The contribution of galenics to patients’ sensory perception of nasal sprays after nasal surgery – data from a prospective randomized, controlled, double-blind, cross-over, multi-centre study


 Introduction:Postoperative care after nasal surgery is commonly achieved with nasal sprays. The current study compared two decongesting, wound healing nasal sprays in patients after nasal surgery in order to investigate their sensoric perception. One of the sprays presented a new galenic formulation (nasic® neo, Cassella-med GmbH & Co. KG).Methods:Using a cross-over design, patients who had undergone nasal surgery applied two different nasal sprays during two treatment periods of 4 days each, interrupted by 3 days wash out period. Sensoric perception of the nasal sprays was assessed with the nasal-spray-sensoric-scale. Throughout the study, nasal obstruction was evaluated by patients, and physical examinations, measurements of vital parameters and rhinoscopic examinations were carried out by investigators. Adverse events were documented during the entire study, and following treatment, patients judged the overall preference, efficacy and tolerability of both products.Results:Overall, no significant differences in sum scores of the assessments of the nasal-spray-sensoric-scale were observed between treatments. Significant periodic effect observed during the cross-over study limited the overall analysis. Nevertheless, it could be shown that significantly more patients preferred the new galenics nasal spray compared to the comparator spray (57.1% vs. 34.7%; p=0.031). Further, 10% more patients rated the efficacy of new galenics as ‘good’ to ‘very good’ compared to the comparator. Importantly, a subgroup population of patients with more pronounced signs of inflammation present at screening evaluated the sensoric perception of new galenics significantly better (p=0.033) compared to the comparator. Within this subgroup, no periodic effect was observed. The application of both nasal sprays was shown to be safe and well-tolerated.Conclusion:The current study showed that the overall sensoric perception of both nasal sprays was evaluated comparably well in patients after nasal surgery and that overall, the application of the new galenics nasal spray was preferred by significantly more patients compared to the comparator nasal spray. Patients with marked nasal abnormalities may have a greater benefit from the contribution of galenics as significant differences in the sensoric evaluation by the nasal-spray-sensoric-scale in favour of the new galenics product were shown for this subgroup.Trial registration: The current study was registered in the EU Clinical Trials Register with the EudraCT No: 2019-004936-52.

subgroup, no periodic effect was observed. The application of both nasal sprays was shown to 48 be safe and well-tolerated. 49 Conclusion: 50 The current study showed that the overall sensoric perception of both nasal sprays was 51 evaluated comparably well in patients after nasal surgery and that overall, the application of the 52 new galenics nasal spray was preferred by significantly more patients compared to the 53 comparator nasal spray. Patients with marked nasal abnormalities may have a greater benefit 54 from the contribution of galenics as significant differences in the sensoric evaluation by the 55 nasal-spray-sensoric-scale in favour of the new galenics product were shown for this subgroup.

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Study design 101 The current study was a prospective, double-blind, randomized, controlled, multi-centre, cross-102 over trial, which was carried out in three ear nose throat outpatient centres in Germany.

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The study was conducted in accordance with the principles of the Declaration of Helsinki, Good  109 Female or male patients (18 to 64 years) with post-operative nasal breathing disorders after 110 surgery on the nasal septum or the nasal conchae were eligible to participate in the trial. Details 111 of in-and exclusion criteria as well as allowed and forbidden medications are listed in Table   112 S1. After signing an informed consent, patients were randomly allocated to treatment sequence 113 1 (new galenics, followed by comparator treatment) or 2 (comparator treatment, followed by 114 new galenics; see Figure 1). Randomization was ensured by block randomization with a block 115 length of 6, and randomization lists were transferred to an external pharmacy for packaging of 116 the investigational products. Patients were assigned ascending treatment numbers in 117 chronological order of appearance at the trial site, and investigational products were applied by 118 patients according to the assigned treatment sequence.

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Treatment was applied in crossover design: the respective first nasal spray was applied for 4 120 days (days 0-3 / treatment period 1), followed by a washout period of 3 days (days 4-6), 121 continued by application of the second nasal spray for another 4 days (days 7-10 / treatment 122 period 2, see Figure 1). During the treatment periods, patients applied the nasal sprays upon demand but maximal 1 spray per nostril 3 times a day; during the washout period, patients did 124 not use any of the investigational products.

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The investigational medicinal product (IMP) used in the trial was the nasal sprays nasic ® 139 The study duration for each patient was 11 days, comprising 4 site visits (V1-V4, see Table   140 S2). During each visit, the investigators carried out a physical examination covering the general 141 health status, ear nose throat (ENT) area (assessed by endoscopic rhinoscopy) and lungs/thorax.

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The status of each parameter was evaluated as 'normal' or 'abnormal' and existing 143 abnormalities had to be described and documented by the investigators. The presence and 144 severity of nasal edema, secretion and redness were investigated by rhinoscopy and evaluated 145 by the rhinoscopy score ranging from 0 = absent to 3 = severe symptom. In addition, blood 146 pressure and heart rate were measured at all visits.
The level of nasal obstruction was assessed by patients during each visit (prior to application 148 of a study product) on a visual analogue scale (VAS) ranging from 'no obstruction' to 'worst 149 obstruction'. allowed to use their nasal spray at home before attending V2 or V4 but had to apply one spray 161 at the site prior to completion of the questionnaire.

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During the final study visit (V4), patients performed a final evaluation of treatments by judging 163 the overall efficacy and tolerability of the two nasal sprays from 0 (not satisfactory) to 3 (very 164 good) and by evaluating which of the two nasal sprays had been preferred (nasal spray applied 165 during days 0-3 or during days 7-10).

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Study endpoints 168 The primary endpoint of the study was the difference in the total score of the sensory 169 assessments of the NSSS (14 items) after first application of either new galenics or the 170 comparator. The differences between the two nasal sprays were analysed independently of each 171 other in cross-over design in the assessments at V1 und V3 at the respective first application of 172 the nasal sprays (inter-group-differences). Results of the NSSS were analysed separately for the

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Overall, 51 patients were randomised, of which 26 were allocated to treatment sequence 1 (new 199 galenicscomparator) and 25 to treatment sequence 2 (comparatornew galenics). All 26 200 patients of treatment sequence 1 completed the treatment. Within treatment sequence 2, two 201 patients only received a single application of medication during V1, whereas 23 patients 202 completed the treatment (see Figure 3).

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The following results reflect data of the entire ITT population (randomised patients with at least 204 complete data sets of V1 and V3, n=49) as well as data of subset populations described later.  Table 1. Patients aged 19 to 58 years were 208 enrolled, and there were no statistically significant differences regarding gender, age and body 209 mass index (BMI) between the treatment sequences.   Importantly, a significant period effect was observed during the study (p=0.004) with both 242 products being evaluated significantly better in the second period than in the first period. The 243 thereof resulting limitations on the crossover evaluation of the endpoints were considered for 244 the following study results.

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Regarding the primary endpoint, the analysis of NSSS data (14 items) demonstrated overall, 246 no significant treatment effect, i.e., no differences of mean sum scores were demonstrated 247 (p=0.487, Figure 5A).

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Analysis of 15 item data confirmed the results above. but not for patients aged above 30 years (p=0.099 in the 14-item analysis).

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The analysis of the secondary endpoints of the study investigated differences of sum scores of 263 the NSSS over the course of the study (from V1 to V2 and from V3 to V4). No significant 264 differences between treatment sequences were shown neither for treatment period 1 (p=0.688) 265 nor for treatment period 2 (p=0.923).   288 At the end of the study, patients evaluated which of the nasal spray was preferred. In total, a 289 significantly higher number of patients (n=28; 57.1%; p=0.031) preferred the new galenics 290 product over the comparator product (n=17; 34.1%). The remaining 4 patients (8.2%) had no 291 preference (see Figure 7). Efficacy and tolerability assessment 294 As shown in Figure 8, the efficacy of both treatments was judged as good to very good by the 295 majority of patients. Numerical values of percentages of patients with a good or very good 296 rating of new galenics (85.7%) were about 10% higher than those of comparator (75.5%); 297 however, differences were not statistically significant (p=0.307).

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The tolerability of both nasal sprays was evaluated as good by patients of both treatment groups 299 without significant differences.

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No serious adverse event occurred during the trial. A total of six adverse events (AEs) in five 303 patients were documented (3 mild, 1 moderate, 2 severe intensity), one of which (nasal burning) 304 was rated as related to treatment with comparator, two AEs (both epistaxis) were rated as 305 probably related to treatment (1 with new galenics, 1 with comparator). All three AEs can be 306 classified as expected, as they are listed in the SPCs of the products. The relationship for the 307 other AEs was rated as unlikely or not related (see Table 2). which had already been successfully applied in other studies [11]. Starting at least one week 318 after surgery, patients were randomly assigned to 4 days treatment with one of the study 319 products, and after 3 days wash out period, patients were crossed over to 4 days treatment with 320 the alternative study product.

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The evaluation of the nasal sensory quality after the first application of the nasal spray showed 322 that no significant differences in NSSS sum scores could be demonstrated (p=0.487).

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Importantly, a significant period effect (p=0.004) was observed during the cross-over study, 324 thereby limiting the overall analysis of results. Overall, natural healing forces proved to have 325 more influence on the overall sensory perception of the patients than the differences in galenics.

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This may be considered as one of the limitations of this study.

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A closer look at this subgroup showed that the majority of these patients was enrolled with 333 residual abnormalities and pronounced symptoms more than 3 weeks after their nasal surgery.

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In contrast, the majority of "normal" patients started their study participation within the first 3 335 weeks after surgery. This may indicate that patients, who still suffer from nasal abnormalities 336 three weeks after their nasal surgery, may respond particularly well to the new galenics 337 treatment. In these patients the healing process may have been delayed and therefore a periodic 338 effect does not play a role.

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The analysis of a subgroup of three items of the NSSS showed that the sensoric perception of 340 the parameters 'amount of medication, that runs into the throat or the nose', 'odour intensity ', 341 and 'taste intensity' was evaluated significantly better following application of new galenics 342 compared to application of comparator. This finding may be explained by the higher viscosity 343 of the new product, which has been achieved by the galenics of the new formulation. The higher 344 viscosity of the formulation may increase the retention time of the nasal spray on the nasal 345 mucosa, thereby decreasing the amount of spray running down nose or throat, which in turn 346 will be perceived as less intense in taste and odour.

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In line with the results above, treatments with new galenics resulted in an increased perception 348 of nasal moisturization in both treatment periods with changes between V3 and V4 (treatment 349 period 2) being statistically significant (p=0.026). It is likely that the new galenics contribute 350 to those beneficial effects on the perception of moisturization over time.

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At the beginning of period 2, both treatment sequences also differed in the parameter 352 obstruction, with a clear advantage of the treatment sequence that was pre-treated with new 353 galenics and then received the comparator in period 2. Obstruction, measured as the patient's 354 subjective assessment on a VAS scale, described the condition at the time of the examination.

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The assessment was made before the application of the respective nasal spray. This is another 356 point that could have contributed to the period effect.

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Literature data support these results demonstrating that the application of products with similar The study was funded by Cassella-med GmbH & Co. KG which also acted as sponsor.  All patients provided informed consent prior to participating in this study.

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No data identifying single patients were included in this study, therefore, informed consent for 426 publication is not needed.