TITLE: Comparison of sensory attributes and immediate efficacy of intranasal ciclesonide and fluticasone propionate in allergic rhinitis: A randomized controlled trial

  ABSTRACT.OBJECTIVES:
Intranasal corticosteroids (INCs) are the most effective modality for treating allergic rhinitis and their sensory attributes are important in patient compliance. This study aimed to compare the sensory attributes (scent, immediate taste, aftertaste, run down to throat, nose run off, soothing feel, nasal irritation, and urge to sneeze) and immediate response to the new intranasal steroid, ciclesonide (CIC), with fluticasone propionate (FLP) in allergic rhinitis.

ABSTRACT.MATERIALS AND METHODS:
A randomized, double blind, single dose, crossover study was done with 74 patients presenting with acute allergic rhinitis. Eligible subjects were randomized in 1:1 ratio to one of the two treatment sequences – CIC followed by FLP or vice versa. Sensory attributes were assessed using a questionnaire to score each item on a seven-point Likert scale, immediately and 2 min after dosing. Total nasal symptom score (TNSS) was calculated to evaluate immediate efficacy 10 min after first drug administration. Overall preference was recorded 10 min after the second drug administration. Patients were queried about treatment emergent adverse events following study drug administration and also 24 h later over the phone.

ABSTRACT.RESULTS:
Patients (58% males; pooled median age 32 years [Interquartile range, IQR, 25–41]; pooled median symptom duration 24 months [IQR 12–72]) preferred FLP over CIC nasal spray overall (55.41% vs. 25.68%, P = 0.007) and also with respect to attributes of scent, soothing feel, and nasal irritation. There was no statistically significant difference in immediate efficacy. Two patients reported mild headache following CIC first, while three felt mild headache, one dizziness, and one nasal congestion following FLP first administration. There were no delayed adverse events.

ABSTRACT.CONCLUSIONS:
There was no difference in immediate outcome following use of either of the two INCs. FLP was preferred over CIC with respect to scent, soothing feel and nasal irritation, and also overall. There were no significant adverse events.

BODY.INTRODUCTION:
Allergic rhinitis is an inflammatory disorder of the nasal mucosa induced by allergen exposure triggering IgE-mediated inflammation. Clinically, it is characterized by four major symptoms – rhinorrhea, sneezing, nasal itching, and nasal congestion. Allergic rhinitis is a global health problem. A large section of the Indian population suffers from allergic rhinitis and symptoms can occur in up to 80% of asthmatic adults.[12]  Intranasal corticosteroids (INCs) are recognized to be the most effective treatment modality for allergic rhinitis.[3] However, patient compliance is central to their successful use. Patient preference for a particular INC is largely influenced by the sensory attributes of the nasal spray, which in turn is largely dependent on formulation factors. For instance, preservatives in the spray formulation may produce nasal irritation, reducing tolerability. Other excipients may impart unacceptable taste or odor to the formulation. Further, the relative osmotic pressure or tonicity of the formulation can modulate nasal retention and absorption, thereby potentially influencing clinical efficacy.  Intranasal ciclesonide (CIC) was introduced in the Indian market in 2008. Since sensory attributes of INCs play an important role in their acceptance and therapeutic compliance,[4] we aimed to assess the sensory attributes along with the immediate efficacy of ciclesonide in comparison to intranasal fluticasone propionate (FLP) that is being used for a longer time in India.

BODY.MATERIALS AND METHODS:
We conducted a randomized, double blind, single dose, crossover study at the Otorhinolaryngology out-patient department of Institute of Postgraduate Medical Education and Research (IPGME&R) and SSKM Hospital, Kolkata, India, between December 2009 and May 2010. Prior to study initiation, the protocol and informed consent documents were approved by the institutional Ethics Committee.  All participants (12 years or above in age) had symptoms of allergic rhinitis for at least 1 year and presented with a total nasal symptom score (TNSS) of six or more plus an individual score of 2 or more for rhinorrhea or nasal congestion. Patients were excluded if they provided history of other nasal pathology (including polyps or respiratory tract malformations), recent nasal biopsy, nasal trauma or surgery, atrophic rhinitis, or rhinitis medicamentosa within last 60 days prior to screening; history of respiratory infections within last 14 days; and use of intranasal/oral corticosteroids, antihistamines, nasal decongestants, or other drugs used for rhinitis within last 7 days. Also excluded were expectant and nursing mothers and subjects with a history of smoking and/or substance abuse. Written informed consent was obtained from each study participant. In the case of enrolled adolescent subjects (between 12 – 18 years), consent was provided by the legal guardian while they themselves provided assent.  The trial comprised a pretreatment screening period to verify inclusion and exclusion criteria, two single-dose treatments separated by 30 min, and a final follow-up over phone after another 24 h. Eligible patients were randomized in 1:1 ratio (simple randomization using a computer generated list) to one of two treatment sequences - aqueous suspension of FLP for intranasal administration (trade name: FLUTICONE, marketed by German Remedies, Mumbai, India) administered as two sprays in each nostril, total dose 200 mcg; followed by aqueous suspension of CIC (trade name: CINASE, marketed by German Remedies, Mumbai, India) administered as two sprays in each nostril, total dose 200 mcg; or the reverse sequence. A 30 min interval was kept between the two treatments. The dosing scheme is shown in Figure 1.  Figure 1Sequence of study drug administration and related assessments. (CIC – ciclesonide, FLP – fluticasone)  Ten minutes before receiving the study drug, participants cleansed their mouth by eating one unsalted biscuit and taking several swallows of water at room temperature. To cleanse the nasal passages of any secretions, they were required to sniff a wool swatch. This washout protocol was repeated before the cross-over drug administration.  To ensure blinding, patients were blindfolded during product administration. In addition, the spray formulation labels were masked, they were coded as A or B, and administered under the supervision of an investigator who was not involved in generation of the randomization sequence. The code to be used first (A or B) was concealed in opaque serially numbered envelopes and revealed just prior to drug use. Thus, both patients and interviewing investigators remained unaware of study drug identity during administration as well as evaluation.  Following each treatment, patients rated seven sensory attributes – scent, immediate taste, aftertaste, run down into the throat, run off from nose, soothing feel, sneezing urge, and nasal irritation – immediately and after 2 min. These were recorded through 13 questions, response to each was rated on a 7-point Likert scale (score 0–6, where 0 denoted absence or most positive response, 6 denoted most negative response, and 3 represented a neutral, i.e., neither positive nor negative response). This questionnaire [Table 1] was adapted from previous studies comparing sensory attributes of INCs.[4–7] Immediate efficacy of treatment was assessed by TNSS that rates each of five items – rhinorrhea, nasal congestion, sneezing, nasal itching, and ocular itching – on a scale of 0 to 3 [0: absent, 1: mild, 2: moderate, and 3: severe]. This was recorded before and 10 min after first drug-administration. Lastly patients were asked about overall preference, 10 min after the second drug administration.   Table 1 The sensory attributes questionnaire   For safety assessment, physical examination was conducted and vital signs (pulse, blood pressure, and breathing rate) were measured at screening and 30 min following study drug administration. Treatment emergent adverse events were captured by careful history taking and clinical examination. A follow-up assessment was conducted 24 h later over phone for delayed adverse events. The safety population was defined as all patients who received at least one actuation of the study spray formulations.

BODY.MATERIALS AND METHODS.SAMPLE SIZE AND STATISTICAL ANALYSIS:
It was calculated that 37 subjects would be required per group for the study to achieve 80% power, at 5% probability of type I error, in detecting a difference of 1 in TNSS following study drug administration. This calculation assumed a pooled standard deviation of 1.5 for TNSS. Numerical variables were compared between the two arms by Mann–Whitney U test. Individual sensory attributes were summarized as the proportion of subjects experiencing or expressing satisfaction with respect to that attribute. Independent proportions were compared between groups by Chi-Square test or Fisher's exact test as appropriate. Paired proportions were compared by McNemar's Chi-square test. Two tailed P-value <0.01 was considered to be statistically significant. Statistica version 6 (Tulsa, Oklahoma: Stat Soft Inc., 2001) software was used for analysis.

BODY.RESULTS:
Ninety subjects were screened, of whom 74 (82.22%) satisfied the selection criteria and consented to participate. There were no dropouts.  The median (interquartile range) age of the participants who received CIC first was 32 (23–42) years while the median symptom duration was 24 (12–72) months. The corresponding figures for the arm receiving FLP first was 32 (28–39) years for age, and 24 (12–84) months for symptom duration. There were 22 (59.46%) and 21 (56.76%) males, respectively, in the two arms. These differences were not statistically significant. The pooled figures for the two arms were 58% males; median age 32 (25–41) years and median symptom duration 24 (12–72) months. The predominant presenting symptoms were rhinorrhea, nasal congestion, and sneezing.  Regarding sensory attributes, patient ratings favored FLP over CIC with respect to satisfying scent, soothing feel and nasal irritation. Thirty seven (50%) patients preferred FLP compared to 6 (8.11%) preferring CIC with regards to satisfying scent (P < 0.001); 42 (56.76%) reported FLP to provide a more soothing feel compared to 15 (20.27%) preferring CIC in this regard (P < 0.001). Only 1 (1.35%) patient reported nasal irritation following FLP administration, in contrast to 21 (28.38%) following ciclesonide use (P = 0.002). Although, only one patient (1.35%) had urge to sneeze following FLP use, compared to 10 following CIC (13.51%), this difference was not statistically significant. The number reporting immediate taste, aftertaste, run down to throat and run off from nose were less with CIC compared to FLP, but these differences were also insignificant statistically. Figure 2 depicts the paired comparisons with regards to the individual sensory attributes.  Figure 2Comparison of sensory attributes irrespective of the sequence of administration. No. of subjects have been shown (n = 74). Difference with respect to scent, soothing feel and nasal irritation are statistically significant (McNemar's Chi-square test)  Regarding immediate efficacy, both CIC and FLP decreased TNSS compared to baseline, as well as individual symptom scores in majority of the subjects, within 10 min of administration. The median (interquartile range) TNSS declined from 8 (7–9) at baseline to 3 (2–4) after drug administration in subjects receiving ciclesonide first. In the fluticasone first arm, the corresponding decline was from 8 (6–10) to 2 (2–4). This difference was not statistically significant. Differences were also not significant when the proportions reporting decrease in individual symptom scores, rather than total score, were compared [Figure 3].  Figure 3Comparison of number of subjects (n = 37 for each treatment sequence group) reporting reduction in intensity of symptoms compared to baseline. The differences are not signifi cant statistically (Fisher's exact test)  Overall, out of 74 subjects, irrespective of sequence of administration, 41 (55.41%) preferred FLP, while 19 (25.68%) preferred CIC. The rest had no selective preference. This difference was statistically significant (P = 0.007).  The overall incidence of adverse events during treatment was 9.46% (7/74). This count excludes events like nasal irritation that are already covered under sensory attributes assessment. Two patients reported minor headache following CIC first, while three felt minor headache, one dizziness, and one nasal congestion following FLP first administration. No delayed adverse events were reported at the 24 h follow-up interview conducted over the phone. There were no adverse events that inconvenienced a subject to more than a mild degree.

BODY.DISCUSSION:
Allergic rhinitis is a common atopic condition of the nasal mucosa affecting a large number of Indians. The effect of rhinitis on the quality of life is remarkable. Standardized quality of life measures indicate that over 60% of allergic rhinitis patients are perturbed while symptomatic. Allergic rhinitis typically presents at a younger age[8] – the pooled median age in our study was 32 years. In a large survey of allergic rhinitis sufferers, participants reported nasal congestion as the most bothersome complaint.[9] This was also applicable and true in our study subjects.  Intranasal corticosteroids are now the mainstay in treatment of allergic rhinitis.[10] This study was designed to assess overall preference based on patients' perceptions of the sensory attributes related to intranasal steroid use and the immediate efficacy of the steroid. We have not found any study comparing sensory attributes and immediate efficacy of intranasal ciclesonide and fluticasone propionate. In our study both drugs were delivered as aqueous nasal spray formulation that allows better dispersal and is considered to be less irritating to the nasal mucosa.  Although the full effects of INCs take several hours to develop, their role in the inflammatory process suggests that onset of action would be rapid and possibly within minutes. It is reported that histamine levels in nasal secretion lavage fluid of allergic rhinitis patients can be counteracted within 30 min by intranasal administration of mometasone furoate.[8] This prompted us to undertake assessment of immediate efficacy of the study drugs, although this will not be the full or maximum effect on symptom scores.  The results suggest that subjects favor fluticasone over ciclesonide with respect to scent, soothing feel, and less nasal irritation. There were no statistically significant differences between the two drugs for other sensory attributes either immediately or 2 min after dosing. Previous studies with nasal steroids have reported that patients usually prefer scentless and tasteless preparations but in our study patients preferred fluticasone that has a mild fruity odor, while ciclesonide has no odor but evokes a more irritating sensation in the nasal mucosa. Although the immediate efficacy of the two drugs was comparable, the differences in sensory attributes probably led to the greater preference for fluticasone over ciclesonide. The tolerability of both preparations was good and therefore this probably has not contributed to the difference in preference.  Fluticasone did, however, produce taste, aftertaste, run down into throat, and run out from nose with greater frequency than ciclesonide, although differences were not statistically significant. In a previous study, comparing sensory attributes of fluticasone with budesonide in allergic rhinitis patients, a significantly greater number of subjects associated scent, taste, aftertaste and run down into throat with fluticasone.[11] Ciclesonide is used as a hypotonic solution that allows more diffusion in the nasal mucosa resulting in less nose run-off and less dripping down the throat.[12] Fluticasone, on the other hand, is used as an isotonic solution that produces more nose runoff and more dripping down the throat due to less absorption through nasal mucosa.[13]  Formulation composition is important for intranasal corticosteroid preparations.[1314] Nasal sprays contain preservatives like benzalkonium chloride (BKC). The effects of such preservatives on the nasal mucosa have not been clearly defined, although benzalkonium chloride (0.05%) has been reported to produce a consistent and significant increase in nasal irritation, burning sensation, and nasal hypersecretion immediately after administration.[15] In our study, the fluticasone nasal spray, despite having 0.02% benzalkonium chloride, did not produce an appreciable nasal irritation in majority of the patients.  It should be pointed out that compliance cannot be postulated on the basis of a single-dose study.[5] However, previous studies have reported that sensory attributes have important role in deciding patient compliance with INC therapy. When drugs within a given treatment class have similar efficacy and safety profiles, other characteristics (e.g., sensory attributes for INCs) can play a central role in product acceptance. Optimization of product formulation to meet the sensory preferences may further increase the patient adherence to INCs.[16]  The study had some limitations. Exposure to any prohibited medication prior to recruitment was assessed only through the information volunteered by the subjects without insisting on detailed medical records. The sensory attributes questionnaire was adopted from those used in previous studies without separate validation. Patient preference seen in this single dose study, potentially may not match that following repeated use. Finally, the categorical rating with respect to both this questionnaire and the nasal symptom scoring is open to some subjective bias.

BODY.CONCLUSIONS:
Sensory attributes are potentially important in evaluation of intranasal products for allergic rhinitis. As newer intranasal corticosteroids are introduced, product attributes and immediate efficacy may decide the patient preference and adherence to therapy and thereby reflect on treatment outcome. In this study, although their immediate efficacy and tolerability were comparable, an overall patient preference was for fluticasone propionate formulation rather than ciclesonide. The former was also preferred over ciclesonide with respect to the sensory attributes of scent, soothing feel, and less nasal irritation. Comparing efficacy, tolerability, and acceptability with respect to various sensory attributes on continued or repeated use deserves further exploration.

Question: Compared to Fluticasone propionate (FLP) what was the result of Ciclesonide (CIC) on Preferred intranasal corticosteroid?
Evidence: There was no statistically significant difference in immediate efficacy.
Answer: significantly decreased