Background incidence rates of adverse events of special interest related to COVID-19 vaccines in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance

Background: Background incidence rates are critical in pharmacovigilance to facilitate identification of vaccine safety signals. We estimated background incidence rates of nine adverse events of special interest related to COVID-19 vaccines in Ontario, Canada. Methods: We conducted a population-based retrospective observational study using linked health administrative databases for hospitalizations and emergency department visits among Ontario residents. We estimated incidence rates of Bells palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barre syndrome, and transverse myelitis during five pre-pandemic years (2015-2019) and 2020. Results: The average annual population was 14 million across all age groups with 51% female. The pre-pandemic mean annual rates per 100,000 population during 2015-2019 were 43.9 for idiopathic thrombocytopenia, 27.8 for Bells palsy, 25.0 for febrile convulsions, 22.8 for acute disseminated encephalomyelitis, 11.3 for myocarditis/pericarditis, 8.6 for pericarditis, 2.9 for myocarditis, 1.9 for Guillain-Barre syndrome, 1.7 for transverse myelitis, and 1.6 for Kawasaki disease. Females had higher rates of acute disseminated encephalomyelitis and transverse myelitis while males had higher rates of myocarditis, pericarditis, and Guillain-Barre syndrome. Bells palsy, acute disseminated encephalomyelitis, and Guillain-Barre syndrome increased with age. The mean rates of myocarditis and/or pericarditis increased with age up to 79 years; males had higher rates than females: from 12-59 years for myocarditis and 12 years and older for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age. Conclusions: Our estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.

COVID MED - An Early Pandemic Trial of Losartan for Hospitalized COVID-19 Patients

Background ACEi/ARB medications have been hypothesized to have potential benefit in COVID-19. Despite concern for increased ACE-2 expression in some animal models, preclinical and observational-retrospective and uncontrolled trials suggested possible benefit. Two RCTs of the ARB losartan from University of Minnesota showed no benefit yet safety signals for losartan in outpatient and hospitalized COVID-19 patients. COVID MED, started early in the pandemic, also assessed losartan in a RCT in hospitalized patients with COVID-19. Methods COVID MED was quadruple-blinded, placebo-controlled, multicenter randomized clinical trial (RCT). Hospitalized COVID-19 patients were randomized to receive standard care and hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued after RCTs showed no benefit. We report data from the losartan arm compared to combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the NCOSS slope of change. Slow enrollment prompted early stopping. Results Of 432 screened patients, 14 were enrolled (3.5%), 9 received losartan and 5 combined control (lopinavir/ritonavir [N=2], placebo [N=3]); 1 hydroxychloroquine arm patient was excluded. Most baseline parameters were balanced. Treatment with losartan was not associated with a difference in NCOSS slope of change in comparison with combined control (p=0.4) or placebo-only control (p=0.05) (trend favoring placebo). 60-day mortality and overall AE and SAE rates were numerically but not significantly higher with losartan. Conclusions In this small blinded RCT in hospitalized COVID-19 patients, losartan did not improve outcome vs. control comparisons and was associated with adverse safety signals.

Safety learning in anxiety, Pavlovian conditioned inhibition and Covid concerns

Experimental studies of fear conditioning have identified the effectiveness of safety signals in inhibiting fear and maintaining fear-motivated behaviours. In fear conditioning procedures, the presence of safety signals means that the otherwise expected feared outcome will not now occur. Differences in the inhibitory learning processes needed to learn safety are being identified in various psychological and psychiatric conditions. However, despite early theoretical interest, the role of conditioned inhibitors as safety signals in anxiety has been under-investigated to date, in part because of the stringent test procedures required to confirm the demonstration of conditioned inhibition as such. Nonetheless, the theoretical implications of an inhibitory learning perspective continue to influence clinical practice. Moreover, our understanding of safety signals is of additional importance in the context of the increased health anxiety and safety behaviours generated by the Covid-19 pandemic.

A review of COVID-19 therapeutics in pregnancy and lactation

Pregnant people have an elevated risk of severe COVID-19-related complications compared to their non-pregnant counterparts, underscoring the need for safe and effective therapies. In this review, we summarize published data on COVID-19 therapeutics in pregnancy and lactation to help inform clinical decision-making about their use in this population. Although no serious safety signals have been raised for many agents, data clearly have serious limitations and there are many important knowledge gaps about the safety and efficacy of key therapeutics used for COVID-19. Moving forward, diligent follow-up and documentation of outcomes in pregnant people treated with these agents will be essential to advance our understanding. Greater regulatory push and incentives are needed to ensure studies to obtain pregnancy data are expedited.

Bias, Precision and Timeliness of Historical (Background) Rate Comparison Methods for Vaccine Safety Monitoring: An Empirical Multi-Database Analysis

Using real-world data and past vaccination data, we conducted a large-scale experiment to quantify bias, precision and timeliness of different study designs to estimate historical background (expected) compared to post-vaccination (observed) rates of safety events for several vaccines. We used negative (not causally related) and positive control outcomes. The latter were synthetically generated true safety signals with incident rate ratios ranging from 1.5 to 4. Observed vs. expected analysis using within-database historical background rates is a sensitive but unspecific method for the identification of potential vaccine safety signals. Despite good discrimination, most analyses showed a tendency to overestimate risks, with 20%-100% type 1 error, but low (0% to 20%) type 2 error in the large databases included in our study. Efforts to improve the comparability of background and post-vaccine rates, including age-sex adjustment and anchoring background rates around a visit, reduced type 1 error and improved precision but residual systematic error persisted. Additionally, empirical calibration dramatically reduced type 1 to nominal but came at the cost of increasing type 2 error.

Cortico-striatal activity characterizes human safety learning via Pavlovian conditioned inhibition

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviours. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (UHF) fMRI to examine the neural basis of inhibitory safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat-omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat-omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation. The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular and dorsolateral prefrontal cortex compared to the standard safety signal, whereas the latter evoked greater activation of the ventromedial prefrontal cortex, posterior cingulate and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of stimulus-safety associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.

P.038 Impact of Disease Severity on Presentation Subtype and OnabotulinumtoxinA Utilization in Patients with Cervical Dystonia in the CD PROBE Completer Population

Background: The impact of cervical dystonia (CD) severity on presentation subtype and onabotulinumtoxinA utilization was examined in the completer population from CD PROBE (CD Patient Registry for Observation of BOTOX® Efficacy). Methods: In this multicenter, prospective, observational registry, patients with CD were treated with onabotulinumtoxinA according to injectors’ standard of care. Completers were patients that completed all 3 treatment sessions and had accompanying data. Results: Of N=1046 patients enrolled, n=350 were completers. Completers were on average 57.3 years old, 74.9% female, 94.6% white, and 60.6% toxin-naïve. Baseline severity was mild in 32.6%, moderate in 54.3%, and severe in 13.1%. Torticollis was the most common presentation at baseline (mild: 44.7%, moderate: 55.8%, severe: 63.0%), followed by laterocollis (mild: 42.1%, moderate: 32.6%, severe: 26.1%). Median onabotulinumtoxinA dose increased over time; 160U–200U for torticollis and 170U–200U for laterocollis. For all severities, median total dose increased from injection 1 to injection 3 (mild: 138U–165U, moderate: 183U–200U, severe: 200U–285U). Eighty-one patients (23.1%) reported 139 treatment-related adverse events. There were no treatment-related serious adverse eventsand no new safety signals. Conclusions: CD severity impacted presentation subtype frequency and onabotulinumtoxinA utilization in CD PROBE, with higher and tailored dosing observed over time and with increasing disease severity.

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database

As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged<75 years and ≥75 years. A signal of disproportionate reporting (SDR) was defined if both IC and PRR were significant. A total of 16,196 ICSRs were included. The median age of patients was 72.9 years, 42.6% of ICSRs concerned patients aged ≥75 years, and 64.2% male patients. More than half (56.2%) of ICSRs resulted in hospitalization or prolonged hospitalization. Among 713 SDRs, 36 potential safety signals emerged in ibrutinib-treated patients, mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders and fractures. All potential safety signals having arisen in this analysis may support patient care and monitoring of ongoing clinical trials. However, owing to the mandatory limitations of this study, our results need further confirmation using population-based studies.