Clinical performance of house-dust-mite-specific subcutaneous immunotherapy in a postmarket noninterventional setting

Clinical premarket trials evaluate efficacy and safety of a therapeutic compound in highly selected participant groups under closely monitored circumstances. In contrast, noninterventional studies (NIS) on marketed products are often considered inferior, but are nevertheless encouraged by authorities, especially in terms of safety of real-life patients. Here, we analysed the tolerability and safety during the updosing phase of a house dust mite (HDM) subcutaneous allergen-specific immunotherapy (SCIT) [1, 2], marketed in Austria shortly before start of this study. The open prospective NIS was conducted in Austria and ran in 7 centres from 2017 to 2019. After having given written informed consent, 32 eligible patients including 5 children (Online Resource 1)


To the editors
Clinical premarket trials evaluate efficacy and safety of a therapeutic compound in highly selected participant groups under closely monitored circumstances. In contrast, noninterventional studies (NIS) on marketed products are often considered inferior, but are nevertheless encouraged by authorities, especially in terms of safety of real-life patients.
Here, we analysed the tolerability and safety during the updosing phase of a house dust mite (HDM) subcutaneous allergen-specific immunotherapy (SCIT) [1,2], marketed in Austria shortly before start of this study.
The open prospective NIS was conducted in Austria and ran in 7 centres from 2017 to 2019. After having given written informed consent, 32 eligible patients including 5 children (Online Resource 1) Overall, no fatality nor serious adverse drug reaction (ADR) occurred during the study. No epinephrine was used. Four ADRs were reported in 3 adults (9.3%). One asthmatic patient with a mild to moderate recurrent airway obstruction classified as grade II systemic reaction discontinued the treatment. Swelling at the injection site (5-10 cm in diameter) occurred in 3 patients during the updosing phase: 1 reaction at 300 standard units (SU) and 2 at 900 SU. Tolerability was mainly rated 'very good' as assessed by the investigators and patients (Table 1).
All symptom scores were lower (by up to 56.3%) at V6 in comparison to the retrospective evaluation at V1 (Fig. 1). The individual symptoms 'sneezing' and 'nasal obstruction' improved the most (Fig. 1, Online Resource 5). Symptomatic medication use was also substantially reduced (Online Resource 6).
Here, we show that the HDM-SCIT is safe and well tolerated during the updosing phase in the scope of standard medical care. ADRs occurred after 2.6% of all injections, which is in line with data from a recent meta-analysis on SCIT [3]. However, of the originally planned 100 participants only 32 patients were included in this study due to an unexpectedly low participation rate of the study centres. The main barrier holding off investigators from participating was the administrative work load to fulfil requirements of the Vienna ethics committee which was comparable to clinical trials.
At the same time, the conduct of NIS is encouraged by regulatory authorities and the community, to demonstrate the clinical use of marketed products in unselected real-life patients. In practice, however, the bar is set so high that the efforts required to participate in a NIS is almost similar to those required for a clinical trial. Hence, only physicians who are experienced in clinical trials and are therefore not afraid of the administrative burden of such a study, are willing to participate. Moreover, the general negative image of NIS also prevented us from reaching the targeted number of included patients.
Despite the low inclusion figures, clinical effects on allergic symptoms were already detected that are comparable to a recent study presenting data after 2 years of treatment [4]. The use of symptomatic medication was also considerably reduced.

Compliance with ethical guidelines
Conflict of interest R. Mösges and S. Allekotte are employees of CRI-Clinical Research International Ltd. which served as the clinical research organisation for this study. E. Raskopf and C. Acikel were employees of CRI-Clinical Research International Ltd. at the time the study was conducted. R. Mösges reports personal fees from ALK, grants from ASIT biotech, personal fees from Allergopharma, personal fees from Allergy Therapeutics, grants and personal fees from Bencard Allergie GmbH, grants from Leti, grants, personal fees and non-financial support from Lofarma, non-financial support from Roxall, grants and personal fees from Stallergenes, grants from Optima, personal fees from Friulchem, personal fees from Hexal, personal fees from Servier, personal fees from Klosterfrau, non-financial support from Atmos, personal fees from Bayer, non-financial support from Bionorica, personal fees from FAES, personal fees from GSK, personal fees from MSD, personal fees from Johnson&Johnson, personal fees from Meda, personal fees and non-financial support from Novartis, non-financial support from Otonomy, personal fees from Stada, personal fees from UCB, non-financial support from Ferrero, grants from BitopAG, grants from Hulka, personal fees from Nuvo, grants from Ursapharm, outside the submitted work. S. Allekotte reports grants and personal fees from Lofarma, personal fees from Servier, personal fees from Hexal, personal fees from Friulchem, outside the submitted work. E. Raskopf reports personal fees from Bayer and personal fees from Gesellschaft für Phytotherapie outside the submitted work. P. Zieglmayer received lecture fees by Alk Abello, Allergopharma, Allergy Therapeutics, Novartis, Stallergenes, Thermo Fisher Scientific, and received scientific and educational grants by Allergopharma, Allergy Therapeutics, Biomay, Calistoga, GSK, HAL, MSD, Ono, Oxagen, RespiVert, Stallergenes and VentirX outside the submitted work. S. Weissenbaeck and M. Moser participated as investigators in this study. K. Birkholz, M. F. Kramer and S. Guethoff are employees of Bencard Allergie GmbH, Vienna, Austria and/or Munich, Germany, the sponsor of the study. C. Acikel declares that he has no competing interests.

Ethical standards
The study upon which this analysis was based was approved by the Medical Ethics Committee of Vienna, Austria (reference number EK16-192-1016). The study was registered at clinical trials.gov with number NCT03127436. Informed consent was obtained from all individual participants included in the study.
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