Citations

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy. The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Introduction This manuscript describes data from an original study, simulating a tele-glaucoma programme in an established clinic practice with an interdisciplinary team. This is a ‘real life’ trial of a telemedicine approach to see a follow-up patient. The goal is to evaluate the accuracy of such a programme to detect worsening and/or unstable disease. Such a programme is attractive since in-clinic time could be reduced for both the patient and provider. This study evaluates agreement between in-person and remote assessment of glaucoma progression. Methods A total of 200 adult glaucoma patients were enrolled at a single institution. The in-person assessment by an optometrist or glaucoma specialist at time of enrolment was used as the gold standard for defining progression. Collated clinical data were then reviewed by four masked providers who classified glaucoma as progression or non-progression in each eye by comparing data from enrolment visit to data from the visit immediately prior to enrolment. Agreement of glaucoma progression between the masked observer and the in-person assessment was determined using Kappa statistics. Intra-observer agreement was calculated using Kappa to compare in-person to remote assessment when both assessments were performed by the same provider ( n = 279 eyes). Results A total of 399 eyes in 200 subjects were analysed. Agreement between in-person versus remote assessment for the determination of glaucoma progression was 63%, 62%, 69% and 68% for each reader 1–4 (kappa values = 0.19, 0.20, 0.35 and 0.33, respectively). For intra-observer agreement, reader 1 agreed with their own in-person assessment for 65% of visits (kappa = 0.18). Discussion Intra-observer agreement was similar to the agreement for each provider who did not see the patient in person. This similarity suggests that telemedicine may be equally effective at identifying glaucomatous disease progression, regardless of whether the same provider performed both in-clinic and remote assessments. However, fair agreement levels highlight a limitation of using only telemedicine data to determine progression compared with clinical detail available during in-patient assessment.

Purpose: Glaucoma specialists and optometrists who work in a team model at a single institution utilize a common definition of glaucoma progression and treatment algorithm. The purpose of this study was to assess the consistency of agreement in identifying glaucoma progression among glaucoma specialists and optometrists of 1 team. Methods: In total, 399 eyes of 200 patients age 18 or older with glaucoma were enrolled over 2 years. Clinical data, disc photographs, optical coherence tomography (OCT), and visual fields were independently reviewed by 2 masked optometrists and 2 masked fellowship-trained glaucoma specialists. Each eye was judged as progression or no progression of glaucomatous disease. The following were assessed: (1) agreement among optometrists; (2) agreement among glaucoma specialists; and (3) agreement among optometrists and glaucoma specialists. The frequency of use of testing modality to determine progression was also studied. κ statistics were used to evaluate agreements. Results: Optometrists agreed with each other for 74.2% of the eyes assessed (κ=0.42), whereas glaucoma specialists agreed with each other for 78.7% of eyes (κ=0.39). All 4 providers agreed with each other for 54.4% of the eyes evaluated (κ=0.37). Providers had the highest agreement when the progression decision was based on disc hemorrhage (92%) and the lowest agreement when based on OCT progression analysis (36%). Compared with optometrists, glaucoma specialists used OCT (P≤0.01) more frequently to determine disease progression. Conclusions: Fair to moderate agreement levels were found among providers in their assessment of glaucoma progression, suggesting that a team approach to glaucoma management may be effective. Further work is needed to investigate ways to optimize consistency within the glaucoma team.

An autoantibody target on brain microvascular endothelial cells in patients with neuromyelitis optica may be exploited to manipulate blood-brain barrier permeability.

Background: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. Objective: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity. Methods: We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. Results: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. Conclusion: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.