HAE patient self-sampling for biomarker establishment

Abstract

Background: Hereditary Angioedema (HAE) is a genetic disorder that leads to frequent angioedema attacks in various parts of the body. In most cases it is caused by pathogenic variants in the SERPING1 gene, coding for C1-Inhibitor (C1-INH). The pathogenic variants in the gene result in reduced C1-INH levels and/or activity, which causes aberrant bradykinin production and enhanced vascular permeability. The standard-of-care diagnostic test is performed biochemically via measuring C1-INH level and activity as well as the C4 level. This, however, does not allow for the diagnosis of HAE types with normal C1-INH. There is an urgent need to identify and characterize HAE biomarkers for facilitating diagnostics and personalizing the treatment. The Hereditary Angioedema Kininogen Assay (HAEKA) study aims to measure the dynamics of cleaved High Molecular Weight Kininogen (HKa) and other metabolite levels during the angioedema and non-angioedema state of the disease. The metabolites will be analyzed and verified by liquid chromatography ion mobility high resolution mass spectrometry (LC/IM-QToF MS) of dried blood spot (DBS) cards upon the study completion. The study design is truly innovative: 100 enrolled participants provide blood samples via DBS: (1) every 3 months within 2 years during regular study site visits and (2) by at-home self-sampling during HAE attacks via finger pricking. We are presenting a project design that permits clinical study activities during pandemic contact restrictions and opens the door for other clinical studies during COVID-19.

Results: As of October 2020, there are 41 patients from 5 sites in Germany enrolled. 90 blood samples were collected during the regular visits, and 19 of the participants also performed self-sampling during the HAE attacks from which a total of 286 attack blood samples were collected. Participating patients rate the study procedures as easy to implement in their daily lives. The concept of home self-sampling is effective, reproducible, and convenient especially in times of contact restrictions due to the COVID-19 pandemic.

Conclusions: It is the hope that the HAEKA study will complete in 2023, reveal biomarker(s) for monitoring HAE disease activity, and may help to avoid HAE attacks via applying medication prior to the symptom onset.

Keywords: Biomarker; Cleaved high molecular weight Kininogen; Hereditary angioedema; Observational clinical study; Self-sampling.

Fig. 1

Recruitment details of the HAEKA study as per 07.10.2020. a Number of participants enrolled per study site. b A boxplot displaying the age distribution of the participants. c Gender distribution of the participants. d Visit status of all participants in the HAEKA study. The number of completed Visits 1–7 is shown. e Prophylactic treatment of HAEKA participants: it is shown how many participants take each respective medication (one subject received both Lanadelumab and Berinert®). f An overview showing how often the different samples a–f of each attack have been collected. g Acute treatment of HAE attacks: it is shown how many percent of the participants take a respective medication to treat an attack. h Overview on the amount of documented attacks per participant. i Exemplary CentoCard® showing the quality of participant’s self-sampled blood spots

Fig. 2

Response of the HAEKA participants for being contacted by the study nurse

Fig. 3

HAEKA Study sampling scheme. The left part shows in which intervals the 7 regular visits of each participant take place. The right part shows at which time points of an acute attack HAEKA participants shall collect samples a–f via finger pricking. The graph shows a hypothetical curve of a potential biomarker that reflects the course of an HAE attack