BackgroundWe present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD).MethodsAll patients (n = 32), (ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint.FindingsOcular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: − 3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of − 5.0 (IQR: − 17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group.Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD.FundingNational Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.
To assess the relationship between human papillomavirus (HPV) vaccination and occurrence of optic neuritis (ON) and to evaluate a claims-based algorithm for identification of ON. Females of 9-26 year olds in the HealthCore's Integrated Research Database (HIRD SM ) with and without claims evidence of HPV vaccination between 2007 and 2012 were included in this study. Potential ON cases were identified using the claims-based algorithm, positive predictive value (PPV) was determined using medical chart review. For the claims analysis, two study designs, a self-controlled temporal scan statistic and a retrospective matched cohort analysis, were used. ON was defined based on an algorithm developed using diagnosis and procedure codes from the medical claims. The PPV for ON cases using charts that had enough information for reviewers to make a determination was 62.5% (95% CI: 49.5%-74.3%). With the selfcontrolled temporal scan statistic, the primary analysis restricting on recommended vaccination schedule timing showed an increased risk of potential ON after second dose (RR D 3.39; p D 0.03), this finding was not confirmed for any of the additional analyses performed for individual or combined doses. With the cohort design, there was no increased risk of potential ON following vaccination in either individual or combined dose analyses. The risk of potential ON was higher among participants with a history of prior autoimmune diseases. In conclusion, identifying confirmed ON cases through administrative claims data proved challenging. The claims-based analysis in this study did not provide evidence for an association of ON with HPV vaccination.
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