A Retrospective Observational Study

[Posted 22/Oct/2024]

AUDIENCE: Ophthalmology, Internal Medicine

KEY FINDINGS: The unaffected eyes of unilateral patients with NTG showed faster RNFL thinning than healthy control eyes, more obviously in the TI sector, and were likely to progress faster when they had a thicker baseline RNFL, and when the NTG eyes had a worse VF MD. In unilateral patients with NTG, initiation of prophylactic treatment could be considered for the unaffected eyes when they are accompanied by a risk of developing glaucoma.

BACKGROUND: Objective of the study is to observe the rate of progressive retinal nerve fiber layer (RNFL) thinning in the unaffected eyes of patients with unilateral normal-tension glaucoma (NTG), in comparison with that of healthy subjects, and to identify the factors associated with progressive RNFL thinning. 95 patients with unilateral NTG and 61 healthy controls were participated.

DETAILS: This study included unilateral NTG and healthy control subjects who were followed up for longer than 4 years and in whom at least 5 reliable retinal nerve fiber layer thickness (RNFLT) measurements were performed using OCT. Factors associated with the rate of thinning of the unaffected eyes of unilateral patients with NTG were identified using regression analysis. Retinal nerve fiber layer thickness decreased significantly in both the unaffected eyes of unilateral patients with NTG and the healthy eyes (both P 0.001). The RNFL thinning was significantly faster in the unaffected eyes of unilateral patients with NTG than in the healthy eyes (P 0.001), specifically in the temporal-inferior (TI) sector (P = 0.003). Factors associated with faster RNFL thinning in the unaffected eyes of unilateral patients with NTG were thicker baseline RNFL of the unaffected eyes (P = 0.002) and a worse visual field (VF) mean deviation (MD) in the NTG eyes (P = 0.040). In the healthy controls, the rate of RNFL thinning in the contralateral eyes was the only factor associated with faster thinning (P = 0.007).

Copyright © The American Academy of Ophthalmology. All rights reserved.

Source: Song, J. E., Lee, E. J., and Kim, T. W. (2024). Rapid Retinal Nerve Fiber Layer Thinning in the Unaffected Contralateral Eyes of Patients With Unilateral Normal-Tension Glaucoma: A Retrospective Observational Study. Ophthalmology Glaucoma. 2024; 7(5): 431-439. Published: September-October, 2024. DOI: S2589-4196(24)00073-5.

A Phase 1, Double-Blind Trial

[Posted 13/Aug/2024]

AUDIENCE: Infectious Disease, Nursing, Ob/Gyn

KEY FINDINGS: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 μg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials.

BACKGROUND: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. Authors did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens.

DETAILS: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 µg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 µg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 µg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 µg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete. Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26.8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 µg CTH522-CAF01 than 15 µg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5.6; p=0.062), with no difference after three injections of 85 µg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p0.001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522.

Copyright © Elsevier Ltd. All rights reserved.

Source: Pollock, K. M., Borges, A. H., Cheeseman, H. M., et al. (2024). An Investigation of Trachoma Vaccine Regimens by the Chlamydia Vaccine CTH522 Administered With Cationic Liposomes in Healthy Adults (CHLM-02): A Phase 1, Double-Blind Trial. The Lancet. 2024; 24(8): 829-844. Published: August, 2024. DOI: 10.1016/S1473-3099(24)00147-6.

[Posted 18/Jan/2024]

AUDIENCE: Endocrinology, Ophthalmology

KEY FINDINGS: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

BACKGROUND: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. Objective of the study was to present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED.

DETAILS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) <= 1 or no additional inflammation or progression in proptosis/diplopia for >=1 year, proptosis >=3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths.

Copyright © The Author(s). Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.

Source: Douglas, R. S., Couch, S., Wester, S. T., et al. (2024). Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity. The Journal of Clinical Endocrinology & Metabolism. 2024; 109(1): 25-35. Published: January, 2024. DOI: 10.1210/clinem/dgad637.

[Posted 12/Sep/2023]

AUDIENCE: Ophthalmology, Internal Medicine

KEY FINDINGS: Experience of introducing PreserFlo MicroShunt surgery showed it was safer than trabeculectomy and is a cost-saving and effective option that offers potential to free up highly limited National Health Service resources.

BACKGROUND: Objective of this study was to conduct clinical evaluation and cost analysis of mitomycin-C–augmented PreserFlo MicroShunt versus trabeculectomy. This retrospective cohort study was done across 3 teaching hospitals with total of 134 consecutive eyes of 129 patients (70 undergoing MicroShunt, 64 trabeculectomy).

DETAILS: Primary and secondary glaucoma cases with uncontrolled intraocular pressure (IOP) were included. Neovascular glaucoma and surgery combined with cataract extraction were excluded. The cost analysis used results from the clinical study to estimate operative costs (equipment and staff costs) and postoperative costs (follow-up visits, nonglaucoma medications, and postoperative procedures) per eye for PreserFlo and trabeculectomy. The primary clinical outcome measure was surgical failure (defined as IOP > 21 mmHg or < 20% reduction from baseline, IOP <= 5 mmHg, reoperation, or loss of light perception) or qualified and complete success (with or without medication) at 18 months. Secondary measures were IOP, glaucoma medications, visual acuity, mean deviation, time to cessation of steroid drops, complications, surgical time, follow-up visits, postoperative interventions, and reoperations. The cost analysis evaluated costs of PreserFlo compared with trabeculectomy. Baseline characteristics were similar, except for more non-White patients in the trabeculectomy group (51% Black and Asian vs. 32% MicroShunt, P = 0.02) and more cases with prior ab externo glaucoma surgery in the MicroShunt group (19% vs. 3% in the trabeculectomy group, P = 0.004). Overall, 59% of eyes had primary open-angle glaucoma. Mean follow-up was 19.9 months for both groups. At 18 months, surgical failure was 25% for MicroShunt compared with 35% for trabeculectomy (P = 0.18). Failure in MicroShunt cases was due to inadequate IOP reduction (84%) or reoperation for glaucoma (16%). Failure in trabeculectomy cases was due to inadequate IOP reduction (58%), persistent hypotony (29%), or reoperation for glaucoma (13%). Combined blebitis and endophthalmitis rate was 1.4% for MicroShunt and 3.1% for trabeculectomy. Cost analysis showed a savings of £245 to £566 per eye in the MicroShunt group, driven mostly by reduced postoperative procedures and follow-up visits. This is in contrast to prior randomized controlled trial data reporting the incremental cost of $2058 of PreserFlo over trabeculectomy.

Copyright © The American Academy of Ophthalmology. All rights reserved.

Source: Van Lancker, L., Saravanan, A., Abu-Bakra, M., et al. (2023). Clinical Outcomes and Cost Analysis of PreserFlo versus Trabeculectomy for Glaucoma Management in the United Kingdom. Ophthalmology Glaucoma. 2023; 6(4): 342-357. Published: September, 2023. DOI: 10.1016/j.ogla.2022.11.006.

A Novel Technique

[Posted 17/Jul/2023]

AUDIENCE: Ophthalmology, Internal Medicine

KEY FINDINGS: Sutureless CSM is a promising alternative to traditional MMCR and sutured CSM based on long-term outcomes, symmetry, shorter operative time, and low complication rate.

BACKGROUND: Müller muscle-conjunctival resection (MMCR) is a popular posterior/internal surgical approach to cases of mild to moderate blepharoptosis with good levator function. MMCR necessitates the removal of healthy conjunctiva and exposes the cornea to suture material. The goal of this study is to describe a novel sutureless conjunctiva-sparing Müllerectomy (CSM) surgery and demonstrate its long-term efficacy, efficiency, and safety.

DETAILS: IRB approved retrospective study of patients undergoing sutureless conjunctiva-sparing posterior ptosis repair surgery. The medical records of 100 patients (171 eyes) who underwent sutureless CSM with a minimum follow-up interval of 6 months were retrospectively reviewed. Photographs were analyzed using ImageJ software. Outcome measures were derived from margin reflex distance 1 (MRD1) and palpebral fissure height (PFH) at various postoperative timepoints. Mean ΔMRD1 and ΔPFH at 6 months were 2.85 ± 0.98 mm and 2.60 ± 1.38 mm, respectively. Symmetry within 1 mm was observed 91% of cases. Sutureless CSM took 4.42 minutes on average compared to 8.45 minutes for traditional MMCR. There were no corneal abrasions or ocular complications. The reoperation rate was 2.3% (1 case of overcorrection and 3 cases of undercorrection) per eye.

Copyright © Elsevier Inc. All rights reserved.

Source: Mancini, R., Forouzan, P., Keenum, Z. G., et al. (2023). Sutureless Conjunctiva-Sparing Posterior Ptosis Repair Surgery: A Novel Technique. American Journal of Ophthalmology. 2023; 251: 77-89. Published: July, 2023. DOI: 10.1016/j.ajo.2023.03.001.

[Posted 18/May/2023]

AUDIENCE: Ophthalmology, Internal Medicine

KEY FINDINGS: The deep learning models were able to accurately estimate both macula GCIPL and ONH RNFL hemiretinal thickness. Using an internal control based on these model predictions may help reduce clinical trial sample size requirements and facilitate investigation of new glaucoma neuroprotection therapies.

BACKGROUND: Aim of the study is to investigate the efficacy of a deep learning regression method to predict macula ganglion cell-inner plexiform layer (GCIPL) and optic nerve head (ONH) retinal nerve fiber layer (RNFL) thickness for use in glaucoma neuroprotection clinical trials. Glaucoma patients with good quality macula and ONH scans enrolled in 2 longitudinal studies, the African Descent and Glaucoma Evaluation Study and the Diagnostic Innovations in Glaucoma Study.

DETAILS: Spectralis macula posterior pole scans and ONH circle scans on 3327 pairs of GCIPL/RNFL scans from 1096 eyes (550 patients) were included. Participants were randomly distributed into a training and validation dataset (90%) and a test dataset (10%) by participant. Networks had access to GCIPL and RNFL data from one hemiretina of the probe eye and all data of the fellow eye. The models were then trained to predict the GCIPL or RNFL thickness of the remaining probe eye hemiretina. Mean absolute error (MAE) and squared Pearson correlation coefficient (r²) were used to evaluate model performance. The deep learning model was able to predict superior and inferior GCIPL thicknesses with a global r² value of 0.90 and 0.86, r² of mean of 0.90 and 0.86, and mean MAE of 3.72 μm and 4.2 μm, respectively. For superior and inferior RNFL thickness predictions, model performance was slightly lower, with a global r² of 0.75 and 0.84, r² of mean of 0.81 and 0.82, and MAE of 9.31 μm and 8.57 μm, respectively. There was only a modest decrease in model performance when predicting GCIPL and RNFL in more severe disease. Using individualized hemiretinal predictions to account for variability across patients, we estimate that a clinical trial can detect a difference equivalent to a 25% treatment effect over 24 months with an 11-fold reduction in the number of patients compared to a conventional trial.

Copyright © The American Academy of Ophthalmology. All rights reserved.

Source: Christopher, M., Hoseini, P., Walker, E., et al. (2023). A Deep Learning Approach to Improve Retinal Structural Predictions and Aid Glaucoma Neuroprotective Clinical Trial Design. Ophthalmology Glaucoma. 2023; 6(2): 147-159. Published: May, 2023. DOI: 10.1016/j.ogla.2022.08.014.