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Background: Hereditary angioedema (HAE) is a rare genetic disease causing unpredictable and potentially life-threatening subcutaneous and submucosal edematous attacks. Cinryze® (Shire ViroPharma Inc., Lexington, MA, USA), a nanofiltered C1 inhibitor (C1-INH), is approved in Europe for the treatment, preprocedure prevention, and routine prophylaxis of HAE attacks, and for the routine prophylaxis of attacks in the USA. This phase 3 study assessed the safety and efficacy of 2 C1-INH doses in preventing attacks in children aged 6-11 years. Methods: A randomized single-blind crossover study was initiated in March 2014. Results for the first 6 patients completing the study are reported here. After a 12-week qualifying observation period, patients were randomly assigned to 1 of 2 C1-INH doses, 500 or 1,000 U, every 3-4 days for 12 weeks and crossed over to the alternative dose for a second 12-week period. The primary efficacy endpoint was the number of angioedema attacks per month. Results: Six females with HAE type I and a median age of 10.5 years received 2 doses of C1-INH (500 and 1,000 U). The mean (SD) difference in the number of monthly angioedema attacks between the baseline observation period and the treatment period was -1.89 (1.31) with 500 U and -1.89 (1.11) with 1,000 U. During the treatment periods, cumulative attack severity, cumulative daily severity, and the number of attacks needing acute treatment were lower. No serious adverse events or study drug discontinuations occurred. Conclusions: Interim findings from this study indicate that routine prevention with intravenous administration of C1-INH is efficacious, safe, and well tolerated in children ≥6 years of age.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.
METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).
RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.
CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141.