Dataset Information

Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

ABSTRACT: To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA).The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline.Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye.While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.).

SUBMITTER: Petrou PA

PROVIDER: S-EPMC4294293 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

Petrou Philip A PA Cunningham Denise D Shimel Katherine K Harrington Molly M Hammel Keri K Cukras Catherine A CA Ferris Frederick L FL Chew Emily Y EY Wong Wai T WT

Investigative ophthalmology & visual science 20141218 1

<h4>Purpose</h4>To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA).<h4>Methods</h4>The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes incl ...[more]

PMID: 25525171

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Project description:Objective/purposeTo 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).DesignRandomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers.SubjectsParticipants with GA.MethodsParticipants 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 measuresRate 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.Results52 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.ConclusionSirolimus 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.

Project description:ObjectiveTo provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).DesignRandomized phase II clinical trial.ParticipantsOne hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320.InterventionsRandom assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22).Main outcome measuresCentral subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks.ResultsAt baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3).ConclusionThese results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.

Project description:ObjectiveTo validate GATHER-1 inclusion criteria and the study's primary anatomic end point by assessing the reproducibility of geographic atrophy (GA) measurements and factors that affect reproducibility.DesignPost hoc analysis of phase II/III clinical trial.SubjectsAll 286 participants included in the GATHER-1 study.MethodsFor each subject, blue-light fundus autofluorescence (FAF), color fundus photographs, fluorescein angiograms, and OCT scans were obtained on the study eye and fellow eye. Geographic atrophy area and other lesion characteristics were independently graded by 2 experienced primary readers. If the 2 readers differed on gradeability, GA area (> 10%) or other lesion characteristics, the image was graded by an arbitrator whose measurement or characterization was the final grade.Main outcome measuresThe main outcome measures were gradeability and reproducibility of FAF imaging data. Imaging data included lesion area, confluence of GA with peripapillary atrophy (PPA), whether GA involved the foveal centerpoint, and type of hyperautofluorescence pattern.ResultsA total of 2004 images (1002 visits, 286 participants) were analyzed. Gradeability (90.5%) and interreader gradeability concordance (90.2%) were high across all visits. Study eye images were more gradable compared with fellow-eye images. A greater proportion of smaller lesions required arbitration, but interreader reproducibility was consistently high for all images. There was no difference in gradeability, gradeability concordance, or lesion-area concordance for images with PPA-confluent GA compared with those with nonconfluent PPA. Foveal centerpoint-involving lesions had lower gradeability and lesion-area concordance. Images with diffuse patterns of hyperautofluorescence had better gradeability and gradeability concordance than those with nondiffuse patterns but had no difference in lesion-area or lesion-area concordance.ConclusionsThere is high gradeability and excellent reproducibility measures across all images. These data support the validity of conclusions from GATHER-1 and the chosen inclusion criteria and end point.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dataset Information

Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

Publications

Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

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