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Randomised trial on performance, safety and clinical benefit of hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline nasal sprays in patients suffering from dry nose symptoms
Limited data exist on the clinical benefits of nasal applications for moistening the nasal mucosa. We therefore investigated the effects of hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline nasal sprays in patients suffering from dry nose symptoms in an otorhinolaryngological outpatient setting.
Methods
240 patients were randomised into this prospective, three-armed clinical trial with two assessment points (baseline and 4 weeks later). Patients received either hyaluronic acid, hyaluronic acid plus dexpanthenol or isotonic saline nasal spray over a period of four weeks. Rhinitis Sicca Symptom Score (RSSS) was assessed as primary endpoint, and individual symptoms and tolerability of all treatments as secondary endpoints. Patient perceptions after first application of the allocated nasal spray were recorded using the Nasal Spray Sensory Scale. Treatment effects were analysed for each study arm first and subsequently compared against each other.
Results
RSSS (hyaluronic acid: mean difference = 8.90 [98.33% CI = 7.34/10.45]; hyaluronic acid plus dexpanthenol: mean difference = 8.42 [98.33% CI = 6.91/9.94]; isotonic saline: mean difference = 8.94 [98.33% CI = 7.33/10.54]), individual symptoms and Endoscopy Score improved significantly (p < 0.001) in all treatment arms. Tolerability was assessed as “flawless” in more than 85% of all treatments, which is reflected in overall high rankings in the Nasal Spray Sensory Scale. Perception of nasal moisturisation was reported to be significantly higher in patients receiving hyaluronic acid plus dexpanthenol as compared to patients receiving hyaluronic acid or isotonic saline. No further significant differences were observed between the three treatments.
Conclusion
All three tested sprays (hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline) proved to be suitable treatments for patients suffering from dry nose symptoms.
The integrity of the mucous membrane is considered a major physiologic defense mechanism against infection. A closely packed network of subepithelial capillaries allows passage of water into the nasal lumen for evaporation and thus conditioning of the inhaled air [
. Beyond that, nasal secretions are derived from anterior serous glands, small seromucous glands and goblet cells, but also from tears, secretions from paranasal sinuses and condensed expiratory water [
]. Still this sensitive balance might be disturbed due to various reasons, leading to dry nose symptoms. Depending on the degree to which the nasal mucosa dries out, mucociliary transport and even the epithelial barrier may be impaired.
“Dry nose”, “rhinitis sicca” or “atrophic rhinitis” are alternative terms for an equivocally defined disease state since diagnosis and definition is rather based on relevant anamnestic information. Commonly observed symptoms range from the subjective feeling of a dry nose, to mild burning sensations, itching and nasal obstruction, and up to visible crustings of the nose, epistaxis, diminished sense of smell and a foetid smelling nasal discharge (ozena). Common characteristic for the disorder is hypotrophy of the nasal mucosa. Rhinitis sicca constitutes furthermore one category among the various forms of nonallergic noninfectious rhinitis, i.e., rhinitis symptoms being independent from any allergic or infectious trigger [
Causes of dry nose sensations include, amongst others, local mechanical irritation (e.g., nose-picking), climatic factors, dry room air, workplace conditions, old age, allergic rhinitis (in particular house dust mites and moulds), chronic bacterial infections, endocrine imbalances, endonasal sinus surgery, surgery on the nose and head and neck radiotherapy (in the later three cases, one frequently speaks of Empty nose syndrome), obstructive sleep apnoea (OSA) and continuous positive airway pressure treatment of OSA, or side effects of specific medications [
Therapy with nasal CPAP (continuous positive airway pressure) in patients with obstructive sleep apnea syndrome (OSAS). II: side-effects of nCPAP therapy. Effect on long-term acceptance.
. Last but not least, dry nose symptoms occur concurrently and may be the first signs of a common cold infection with a runny nose.
Moistening and care of the nasal mucosa by topical application of nasal sprays or ointments represents an obvious and important therapeutic measure for dry nose symptoms. Isotonic saline nasal sprays are commonly used, but also supposedly superior formulations containing hyaluronic acid or dexpanthenol are available on the market.
Hyaluronic acid is a physiological component of the nasal mucus [
]. This compound was reported to enhance the nasal bioavailability of some drugs, and improved absorption was shown to be due to the high viscosity and mucoadhesion of the hyaluronic acid solutions [
]. In the nasal mucosa hyaluronic acid is furthermore involved in the regulation of vasomotor tone and gland secretion while simultaneously retaining enzymes which are important for homeostasis in the apical surface. Furthermore a significant contribution to mucosal host defense by stimulating mucociliary clearance of foreign bodies was reported [
Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan.
]. Hyaluronic acid and its solutions are highly osmotic and form a scaffold that several sulfur proteoglycans can bind to. Such structures can reach large size and are able to trap large quantities of water and ions, providing hydration and tissue turgescence. Some studies indicate that hyaluronic acid enables the control of tissue hydration during inflammatory processes and/or the response to tissue injury, without exhibiting allergenic or immunogenic potential [
Dexpanthenol is the alcohol analogue of pantothenic acid. Pantothenic acid, which is formed from dexpanthenol after permeation into the skin or the mucous membrane, is a component of coenzyme A (CoA) that is an essential cofactor for a number of enzymes catalysing reactions like the breakdown and synthesis of fats, carbohydrates and amino acids. The highest content of CoA is found in the continuously regenerating skin epidermal cells. The beneficial effect of dexpanthenol on the re-epithelialisation of non-infectious, trophic damage is known since decades [
]. Dexpanthenol is a hygroscopic substance with a high water-retentive capacity. It has been shown that the local application of dexpanthenol-containing products increases the hydration of epithelia [
To date, only limited data are available that compare performance, safety and clinical benefit of such different nasal applications. We therefore initiated a randomised prospective comparative clinical trial in order to compare the effects of hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline nasal sprays in patients suffering from dry nose symptoms within the scope of routine care in an otorhinolaryngological outpatient setting.
2. Materials and methods
2.1 Trial design
This clinical trial was based on a prospective, randomised, three-armed longitudinal design with two points of measurement, an initial and a final visit. The final visit was scheduled 4 weeks ± 4 days after the initial examination. The trial was conducted according to §23b of the German Medical Device Act in patients that had an indication for application of moistening nasal sprays, including but not limited to rhinitis sicca, dry nose symptoms due to side effects of specific medications and as concomitant therapy in case of rhinosinusitis or allergy. The study was carried out in 5 trial centers in Germany during the period December 2017–November 2018. The trial was performed according to the German Medical Device Act and the Declaration of Helsinki, was registered in the German Clinical Trial Register (DRKS-ID: DRKS00013357), and was approved by the Institutional Review Board of the Freiburg Ethics Commission International (Code: 017/1833).
2.2 Eligibility criteria
Adults and children with no restrictions regarding the age of the patients that had an indication for treatment with a moistening nasal spray (rhinitis sicca, dry nose symptoms due to the intake of special medications or concomitant therapy of rhinosinusitis or allergies) were eligible for the study. Thus patients suffering from following main symptoms were considered: sensation of dry nose, impairment of nasal breathing/nasal obstruction, crusting, itching/sneezing attacks, pain in the nose, nasal discharge anterior/runny nose, thick nasal discharge, desire to clear one's throat/ dry throat, impairment of smell and impairment of sleep. Patients assessed these symptoms on an ordinal scale of 0–4 (0 = none, 1 = mild, 2 = moderate, 3 = strong, 4 = very strong), and inclusion into the analyses was only possible if at least three main symptoms were rated as “mild” or more severe, or at least two symptoms were rated as “strong” or “very strong”.
No further inclusion or exclusion criteria were defined beyond the information given in the Instruction For Use, in order to gain a realistic picture of common therapy and therapeutic output. However, the decision to prescribe/recommend a moistening nasal spray to the respective patient must have been made by the physician before the inclusion of the patient in the trial, and patients were enrolled only after they had been given sufficient information and had provided written consent concerning their participation in the trial.
2.3 Randomisation
After inclusion into the trial, patients were randomly assigned to either one of the treatment arms hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline nasal spray (block randomisation, stratified for each study centre). Both investigators and patients were blinded regarding the allocation of trial products, subsequent therapy after allocation was performed open-label, however.
2.4 Trial products
The medical devices used in this trial were manufactured by Ursapharm Arzneimittel GmbH, Saarbruecken, Germany. The hyaluronic acid nasal spray (hysanⓇ Hyaluronspray) contains 0.04% hyaluronic acid, a phosphate buffer, sodium chloride and purified water. The hyaluronic acid plus dexpanthenol nasal spray (hysanⓇ Pflegespray) contains 0.025% hyaluronic acid, 2% dexpanthenol, a phosphate buffer, sorbitol and purified water. The isotonic saline nasal spray (Ocean-Spray Plus) contains sodium hydrogen carbonate (anhydrous), sodium chloride, potassium chloride, calcium chloride, magnesium chloride and purified water.
Patients were advised to apply the nasal spray several times a day while spraying 1–2 sprays into each nostril, in compliance to the manufacturer's Instruction For Use. Differing dosing recommendations had to be recorded in the case report form. With each spray 0.14 mL of solution were dispensed. In case of concomitant treatment with other nasal sprays or nasal drops, patients were advised to comply with a time interval of at least 30 min between the applications. In case of the occurrence of hypersensitivity reactions, patients were advised to discontinue use of the product.
2.5 Efficacy and safety measurements
All data for this study were recorded on a single case report form (CRF) that was filled in by the physician. Indications for application of moistening nasal sprays were documented at the initial examination, and symptoms and clinical signs were subsequently documented at both visits (initial and final examination).
Primary endpoint: The primary endpoint for assessment of the performance of each nasal spray was the Rhinitis Sicca Symptom Score that constituted the sum of the following individual symptoms: sensation of dry nose, impairment of nasal breathing/nasal obstruction, crusting, itching/sneezing attacks, pain in the nose, nasal discharge anterior/runny nose, thick nasal discharge, desire to clear one's throat/ dry throat, impairment of smell and impairment of sleep. Patients assessed each of these symptoms on an ordinal scale of 0–4 (0 = none, 1 = mild, 2 = moderate, 3 = strong, 4 = very strong).
Secondary endpoints: Clinical symptoms recorded for assessment of the primary endpoint were also evaluated as single items for each nasal spray. Furthermore, a sum score was built from parameters dry nose, impairment of nasal breathing/nasal obstruction and crusting in accordance to a recent publication [
Tolerability and effects on quality of life of liposomal nasal spray treatment compared to nasal ointment containing dexpanthenol or isotonic NaCl spray in patients with rhinitis sicca.
After random allocation, the nasal sprays were immediately applied during the first examination. Immediately after the first application and after two further minutes, patient perceptions were recorded by use of the Nasal Spray Sensory Scale [
]. In short, patients rated the parameters overall impression, amount running out of the nose/into the throat, irritation, sneezing attacks, odour intensity, odour sensation, taste intensity, bitterness, sense of taste, nasal moisturisation (immediately after first use), intensity of aftertaste, irritation, amount running out of the nose/into the throat and overall impression (2 min after first use) by marking a visual analog scale (0 = worst grading, 10 = best grading).
Patients furthermore reported the duration of action after first application (< 10 min, < 30 min, < 1 h, < 2 h, > 2 h, no effect).
Dryness, atrophy, redness and oedema of the nasal mucosa as well as crustings were assessed on an ordinal scale of 0–4 (0 = none, 1 = mild, 2 = moderate, 3 = strong, 4 = very strong) by the physicians through endoscopic examination at initial and final visits. Both single items as well as a summary score (Endoscopy Score) were used for a before/after comparison of symptoms.
In order to evaluate the clinical benefit of the therapy with the respective nasal spray, the physicians involved were also asked to assess the treatment with the product overall (very good – good – satisfactory – bad), the compliance of the patient (very good – good – satisfactory – bad), whether treatment with the nasal spray should be continued (yes – no), and whether they would prescribe/recommend the product again under similar conditions (yes – no – possibly).
During the final examination, the patients evaluated the overall treatment effect (significantly better – better – no difference – worse – significantly worse), overall impression and nasal moisturisation by marking a visual analog scale (0 = worst grading, 10 = best grading), whether they would use it again under similar conditions (yes – no), and whether they would recommend the product to others (yes – no).
Tolerability of the products was evaluated by the physicians at the final examination using the ratings “flawless”, “acceptable” and “not acceptable”. Adverse events and severe adverse events had to be documented in the case report form by the investigator. The occurrence of severe adverse events had to be reported to the sponsor of the study within 24 h. Since pregnant and nursing women were not excluded from study participation, follow-up of pregnancy and monitoring of the health status of the newborn or nursing child was prespecified.
2.6 Sample size and statistical analysis
Sample size calculation was based on the primary endpoint, the change of the Rhinitis Sicca Symptom Score. Before/after comparison of the primary endpoint was conducted separately for each treatment group. An effect of d = 0.5 was assumed to be clinically relevant. To detect an effect of d = 0.5 with an aimed power of 1-β = 90% at a significance level of α = 0.0167 (Bonferroni correction for multiple testing), 60 patients per group are necessary for paired t-tests. Compensating for a lost-to-follow-up rate of 10%, 67 patients per treatment group were needed. We allowed for additional patients in the predefined recruitment period in order to gain more data for safety analyses.
Baseline characteristics and safety evaluations were assessed on the safety population (all included patients with at least one intervention). Primary and secondary endpoints were assessed on the intention-to-treat population (ITT, all randomised patients meeting inclusion criteria).
Data are presented as mean (m) ± standard deviation (SD) for continuous and ordinal scaled variables or as relative percentages (%) for categorical variables.
To compare the primary endpoint Rhinitis Sicca Symptom Score between initial and final examination within each treatment group, paired t-tests (t) or in case of outliers Wilcoxon signed-rank tests (z) were used. Due to multiple comparisons the significance level (5%/3 = 1.67) and confidence intervals (98.33% CI) were adjusted.
For secondary endpoints, explorative analysis was used (no adjustment of the p-values). Changes in single clinical symptoms, Endoscopy Score as well as single items of the Endoscopy Score were assessed with Wilcoxon signed-rank tests. Chi-Square-test (χ) was used to compare the duration of moistening effect between the nasal sprays. The difference in perception of moisturisation between the three nasal sprays was assessed by Kruskal–Wallis H-test.
Sample size calculation and analyses were performed with SAS 9.4 (SAS Institute).
3. Results
A total of 240 patients were included in the study. Informed consent was lacking for one patient, therefore the data of this patient were not collected from the study centre and consequently excluded from analysis, resulting in 239 patients (97 males, 142 females) to be analysed (first patient in: 04.12.2017; last patient out: 21.11.2018). One patient breached an inclusion criterion by exhibiting only minor symptoms at baseline and was therefore excluded from ITT analysis. Four patients were lost to follow-up. Thus the ITT population included n = 238 patients at baseline, and n = 234 at the final examination. The safety population included all analysed patients (n = 239) (Fig. 1). Two patients were pregnant during use of the isotonic saline nasal spray. On average, the final examination took place 30.90 (± 6.58) days after the initial examination for the hyaluronic acid plus dexpanthenol nasal spray, after 31.09 (± 8.73) days for the hyaluronic acid nasal spray and after 31.25 (± 6.10) days for the isotonic saline nasal spray.
Overall, compliance with administering the spray as prescribed was assessed by the physicians as “very good” in 64/73/65%, as “good” in 28/22/27%, as “satisfactory” in 4/4/6% and as “bad” in 4/1/1% of the patients for the hyaluronic acid plus dexpanthenol nasal spray, the hyaluronic acid nasal spray and the isotonic saline nasal spray, respectively. In the majority of cases the frequency of use was 1–2 sprays in all three groups (89% for hyaluronic acid plus dexpanthenol, 89% for hyaluronic acid and 93% for the isotonic saline nasal spray) and the spray was used as prescribed (86% for hyaluronic acid plus dexpanthenol, 90% for hyaluronic acid and 96% for the isotonic saline nasal spray).
Demographic data and indications for use of the moistening nasal spray are given in Tables 1 and 2. Sex difference approaches statistical significance between treatment arms, as can be seen from Table 1. However, additional correlational analyses showed that sex was not associated with the key dependent variables RSSS and Endoscopy score, neither at visit 1 nor at visit 2, nor with regard to the change in scores from visit 1 to visit 2 (all p-values > 0.10). The investigation was performed under “real-world conditions”, thus use of medications for treatment of concomitant diseases was possible. Local treatments that may affect the therapeutic outcome, such as the use of intranasal corticosteroids and nasal decongestants, were analysed. Only 26/239 (11%) patients used either intranasal corticosteroids or nasal decongestants and these patients were evenly distributed across the three treatment arms: n = 10 hyaluronic acid plus dexpanthenol, n = 8 hyaluronic acid, and n = 9 isotonic saline nasal spray. Due to the low number of patients, additional statistical analyses were not conducted. Furthermore, no relevant changes were observed in the use of concomitant medications from visit 1 to visit 2.
Table 1Baseline characteristics of included patients given as number (sex) or mean (± st.dev.).
The Rhinitis Sicca Symptom Scores (RSSS) for the initial and final examination are given in Fig. 2. The Score improved significantly between initial and final examination for all products tested (hyaluronic acid plus dexpanthenol: t(78) = 14.01, p < 0.001; mean difference = 8.90 [98.33% CI = 7.34/10.45]; hyaluronic acid: z = −7.28, p < 0.001, n = 78, mean difference = 8.42 [98.33% CI = 6.91/9.94]; isotonic saline: t(76) = 13.62, p < 0.001; mean difference = 8.94 [98.33% CI = 7.33/10.54]).
Fig. 2Boxplots of Rhinitis Sicca Symptom Scores for initial and final examination, representing the sum of symptom scores for sensation of dry nose, impairment of nasal breathing/nasal obstruction, crusting, itching/sneezing attacks, pain in the nose, nasal discharge anterior/runny nose, thick nasal discharge, desire to clear one's throat/ dry throat, impairment of smell and impairment of sleep. Blue = initial examination; red = final examination. The individual items that make up the Rhinitis Sicca Symptom Score are shown in Table 3. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Significant improvements were also observed when dry nose, impairment of nasal breathing/nasal obstruction and crusting were evaluated as sum score according to the publication of Hahn et al. [
Tolerability and effects on quality of life of liposomal nasal spray treatment compared to nasal ointment containing dexpanthenol or isotonic NaCl spray in patients with rhinitis sicca.
] (data not shown). Furthermore, all single items of the clinical symptoms recorded for assessment of the primary endpoint improved significantly for each nasal spray when initial and outcome values were compared (p < 0.010). Table 3 gives an overview on baseline and outcome ratings of all single symptoms.
Table 3Baseline and outcome ratings for initial and final examination for all individual symptoms (each symptom was assessed on an ordinal scale of 0–4, given as mean ± st.dev). The Rhinitis Sicca Summary Score that is composed of these single symptoms is depicted in Fig. 2.
Endoscopic examination of dryness, atrophy, redness and oedema of the nasal mucosa as well as crustings by the physicians at initial and final visits confirmed the patients’ perception of symptom improvement: Both single items as well as the Endoscopy Score improved significantly in all treatment groups (Endoscopy Score for: hyaluronic acid plus dexpanthenol: z = −7.34, p < 0.001, n = 79, mean difference = 5.29 [95% CI = 4.44/6.14]; hyaluronic acid: z = −7.41, p < 0.001, n = 77, mean difference = 5.43 [95% CI = 4.70/6.16]; isotonic saline: z = −7.37, p < 0.001, n = 77, mean difference = 5.44 [95% CI = 4.65/6.23]). Evaluations of single items after endoscopic examinations are given in Table 4.
Table 4Baseline and outcome ratings for initial and final endoscopic examination (assessed on an ordinal scale of 0–4, given as mean ± st.dev).
Patients perceptions immediately and 2 min after the first use of the respective nasal spray was recorded as single items and by use of the Nasal Spray Sensory Scale. Results are given in Table 5. On the Nasal Spray Sensory Scale (maximum: 140 points), the hyaluronic acid plus dexpanthenol nasal spray reached 120.89 ± 10.72 points, the hyaluronic acid nasal spray 120.25 ± 7.93 points and the isotonic saline nasal spray 119.03 ± 11.48 points.
Table 5Patients perceptions immediately and 2 min after the first use of the nasal spray, Nasal Spray Sensory Scale (single items assessed on an ordinal scale of 0–10, Nasal Spray Sensory Scale ranging from 0 to 140, given as mean ± st.dev).
Overall impression
Amount running out of the nose/into the throat
Irritation
Sneezing attacks
Odour intensity
Hyaluronic acid plus dexpanthenol
7.83 ± 1.64
7.84 ± 2.23
9.54 ± 0.52
9.43 ± 0.96
8.94 ± 1.60
Hyaluronic acid
7.73 ± 1.91
7.46 ± 2.51
9.23 ± 1.17
9.52 ± 0.64
9.25 ± 1.22
Isotonic saline
7.68 ± 1.75
7.94 ± 2.16
9.44 ± 1.16
9.41 ± 1.19
8.91 ± 1.75
Odour sensation
Taste intensity
Bitterness
Sense of taste
Nasal moisturisation
Hyaluronic acid plus dexpanthenol
7.57 ± 2.06
9.19 ± 1.19
9.33 ± 1.11
7.42 ± 2.17
7.66 ± 1.67
Hyaluronic acid
7.60 ± 2.09
9.23 ± 1.03
9.48 ± 0.70
7.65 ± 2.01
7.62 ± 1.76
Isotonic saline
7.35 ± 2.16
8.85 ± 1.80
9.40 ± 0.87
7.32 ± 2.10
7.56 ± 1.56
Intensity of aftertaste - 2 min after first use
Irritation- 2 min after first use
Amount running out of the nose/into the throat - 2 min after first use
Duration of action was assessed by most of the patients (29%) as “less than one hour” for both the hyaluronic acid plus dexpanthenol nasal spray and the hyaluronic acid nasal spray and as “less than two hours” by 28% of the patients of the isotonic saline nasal spray group, with no significant differences observed between the groups (χ2(2) = 0.459, p = 0.795, refer to Table 6).
Table 6Duration of moistening effect after first application of the nasal spray (given in percentages of patient evaluations).
At the final examination, physicians assessed the treatment with the hyaluronic acid plus dexpanthenol nasal spray, the hyaluronic acid nasal spray and the isotonic saline nasal spray, respectively, as very good (38/49/34%), good (38/35/39%), satisfactory (18/13/25%) or bad (6/4/3%).
Physicians would prescribe the hyaluronic acid plus dexpanthenol, the hyaluronic acid and the isotonic saline nasal spray, respectively, again in patients with identical diagnoses in 86/85/81% of the cases, would not prescribe it in 5/4/4% and would possibly prescribe it again in 9/12/16% of the cases.
27/28/21% of the patients felt significantly better during treatment, 47/51/55% rated their condition as better, 23/19/25% recognised no difference, 4/1/0% rated their condition as worse and 0/0/0% as significantly worse for the hyaluronic acid plus dexpanthenol, the hyaluronic acid and the isotonic saline nasal spray, respectively.
81/87/83% of the patients would use the hyaluronic acid plus dexpanthenol, the hyaluronic acid and the isotonic saline nasal spray, respectively, again under similar conditions, and 19/13/17% would not. 81/85/78% of these patients would recommend the nasal spray to others, 19/15/22% would rather not recommend use of the product.
Overall impression and nasal moisturisation was evaluated by the patients at the final examination by marking a visual analog scale (0 = worst grading, 10 = best grading): overall impression was on average 8.28 ± 1.75 for the hyaluronic acid plus dexpanthenol nasal spray, 7.97 ± 1.77 for the hyaluronic acid nasal spray and 7.81 ± 1.96 for the isotonic saline nasal spray. Nasal moisturisation was assessed as 7.58 ± 1.71 for the hyaluronic acid plus dexpanthenol, 6.81 ± 2.18 for the hyaluronic acid and 6.74 ± 2.06 for the isotonic saline nasal spray.
Perception of nasal moisturisation was significantly higher in patients receiving the hyaluronic acid plus dexpanthenol nasal spray as compared to patients receiving the hyaluronic acid nasal spray (p = 0.008) and the isotonic saline nasal spray (p = 0.024). No further significant differences in symptoms and clinical signs were observed between the three treatments.
All analyses were repeated for the PP-population (see Fig. 1) and results confirmed the ITT findings (data not shown).
3.2 Safety evaluation
Tolerability was assessed as “flawless” in 91/91/86% of the patients, as “acceptable” in 8/9/14% and as “not acceptable” in 1/0/0% of the patients for the hyaluronic acid plus dexpanthenol, the hyaluronic acid and the isotonic saline nasal spray, respectively. One patient receiving the hyaluronic acid plus dexpanthenol nasal spray reported thrice about the occurrence of cephalgia, which was assessed by the physician as being “possibly related” to the application of the nasal spray.
Two patients were pregnant during application of the isotonic saline nasal spray. Follow-up of the pregnancy, thus monitoring of the health status of the newborn, could be conducted in one case. One case was lost to follow-up. No signals of a negative effect on health of the unborn child after application of the nasal spray to the patients were observed.
4. Discussion
Rhinitis sicca is a chronic inflammatory disease accompanied by dryness and hypotrophy of the nasal mucosa, being frequently further characterised by viscous secretions and the formation of crusts. According to the ICD coding system, rhinitis sicca is coded J31.0. This single code, however, does not represent the various appearances of rhinisis sicca from a patient's perspective. Rhinitis sicca can take different forms, such as rhinitis sicca anterior and primary or secondary atrophic rhinitis. The exact pathophysiology underlying this disease is not understood yet [
. Effective treatment of rhinitis sicca is important, however, since disturbances of the physiologic function of the mucous membrane may - besides quality of life reducing symptoms from the disease itself - pave the way for subsequent upper respiratory tract infections. Severe forms of atrophic rhinitis such as ozena with a foul-smelling mucus that commonly forms a greenish crust might even lead to social isolation of the patients.
Local treatments of dry nose include the application of nasal sprays, nasal rinses, nasal ointments, nasal oils and inhalations. Primary aim of such treatment is the restoration of nasal moistening, the softening of crusts and the regeneration of the nasal mucosa.
In this trial we set out to investigate and to compare the effects of a hyaluronic acid nasal spray, a hyaluronic acid plus dexpanthenol and an isotonic saline nasal sprays in patients suffering from dry nose symptoms. We included patients with various underlying diseases in order to obtain a broad overview on the clinical benefit of the respective nasal spray (refer to Table 2). Indeed, besides numerically dominating indications such as rhinitis sicca anterior or dry nose symptoms due to the intake or application of other medications, as expected, also notable special fields such as dry nose symptoms as consequence of continuous positive airway pressure device applications or extensive nasal douchings were addressed that might warrant further investigations.
Treatment with all test products yielded significant reductions in the primary parameter, Rhinitis Sicca Symptom Score, during the four-week observation period (Fig. 2). Moreover, significant improvements were observed for all single items tested (Table 3), and endoscopic evaluations by the physicians confirmed the clinical improvement of dryness of the nasal mucosa and accompanying symptoms under all treatments (Table 4). The duration of the moistening effect was assessed by most of the patients as lasting longer than 30 min for all treatments (Table 6). Taken together, hyaluronic acid as well as hyaluronic acid plus dexpanthenol and the tested isotonic saline nasal spray fully meet the requirements to fulfill their intended purpose. Similar results were observed in previous investigations on the efficacy of moistening nasal products [
Tolerability and effects on quality of life of liposomal nasal spray treatment compared to nasal ointment containing dexpanthenol or isotonic NaCl spray in patients with rhinitis sicca.
]. We did not observe superiority of any of the three treatments, and also not inferiority of isotonic saline solution, as reported in earlier trials. Only perception of nasal moisturisation during the final evaluation was significantly higher assessed by the patients receiving the hyaluronic acid plus dexpanthenol nasal spray as compared to patients receiving the hyaluronic acid and the isotonic saline nasal spray.
There may be several explanations for this finding. First, the self-limiting course of symptoms must be considered, but taking in account that the majority of indications listed in Table 2 indeed resemble chronic disease states, this potential bias does not appear to be a critical factor. Seasonal and regional factors, thus periods and locations with low and high outdoor absolute humidity, will influence the severity of dry nose symptoms and thereby the outcome of treatments. The randomised design, the inclusion of several study centres throughout Germany and the study conduction over a period of one year should have limited seasonal and regional factors, however. Taking a closer look at the previously performed studies cited above, it becomes apparent that out of these four trials, only Hahn et al. [
Tolerability and effects on quality of life of liposomal nasal spray treatment compared to nasal ointment containing dexpanthenol or isotonic NaCl spray in patients with rhinitis sicca.
] compared the effects of isotonic sodium chloride solutions versus other nasal products. Meanwhile Hahn et al. reported positive results for the saline solution tested, the latter three authors observed poor effects. It thus appears that the chemical composition of “saline solutions” indeed affects the clinical outcome, and that more complex mixtures such as natural seawater or the salt composition used in our trial might have advantageous properties as compared to pure sodium chloride solutions. This hypothesis needs to be proven however, by head-to-head comparisons of different salt solutions. Still physicians should be sensitised that the exact chemical composition of “simple” salt solutions might have impact on the clinical outcome. This should be considered in particular in hypersensitive patients, or when initial treatment approaches fail.
Finally, the study design may be considered as not suitable for the detection of differences between trial arms. The sample size calculation was based on the primary intention to prove efficacy for each product tested, in first instance. On the other hand, differences were observed in comparable patient numbers in the studies cited above, meanwhile results observed in our trial do not indicate clear trends in favor of any of the tested products. Augmenting a baseline/follow-up design with additional visits, or preferentially use of a patient diary, will certainly increase the probability of detection of differences in treatment effects and should be considered in subsequent clinical trials.
Tolerability of all tested products can be assessed as excellent, and only one out of 239 included patients reported about an adverse event.
Taken together, all three tested sprays (hyaluronic acid, hyaluronic acid plus dexpanthenol and isotonic saline) proved to be suitable treatments for patients suffering from dry nose symptoms. Last but not least, patients’ individual preferences should be taken into consideration in order to find the most suitable treatment.
Declaration of Competing Interest
The trial was funded by URSAPHARM Arzneimittel GmbH. Peter Meiser is employed at URSAPHARM Arzneimittel GmbH. The authors have declared that there is no further financial support or relationship that may pose a conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study. Consent from Legally Authorised Representatives was additionally obtained in participants under the age of 18.
Therapy with nasal CPAP (continuous positive airway pressure) in patients with obstructive sleep apnea syndrome (OSAS). II: side-effects of nCPAP therapy. Effect on long-term acceptance.
Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan.
Tolerability and effects on quality of life of liposomal nasal spray treatment compared to nasal ointment containing dexpanthenol or isotonic NaCl spray in patients with rhinitis sicca.
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