3 ± 7.6) years in France | 8 months | 5 mg L and 1 mg Z * (multivitamin); placebo |
Reflectometry | Non-significant trend toward greater MPOD levels reported in patients with neovascular AMD |
| Corvi (2017) [214] | - | 39 patients with early AMD; aged (78.0 ± 6.5) years in France | 3 months | 10 mg L and 2 mg Z * (multivitamin) | HFP | Significant rise in MPOD only in eyes with reticular pseudodrusen (n = 19; p = 0.002) after 3 months |
| Davey (2020) [53] | - | 56 patients with subclinical AMD; aged (68.4 ± 5.3) years in USA | 6 months | 15 mg L, 10 mg MZ and 2 mg Z * (Lumega-Z); 10 mg L and 2 mg Z * (AREDS-2 multivitamin); placebo | HFP | Statistically significant CS improvements for Lumega-Z group only (p < 0.001) with a positive linear trend with treatment time (p < 0.001) |
| Sawa (2020) [229] | Sakai Lutein Study | 39 patients with neovascular AMD; aged (70.7 ± 5.3) years in Japan | 6 months | 20 mg L and 3 mg Z (beeswax capsule); 20 mg L and 3 mg Z (glycerol capsule) | Fundus AFI | No significant changes were observed in CS, mesopic glare or MPOD in both treatment groups |
* Multivitamin treatment containing carotenoids in combination with other antioxidants; † Secondary analyses reported in AREDS2 Report No. 3 [203]; Abbreviations: MPOD, macular pigment optical density; L, lutein; Z, zeaxanthin; MZ, meso-zeaxanthin; AMD, age-related macular degeneration; LAST, Lutein Antioxidant Supplementation Trial; HFP, heterochromatic flicker photometry; ODU, optical density units; BCVA, best-corrected visual acuity; CS, contrast sensitivity; cpd, cycles per degree; TOZAL, Taurine, Omega-3 fatty acids, Zinc, Antioxidants and Lutein; LUNA, Lutein Nutrition effects measures by Autofluorescence; AFI, autofluorescence imaging; CARMIS, Carotenoids in Age-Related Maculopathy Italian Study; mfERG, multifocal electroretinogram; MOST, meso-zeaxanthin Ocular Supplementation Trial; cHFP, customized HFP; ZVF, Zeaxanthin and Visual Function; LISA, Lutein Intervention Study Austria; AREDS-2, Age-Related Eye Disease Study 2; CARMA, Carotenoids in Age-Related Maculopathy; LUTEGA, Lutein/zeaxanthin and omega-3 supplementation on optical density of AMD patients; CLEAR, Combination of Lutein Effects in the Aging Retina; CREST, Central Retinal Enrichment Supplementation Trials.