Search

Purpose To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (TE intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 μm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome. Main Outcome Measures Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24. Results Of the 349 participants randomized (intensive arm, n = 174; relaxed arm, n = 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P = 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P = 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P = 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P = 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P = 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P = 0.005). Conclusions Patients treated with a ranibizumab T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

Background Patients with severe, uncontrolled asthma, particularly those with a non-eosinophilic phenotype, have a great unmet need for new treatments that act on a broad range of inflammatory pathways in the airway. Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, an epithelial cytokine. In the PATHWAY phase 2b study (NCT02054130), tezepelumab reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline eosinophilic inflammatory status. This article reports the design and objectives of the phase 2 CASCADE study. Methods CASCADE is an ongoing exploratory, phase 2, randomized, double-blind, placebo-controlled, parallel-group study aiming to assess the anti-inflammatory effects of tezepelumab 210 mg administered subcutaneously every 4 weeks for 28 weeks in adults aged 18–75 years with uncontrolled, moderate-to-severe asthma. The primary endpoint is the change from baseline to week 28 in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies. Epithelial molecular phenotyping, comprising the three-gene-mean technique, will be used to assess participants’ type 2 (T2) status to enable evaluation of the anti-inflammatory effect of tezepelumab across the continuum of T2 activation. Other exploratory analyses include assessments of the impact of tezepelumab on airway remodelling, including reticular basement membrane thickening and airway epithelial integrity. At the onset of the COVID-19 pandemic, the protocol was amended to address the possibility that site visits would be limited. The amendment allowed for: at-home dosing of study drug by a healthcare professional, extension of the treatment period by up to 6 months so patients are able to attend an onsite visit to undergo the end-of-treatment bronchoscopy, and replacement of final follow-up visits with a virtual or telephone visit. Discussion CASCADE aims to determine the mechanisms by which tezepelumab improves clinical asthma outcomes by evaluating the effect of tezepelumab on airway inflammatory cells and remodelling in patients with moderate-to-severe, uncontrolled asthma. An important aspect of this study is the evaluation of the anti-inflammatory effect of tezepelumab across patients with differing levels of eosinophilic and T2 inflammation. Trial registration NCT03688074 (ClinicalTrials.gov). Registered 28 September 2018.

Background Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. Methods DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. Discussion DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. Trial registration NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Purpose To present the visual and safety outcomes of surgery for primary idiopathic macular holes including predictors of visual acuity and the impact of combined phacovitrectomy surgery. Design Registry-style, prospective, nonrandomized, observational cohort study. Participants Patients with idiopathic macular holes undergoing primary surgery. Methods Surgeons were invited to submit clinical details of all macular hole cases receiving surgery. Baseline demographic and clinical information, and details of surgical intervention were collected. Primary follow-up data were collected at 3 months postoperatively or before revision surgery, and surgeons were also asked to submit data at 12 and 24 months postoperatively. Main Outcome Measures Visual acuity improvement ≥15 letters and ≥0 letters, change in mean visual acuity, visual acuity ≥70 letters (20/40), retinal detachment, and endophthalmitis. Results A total of 2455 eyes of 2366 patients were included in the study, and hole closure was achieved in 95.6% of eyes with a single procedure. Mean baseline vision was 48.3 letters. The proportion of successful eyes improving ≥15 letters at 3, 12, and 24 months was 59.1%, 69.4%, and 68.2%, respectively. The mean improvement in acuity at 3, 12, and 24 months was 16.0, 19.2, and 23.6 letters, and 92.4%, 93.4%, and 95.8% improved ≥0 letters at 3, 12, and 24 months, respectively. Eyes receiving SF6 gas had better visual acuities at all time points postoperatively (adjusted effect 3.4, 3.1, and 4.6 letters better at 3, 12, and 24 months vs. longer-acting gas, respectively). Combined phacovitrectomy in phakic eyes was associated with better corrected visual acuity postoperatively (vs. vitrectomy surgery alone), a difference that vanished when eyes went on to have subsequent cataract surgery. The rate of retinal detachment postoperatively was 1.3%, and the odds of detachment were greater in eyes receiving longer-acting gases versus SF6 gas (adjusted odds ratio, 2.2; 95% confidence interval, 1.04–4.77; P = 0.039). There were no reported cases of endophthalmitis. Conclusions Macular hole surgery substantially improved acuity in approximately two thirds of patients and was seldom associated with loss of vision. SF6 gas was associated with better visual outcomes, an effect that warrants further study.

Purpose: To evaluate the efficacy and safety of early pars plana vitrectomy (PPV) for the treatment of acute infective endophthalmitis, and identify prognostic factors for better visual outcome. Design: Retrospective cohort study. Methods: Consecutive patients who underwent early PPV within 72 hours of presentation for the treatment of acute infective bacterial endophthalmitis and presented to a large tertiary referral center in New South Wales, Australia, between January 2009 and December 2013 were included. Changes in best-corrected visual acuity (VA) from baseline to 1 year were examined. Results: A total of 64 patients were included. The inciting events were cataract surgery (53%), intravitreal injection (36%), trabeculectomy (3%), and endogenous (3%). The mean VA improved from 3.1 logMAR (hand motion) at baseline to 1.02 (approximately 20/200) at 1 year, with 42% achieving final VA equal to or better than 0.477 logMAR (20/60) following early PPV. Positive prognostic factors were negative microbial cultures (P < 0.01) and etiology of post-cataract surgery (P < 0.01). In multivariable analyses adjusting for age and prognostic factors, patients with baseline VA of light perception and hand motion achieved greater visual gains than those with counting fingers, with gains of logMAR of -2.68, -2.09, and -0.85, respectively (P < 0.0001). Conclusions: Most patients who undergo early PPV experience substantial VA improvement. Negative microbial cultures and endophthalmitis after cataract surgery were associated with better final visual outcome. Patients with presenting VA of light perception or hand motion achieved higher visual gains than those with counting fingers, suggesting the possibility that early PPV may be beneficial in both groups.

Purpose Tezepelumab is an anti–thymic stromal lymphopoietin monoclonal antibody therapeutic in development for patients with severe, uncontrolled asthma. In ongoing Phase III studies, tezepelumab is administered via subcutaneous (SC) injections using a vial-and-syringe (V–S). This study compared the pharmacokinetic (PK) parameters, safety, and tolerability of tezepelumab administered subcutaneously via V–S versus via an accessorized prefilled syringe (APFS) or autoinjector (AI). Methods This single-center, randomized, open-label, parallel-group study was conducted in healthy volunteers aged 18–65 years. Participants, stratified according to weight (50 to Findings A total of 315 adults were randomized to treatment. Geometric mean ratios for comparisons between device groups of Cmax, AUC0–∞, and AUC0–last were close to 1, with 90% CIs all within the range of 0.8–1.25, meeting bioequivalence criteria. PK variables were also similar between devices across injection sites and weight categories. Across devices, thigh injection resulted in slightly higher exposure than upper arm injection, and abdomen injection resulted in exposure similar to or slightly lower than thigh injection; however, these differences were not clinically meaningful. Treatment-emergent anti-tezepelumab antibodies were present in 3 (2.9%), 1 (1.0%), and 0 participants in the V–S, APFS, and AI groups, respectively. Treatment-related adverse events were reported in 15.0% of participants overall (V–S, 10.7%; APFS, 18.1%; AI, 16.0%), including ISRs in 1 (1.0%), 3 (2.9%), and 3 (2.8%) participants in the V–S, APFS, and AI groups. Median visual analog scale pain score (0–100 mm scale) was 2 mm immediately after injection and was 0 mm at 30 min for all groups. Implications Tezepelumab PK parameters after a single 210-mg SC dose were comparable when administered via V–S, APFS, or AI. In all groups, immunogenicity rate and injection site pain were low, and ISRs were uncommon. These findings support administration of tezepelumab via APFS or AI, in addition to V–S, providing patients and physicians with greater choice and the potential convenience of at-home use. ClinicalTrials.gov identifier: NCT03989544.

Background Endogenous Klebsiella pneumoniae endophthalmitis (EKPE) is a well-known entity in South-East Asia. We demonstrate a range of differing clinical features and outcomes of EKPE, and highlight the increasing incidence of EKPE in major centres in Sydney and Melbourne, Australia. Design Retrospective observational case study and case series in the hospital setting. Participants Four cases of EKPE. Methods EKPE cases from 2005 to 2015 were identified through established endophthalmitis databases as well as hospital-based microbiological searches. Main Outcome Measures EKPE cases were confirmed with positive K. pneumoniae intraocular samples. Results Rising trends of EKPE were noted in major centres in Australia. Six eyes of four patients with EKPE from January 2011 to December 2015 are reported. The mean age was 49 years (range 43–58 years). Two patients had bilateral involvement. There were systemic symptoms up to 10 days prior to ocular symptoms. The source of sepsis in all cases was a hepatic abscess. Two patients had diabetes mellitus. Five eyes had hypopyon panuveitis on presentation. All eyes underwent vitrectomy. The patient with the most delayed presentation underwent enucleation following globe perforation. Final best corrected visual acuity (BCVA) in one patient with bilateral EKPE was light perception (LP) only. The other three eyes had BCVA in at least one eye of 6/24 or better. Conclusions EKPE is an emerging condition in Australia. Although rare, EKPE is a sight-threatening and potentially life-threatening emergency that can initially present to ophthalmologists. One should suspect EKPE in septic patients with a B-scan showing a vitreous or retinal abscess.

Purpose To describe the anatomic and visual outcomes of eyes undergoing reoperation after failed primary surgery for idiopathic macular hole. Design Prospective registry study. Participants One hundred three patients who had undergone failed macular hole surgery. Methods Unclosed idiopathic macular holes were identified from a large national prospective registry run by the Australian and New Zealand Society of Retinal Specialists. Unclosed idiopathic macular holes were defined as idiopathic macular holes that underwent vitrectomy surgery for the first time, but were never observed to close in the postoperative period. Surgeons were contacted to submit retrospectively details of subsequent management and long-term outcome of these eyes. Main Outcome Measures Macular hole closure; visual acuity (VA) change relative to baseline at 3, 12, and 24 months; and hole size at all time points. Results One hundred three patients with failed macular hole surgery were identified, among whom 53 underwent reoperation, 49 did not, and 1 was lost to follow-up. Macular hole closure was achieved in 45 of 53 patients (85%) undergoing revision surgery. Mean change in VA from baseline in eyes undergoing revision surgery versus eyes that did not was +2.8 letters versus −1.9 letters at 3 months ( P = 0.278), +8.2 letters versus −1.9 letters at 12 months ( P = 0.167), and +18.3 letters versus −3.4 letters at 24 months ( P = 0.022). Thirty-six percent of eyes with reoperated holes showed improved VA of 15 letters or more at 3 months after operation, increasing to 48% at 12 months and 65% at 2 years. Before revision surgery, mean macular hole size was observed to increase from 483 μm to 562 μm after failed primary surgery ( P = 0.046). Conclusions In eyes undergoing revision surgery, reoperation for unclosed macular holes was significantly better than observation, although these visual gains took some time to occur. The surgical success rate was lower than that for primary idiopathic macular hole. The selection criteria for revision surgery need to be defined.