Dataset Information

Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

ABSTRACT: Objective/Purpose:To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA). Design:Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers. Subjects:Participants with GA. Methods:Participants eligible in one eye were randomly assigned to a monthly intravitreal injection of sirolimus (20 µL [440 µg]) or sham treatment while participants with two study eyes were assigned to a monthly intravitreal injection in a randomly-selected eye. Best-corrected visual acuities (BVCA), spectral domain optical coherence tomography (OCT), fundus color photography and fundus autofluorescence (FAF) images were obtained at baseline and every 6 months until visit month 24. Main Outcome Measures:Rate of progression of GA (mm2/year) measured on color fundus photograph from baseline to 24 months. Secondary outcome measures include change in BVCA, worsening of vision by ?3 lines, and changes in area of GA measured on FAF and OCT. Results:52 participants (mean age 79 years) were enrolled with 27 study eyes assigned to sirolimus from May 2012 to March 2014. The baseline median area of GA was 4.73 DA (12.01 mm2). The mean (standard deviation) growth rates of GA detected on color fundus photographs were 2.27 (2.17) mm2 and 1.91 (2.27) mm2 at month 12, and 4.94 (2.96) mm2 and 5.72 (3.97) mm2 at month 24, for the sirolimus and sham groups, respectively. There was no statistically significant difference in the GA growth rates between the two treatment groups (P=0.33). Median visual acuity changes and incidence of 15-letter loss from baseline were not different between the 2 treatment groups (p=0.19). The intervention was stopped early because of sterile endophthalmitis that occurred in 3 participants in the sirolimus group. Participants were followed for safety until the study was closed in May 2015 due to lack of efficacy. Conclusion:Sirolimus did not result in different rates of GA growth in this phase 2 study. Immunosuppression may be important for some stages of the AMD process but may not necessarily be the main pathway for the development of GA.

SUBMITTER: Gensler G

PROVIDER: S-EPMC5967618 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

Gensler Gary G Clemons Traci E TE Domalpally Amitha A Danis Ronald P RP Blodi Barbara B Wells Jack J Rauser Michael M Hoskins John J Hubbard G Baker GB Elman Michael J MJ Fish Gary E GE Brucker Alexander A Margherio Alan A Chew Emily Y EY

Ophthalmology. Retina 20180501 5

<h4>Objective/purpose</h4>To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA).<h4>Design</h4>Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers.<h4>Subjects</h4>Participants with GA.<h4>Methods</h4>Participants eligible in one eye were randomly assigned to a mon ...[more]

PMID: 29806044

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Project description:PurposeTo determine whether closer adherence to a Mediterranean diet was associated with altered speed of geographic atrophy (GA) enlargement.DesignPost hoc analysis of a cohort within the Age-Related Eye Disease Study 2.ParticipantsThe study included 1155 eyes (850 participants; mean age, 74.9 years) with GA at 2 or more visits.MethodsGeographic atrophy area was measured from color fundus photographs at annual visits. An alternative Mediterranean Diet index (aMedi) was calculated for each participant by food frequency questionnaire. Mixed-model regression of square root GA area was performed by aMedi.Main outcome measuresChange in square root of GA area over time.ResultsOver a mean follow-up of 3.1 years, the mean GA enlargement rate was 0.282 mm/year (95% confidence interval, 0.270-0.293). Enlargement was significantly slower in those with higher aMedi at 0.256 mm/year (0.236-0.276), 0.290 (0.268-0.311), and 0.298 (0.280-0.317; P = 0.008) for aMedi tertiles 3, 2, and 1, respectively. Of the 9 aMedi components considered separately, significant differences in enlargement rate were observed for 4 (whole fruit [P = 0.0004], red meat [P = 0.0002], alcohol [P = 0.006], and monounsaturated fatty acid to saturated fatty acid ratio ([MUFA:SFA] [P = 0.040]) but not for fish (P = 0.14). Enlargement was slower in those with higher whole fruit, lower red meat, moderate alcohol, and higher MUFA:SFA intake. In the 768 eyes with noncentral GA, aMedi was not associated with slower progression to central involvement: hazard ratios were 1.11 (0.83-1.48) and 0.95 (0.71-1.26) for tertiles 2 and 3, respectively.ConclusionsA Mediterranean-type diet was associated with slower GA enlargement. Diet patterns like this may therefore lead to clinically meaningful delays in vision loss. Several components seemed to contribute most to this association in a pattern that differed from those most associated with decreased progression to GA. Hence, the Mediterranean diet is associated with protection against both faster progression to GA and faster enlargement of GA but for partially distinct reasons. These findings may help inform evidence-based dietary recommendations. Understanding the mechanisms responsible may provide insights into the underlying biology and lead to the development of nutritional supplements.

Project description:Purpose:To identify the development and progression of macular retinal pigment epithelial atrophy in eyes with neovascular (CNV) age-related macular degeneration (AMD) and to correlate with visual acuity (VA). Design:Cohort study. Participants:Age-Related Eye Disease Study 2 (AREDS2) participants with intermediate AMD enrolled in a randomized controlled clinical trial of oral supplements. Analyses were conducted in the subset of AREDS2 participants who were also enrolled in the fundus autofluorescence ancillary (FAF) ancillary study. Methods:Color photographs and FAF images were evaluated in eyes that developed CNV. Presence of geographic atrophy (GA) prior to the incidence of CNV and the development of macular atrophy following incident CNV were assessed. Areas of hypoautofluorescence representing atrophy were measured for area and macular involvement. Enlargement rate of atrophy and change in visual acuity over time were analyzed. Main Outcome Measures:incidence and enlargement rate of atrophy and VA changes in eyes with incident CNV. Results:Incident CNV developed in 334 (9.2%) of eyes evaluated in the AREDS2 FAF substudy. Of these, 40% had macular atrophy at incidence of CNV with half of these attributable to pre-existing GA. Atrophy developed in 14.7 % of eyes over 4 years of follow-up. Mean area of atrophy was largest in eyes with pre-existing GA and CNV (5.17 mm2, p<0.001), and atrophy involved the center of the macula in > 65% of eyes. Mean VA letter score at the annual visit in which CNV was documented was similar in the three groups with atrophy; eyes with CNV and pre-existing GA, incident atrophy at the first visit with CNV, and atrophy during follow up (60 letters). Enlargement rate of atrophy was also similar in eyes in the three groups (1.23 - 1.86 mm2, p = 0.47). Eyes with macular atrophy lost more visual acuity compared to eyes without atrophy, particularly after 2 years of follow-up (-10.9 vs. - 3.6 letters, p = 0.07). Conclusion:Atrophy is commonly seen in neovascular AMD and often can be attributed to pre-existing GA. Macular atrophy and GA appear to be a continuum of the same disease process and are both associated with poor vision.

Project description:BackgroundTo determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment.MethodsThis institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness.Results20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 μm compared to 0.1 μm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension.ConclusionThere was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits.Trial registrationClinicalTrials.gov, NCT02732899. Registered 11 March 2016, https://clinicaltrials.gov/ct2/show/NCT02732899 . This trial was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

Dataset Information

Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

Publications

Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study.

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