Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial.

PURPOSE: Injection of pharmacotherapy into the suprachoroidal space, between the sclera and choroid, is an alternative delivery technique developed with the rationale of providing higher drug concentrations to posterior ocular structures compared with other intraocular and periocular injection procedures. This study was conducted to evaluate the safety and efficacy of suprachoroidally injected triamcinolone acetonide formulation (CLS-TA), a suspension of triamcinolone acetonide, in improving vision among patients with noninfectious uveitis complicated by macular edema (ME). DESIGN: Phase 3 masked, randomized trial. PARTICIPANTS: One hundred sixty patients with ME secondary to noninfectious uveitis. Patients were required to have a best-corrected visual acuity (BCVA) of 5 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters (Snellen equivalent, 20/800) and 70 or fewer ETDRS letters read (Snellen equivalent, 20/40) in the study eye. METHODS: Patients were randomized 3:2 to suprachoroidally injected CLS-TA or sham treatment, with administrations at day 0 and week 12. MAIN OUTCOME MEASURES: The primary end point was improvement from baseline of 15 or more ETDRS letters in BCVA at week 24. The secondary end point was reduction from baseline in central subfield thickness (CST) at week 24. RESULTS: In the CLS-TA arm, 47% of patients gained 15 or more ETDRS letters in BCVA versus 16% in the control arm (P < 0.001), meeting the primary end point. Mean reductions in CST from baseline were 153 µm versus 18 µm (P < 0.001). No serious adverse events (AEs) related to treatment were reported. Corticosteroid-associated AEs of elevated intraocular pressure occurred in 11.5% and 15.6% of the CLS-TA and control groups, respectively. Cataract AE rates were comparable (7.3% and 6.3%, respectively). CONCLUSIONS: Patients in the CLS-TA study arm experienced clinically significant improvement in vision relative to the sham procedure, demonstrating the efficacy of suprachoroidal injection of CLS-TA for the treatment of ME in a vision-threatening disorder.

Suprachoroidal Corticosteroid Administration: A Novel Route for Local Treatment of Noninfectious Uveitis.

PURPOSE: To evaluate the safety, tolerability, and preliminary efficacy of suprachoroidal injection of triamcinolone acetonide (TA) in patients with noninfectious uveitis. METHODS: In this Phase 1/2 open-label clinical study, a single suprachoroidal injection of 4-mg TA in 100 µL was performed in the study eye of patients with noninfectious intermediate, posterior, or pan-uveitis, and follow-up obtained for 26 weeks. RESULTS: Nine individuals with chronic uveitis were enrolled. There were 38 reported adverse events (AEs); most were mild or moderate in severity. Approximately half the AEs were ocular. The most common AE was reported by four subjects who experienced ocular pain at or near the time of the injection. All systemic AEs were unrelated to study drug. No steroid-related increases in intraocular pressure (IOP) were observed and no subject required IOP-lowering medication. All eight efficacy-evaluable subjects had improvements in visual acuity. Four subjects, who did not need additional therapy, had on average a greater than 2-line improvement in visual acuity through week 26. Three of four had macular edema at baseline, and two of three had at least a 20% reduction in macular edema at week 26. CONCLUSIONS: The safety and preliminary efficacy data support further investigations of suprachoroidally administered TA as a therapeutic option for the treatment of noninfectious uveitis. TRANSLATIONAL RELEVANCE: Targeted suprachoroidal administration of corticosteroid is a potential local route for the treatment of ocular inflammatory disease, which merits further investigation. (www.ClinicalTrials.gov, NCT01789320).

Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses.

BACKGROUND: When the decision was made to prepare for a deliberate release of smallpox, the United States had approximately 15 million doses of Wyeth Dryvax vaccine, which was known to induce significant morbidity when used undiluted; Sanofi Pasteur, Inc., later identified approximately 85 million additional doses in storage. METHODS: Eleven vaccine-dose groups, each with 30 vaccinia-naive subjects, were given diluted Dryvax vaccine or 1 of 2 lots of Sanofi Pasteur smallpox vaccine and were evaluated for vaccination success rates, morbidity, and immune responses. RESULTS: Estimated doses of 10(6.6)-10(8.2) pfu of virus/mL induced major reactions (or "takes") in 93%-100% of subjects in each dose group. No differences in vaccination take rates, lesion size, erythema, and induration or in serum neutralizing-antibody response were detected between the groups. However, systemic reactogenicity and missed activities were significantly lower for the vaccine groups given doses of 10(6.6)-10(7.2) pfu/mL than for those given doses of 10(7.6)-10(8.2) pfu/mL. CONCLUSIONS: These findings support the use of a higher dilution of Wyeth Dryvax vaccine and Sanofi Pasteur smallpox vaccine, given that the resulting morbidity should be significantly lower without loss of vaccine effectiveness. A plan for use of higher dilutions would create an enormous stockpile of vaccine.