Response to Karadag

We agree insofar with Ahmed Karadag, that isotonic saline (IS) can have positive effects when applied as an adjunct therapy for cleansing the upper airways from secretions and crusts. Although a recent Cochrane Database Systemic Review concludes that ‘included trials were too small and had too high a risk of bias to be confident about the possible benefits of nasal saline irrigation in acute upper respiratory tract infections’ [[1]Kassel J.C. King D. Spurling G.K. Saline nasal irrigation for acute upper respiratory tract infections.Cochrane Database Syst Rev. 2010; 3 ([Epub 2010/03/20]): CD006821PubMed Google Scholar], we recommend this approach to our patients suffering from rhinosinusitic symptoms for CF and other respiratory diseases. Therapeutic nasal lavages are commonly applied rinsing 125 mL of IS through each nasal side (resulting total volume 250 mL). We do not doubt that such volumes have the potential to also remove allergens and some pathogens together with inflammatory mediators. However, we deem it unreasonable to compare 5 drops of IS applied every 4 h with the dornase alfa treatment applied within our trial. There is evidence that nasal drops or sprays, nasal lavage, and conventional aerosols inhaled through the nasal airways do not reach the paranasal sinuses unless the ostia have previously been widened to about 4 mm, as shown by Grobler et al. [[2]Grobler A. Weitzel E.K. Buele A. Jardeleza C. Cheong Y.C. Field J. et al.Pre- and postoperative sinus penetration of nasal irrigation.Laryngoscope. 2008; 118: 2078-2081Crossref PubMed Scopus (130) Google Scholar]. In contrast, in-vitro deposition studies presented in Fig. 1 of our publication [[3]Mainz J.G. Schien C. Schiller I. Schädlich K. Koitschev A. Koitschev C. et al.Sinonasal inhalation of dornase alfa administered by vibrating aerosol to cystic fibrosis patients: a double-blind placebo-controlled cross-over trial.J Cyst Fibros. Jul 2014; 13: 461-470Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar] showed that about 19% of the 2.5 mL of dornase alfa or IS applied with pulsating aerosols reaches the nasal cavity, 7.5% of which reaches the paranasal sinuses. In-vivo studies affirmed that only pulsating aerosols are deposited within maxillary and ethmoidal sinuses [[4]Möller W. Schuschnig U. Khadem Saba G. Meyer G. Junge-Hulsing B. Keller M. et al.Pulsating aerosols for drug delivery to the sinuses in healthy volunteers.Otolaryngol Head Neck Surg. 2010; 142 ([Epub 2010/02/23]): 382-388Crossref PubMed Scopus (54) Google Scholar]. The issue is clearly addressed in the results and discussion of our publication on sinonasal inhalation of dornase alfa. We provided a detailed comparison of effects of recombinant dornase alfa and IS (see Fig. 3): sinonasal vibrating inhalation of dornase alfa improved the symptoms by a mean of −7.14 SNOT-20 points whereas IS reduced symptoms for only −1.27 points. Thus, IS had only non-significant effects on sinonasal symptoms (see Fig. 2). An improvement of ≥ 5 SNOT-20 points is considered to be clinically relevant. Nevertheless, the objection against IS as placebo is worth to be discussed more profoundly under the following two issues:1.Which alternative comparators exist to assess the effects of dornase alfa?2.What is the general definition of a placebo and how should this be applied to our trial comparing dornase alfa and IS? (1) The choice of a comparator for assessment of a drugs' effects within a clinical trial is limited to some extent: even a sugar tablet can influence the patients' organism and distilled water as an agent-free solution has strong osmotic effects when applied to living organisms or tissues. Furthermore, blinding can be difficult e.g. if, not as in our trial, dornase alfa as color- and smell less solution is applied. In former times, the subjects' safety was not controlled as it is today: for the assessment of the effectivity of, e.g., antibiotics, the drugs' carrier solution was taken as a placebo. This could consist of isotonic or half isotonic saline, together with additives like phenols as stabilisators. Nowadays, such a combined placebo would need to pass through a pharmacologic and toxicologic drug admission processes before being admitted for a clinical trial. As a result, solutions like IS are frequently used as a placebo. This leads to the question about the definition of placebo. (2) Unfortunately, there is no unified definition, but rather an intriguing discussion about placebo effects making it a field of research of its own. This is why we were guided by the European Medicines Agency (CPMP/ICH/364/96): “In a placebo-controlled trial, subjects are randomly assigned to a test treatment or to an identical-appearing treatment that does not contain the test drug”. Due to the absence of dornase alpha (test drug) and equivalent physical characteristics, IS met the requirements for the designation as placebo in our study. Altogether, the use of a substance as placebo or control, which by itself can have some positive effects on the studies' endpoints, has the consequence that effects of the assessed drug must be higher to achieve significant changes compared to the control substance. Karadag submitted a very similar Letter to the Editor of ‘Drug Design, Development and Therapy’. In this journal we recently published a pilot trial on sinonasal inhalation with tobramycin as vibrating aerosol [[5]Mainz J.G. Schädlich K. Schien C. Michl R. Schelhorn-Neise P. Koitschev A. et al.Sinonasal inhalation of tobramycin vibrating aerosol in cystic fibrosis patients with upper airway Pseudomonas aeruginosa colonization: results of a randomized, double-blind, placebo-controlled pilot study.Drug Des Devel Ther. 2014; 8 ([Epub 2014/03/07]): 209-217Crossref PubMed Scopus (57) Google Scholar], which also had IS as a placebo. In our response (publication in process) we could exclude relevant antibacterial effects of IS on the primary endpoint of this trial Pseudomonas aeruginosa colony counts in diagnostic nasal lavage compared to the applied antibiotic [[6]Hentschel J. Muller U. Doht F. Fischer N. Boer K. Sonnemann J. et al.Influences of nasal lavage collection-, processing- and storage methods on inflammatory markers—evaluation of a method for non-invasive sampling of epithelial lining fluid in cystic fibrosis and other respiratory diseases.J Immunol Methods. 2014; 404: 41-51Crossref PubMed Scopus (34) Google Scholar]. Nasal saline as a placebo in chronic rhinosinusitisJournal of Cystic FibrosisVol. 13Issue 5PreviewI read with interest Mainz et al’s article in the July issue of your journal [1]. The authors concluded that; vibrating sinonasal inhalation of dornase alfa reduces rhinosinusitis symptoms in cystic fibrosis. We question the interpretation of the results. Full-Text PDF Open Archive