A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology

doi:10.1016/S0091-6749(05)80069-7

Journal of Allergy and Clinical Immunology

Volume 86, Issue 2, August 1990, Pages 221-230

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https://doi.org/10.1016/S0091-6749(05)80069-7 Get rights and content

Fluticasone propionate is a new glucocorticosteroid with potent topical activity. In a double-blind, randomized, parallel-group study, 423 adult patients with moderate to severe seasonal allergic rhinitis received placebo or fluticasone propionate aqueous nasal spray at doses of 25, 100, or 400 μg twice daily (b.i.d.) for 2 weeks. Efficacy was evaluated by nasal symptom scores, nasal airflow, nasal cytology, and global evaluation. All doses of fluticasone propionate were significantly better than placebo in reducing symptoms of seasonal allergic rhinitis. Patients receiving the largest dose of fluticasone propionate (400 μg b.i.d.) had a slightly greater reduction (not significant) in symptom scores than patients receiving the smallest dose (25 μg b.i.d.). Symptom improvement was evident within 3 days of treatment. Nasal airflow improved in the groups treated with fluticasone propionate, 100 and 400 μg b.i.d. Examination of nasal cytograms revealed a striking decrease in both eosinophils and basophils in all three groups receiving active treatment compared with placebo. There were few adverse events and no treatment-related abnormalities in laboratory assays or evaluations of hypothalamo-pituitary-adrenocortical axis function. Comparison of treatment groups indicated that fluticasone propionate aqueous nasal spray was as safe as placebo at the doses studied.

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Efficacy of EDS-FLU for Chronic Rhinosinusitis: Two Randomized Controlled Trials (ReOpen1 and ReOpen2)
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Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration–approved for the most common form, CRS without nasal polyps (also called “chronic sinusitis”). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays.
Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps).
Two randomized, EDS-placebo–controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week 24.
ReOpen1 (N = 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was −1.58 and −1.60 versus −0.62 (P < .001, P < .001); ReOpen2 (N = 223), −1.54 and −1.74 versus −0.81 (P = .011, P = .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was −5.58 and −6.20 versus −1.60 (P = .045, P = .018), and in ReOpen2, −7.00 and −5.14 versus +1.19 (P < .001, P = .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P = .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverse events were similar to standard-delivery intranasal steroids.
EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.
Safety of intranasal corticosteroids
2016, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
For fluticasone propionate, results are mixed. In a study of 423 adult patients with moderate to severe seasonal allergic rhinitis, there was no evidence that fluticasone propionate (25, 100, or 400 μg taken twice daily for 2 weeks) suppressed the HPA axis.19 Similarly, there was no evidence that fluticasone propionate (100 μg or 200 μg taken daily for 2 weeks) suppressed the HPA axis in 250 children aged 4 to 11 years with seasonal allergic rhinitis.20
Concurrent use of intranasal corticosteroids (INCSs) and inhaled corticosteroids (ICSs) is indicated for patients who are comorbid for asthma and allergic rhinitis. Clinicians need to know the data regarding INCS safety for their patients with asthma.
To discuss INCS safety data for the use of INCSs in patients with asthma and allergic rhinitis.
INCS safety studies were selected for their relevance to the discussion.
To date, most studies regarding INCS safety are performed in patients with allergic rhinitis. These studies reveal no evidence of increased risk of nasal atrophy, and only isolated cases of septal perforation have been reported. Evidence of hypothalamic-pituitary-adrenal axis suppression is inconsistent and not clinically significant. Early growth studies indicated that beclomethasone dipropionate but not other INCSs have systemic effects on growth; however, newer, larger, and better designed studies are detecting small but significant growth effects in other INCSs. INCSs do not increase the risk of cataracts or glaucoma, although there are anecdotal data on transient elevated intraocular pressure. Data on concurrent use of INCSs and ICSs are limited, but these limited data reveal no evidence of systemic effects on the hypothalamic-pituitary-adrenal axis.
More studies of concurrent therapy are needed because concurrent use of ICSs and INCSs is common in practice. Clinicians might want to consider monitoring whether there are risk factors, such as a family history of glaucoma.
Efficacy of the oral chemoattractant receptor homologous molecule on T <inf>H</inf>2 cells antagonist BI 671800 in patients with seasonal allergic rhinitis
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Citation Excerpt :
Clinical efficacy was not proved for the 50-mg twice-daily and 400-mg twice-daily doses, although this trial was not designed or powered to assess a formal dose response for BI 671800. The absence of greater activity at the highest investigational dose studied has been noted in other AR studies considering nasal steroids21,22 and might represent variability because of lack of power to assess the dose response or a plateau of the effect at higher doses. Although a false-positive finding with 200 mg of BI 671800 twice daily cannot be excluded, it is less likely because significant changes were detected in symptom scores and in biomarkers in parallel in this dose group only.
The inflammatory response in patients with seasonal allergic rhinitis (SAR) is partly mediated by the prostaglandin D₂ receptor chemoattractant receptor homologous molecule on T_H2 cells (CRTH2).
We sought to investigate the efficacy and safety of the oral CRTH2 antagonist BI 671800 (50, 200, and 400 mg twice daily), fluticasone propionate nasal spray (200 μg once daily), or oral montelukast (10 mg once daily) administered for 2 weeks in patients with SAR.
In this randomized, double-blind, placebo-controlled, partial-crossover study, participants aged 18 to 65 years with a positive skin prick test to Dactylis glomerata pollen were exposed to out-of-season allergen in the environmental challenge chamber for 6 hours. The primary efficacy variable was the total nasal symptom score assessed as the area under the curve (AUC)_0-6h.
In total, 146 patients (63.7% male; mean age, 36.1 years) were randomized. The adjusted mean total nasal symptom score AUC_0-6h was significantly reduced versus placebo with 200 mg of BI 671800 (absolute difference, −0.85; percentage difference, −17%; P = .0026), montelukast (absolute difference, −0.74; percentage difference, −15%; P = .0115), and fluticasone propionate (absolute difference, −1.64; percentage difference, −33%; P < .0001). Compared with placebo, BI 671800 significantly reduced nasal eosinophil values (P < .05 for all doses), significantly inhibited nasal inflammatory cytokine levels (IL-4 and eotaxin, P < .05; 200 mg twice daily), and induced a dose-related reduction in ex vivo prostaglandin D₂–mediated eosinophil shape change.
Two hundred milligrams of BI 671800 twice daily demonstrated efficacy in treating SAR symptoms induced by environmental challenge chamber allergen exposure and had a favorable safety profile.
International Primary Care Respiratory Group (IPCRG) Guidelines: Management of allergic rhinitis
2006, Primary Care Respiratory Journal
The association between the upper and lower airways has been recognised for almost 2000 years. Epidemiological data suggest that most asthma patients also suffer from allergic rhinitis, and that both diseases share similar trigger factors and pathophysiology. This IPCRG Guideline on the management of rhinitis in primary care is fully consistent with the ARIA guidelines. It highlights the treatment goals and the classification of the condition according to symptom frequency (intermittent or persistent) and severity (mild or moderate-severe). It covers the need for allergen avoidance, pharmacologic therapy including immunotherapy, alternative therapies, management of ocular symptoms, the management of co-existing allergic rhinitis and asthma, and the need for follow-up and ongoing care for patients with rhinitis.
Clinical outcomes and adverse effect monitoring in allergic rhinitis
2005, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Several different outcome measures have been used to assess the clinical status of the nose. These measures include indices such as nasal symptom severity, as discussed, as well as objective measures relating to specific aspects of nasal function and status, including rhinomanometry, nasal cytology, and nasal hyperreactivity.7,8 These measures are important in providing detailed information about specific aspects of the nose itself but do not provide an estimate of the impact on patients' daily functioning, and as such, at best there are only weak to moderate correlations between conventional clinical markers of nasal inflammation and the patient's rhinitis-specific QOL.4,8
The subjective recording in diary cards of symptoms of itch, sneeze, nose running, and blockage, with the use of a rating scale to indicate the level of severity, is usual for clinical trials in allergic rhinitis. The primary outcome measure is usually a composite score that enables a single total symptoms score endpoint. It is appreciated, however, that rhinitis has a greater effect on the individual than is reflected purely by the recording of anterior nasal symptoms. Nasal obstruction is troublesome and may lead to sleep disturbance in addition to impaired daytime concentration and daytime sleepiness. These impairments affect school and work performance. Individuals with rhinitis find it socially embarrassing to be seen sneezing, sniffing, or blowing their nose. To capture these and other aspects of the disease-specific health-related quality of life, questionnaires such as the Rhinoconjunctivitis Quality of Life Questionnaire have been developed and validated for clinical trial use. The adoption of health-related quality of life questionnaires into clinical trials broadens the information obtained regarding the effect of the therapeutic intervention and helps focus on issues relevant to the individual patient. It must be appreciated that it is not only the disease that may adversely affect health-related quality of life; administered therapy, although intended to be beneficial, may also cause health impairment. Adverse-event monitoring is thus essential in clinical trials.
The first-generation H₁-histamines, because of their effect on central H₁-receptors, are classically associated with central nervous system (CNS) effects such as sedation. Although this is not always perceived by the patient, it is clearly evident with objective performance testing, and positron emission tomography scanning has directly demonstrated the central H₁-receptor occupancy. The second-generation H₁-antihistamines have reduced central H₁-receptor occupancy and considerably reduced or absent CNS sedative effects. Therefore, the CNS effects are entirely avoidable, and the first-generation H₁-antihistamines should no longer be used in the management of allergic rhinitis. The considerably rarer but potentially very serious cardiac arrhythmogenic effects of H₁-antihistamines are appreciated to be molecule-specific rather than class-specific. The in vitro screening of new compounds to eliminate the further development of those with cardiotoxicity ideally will lead to this adverse effect being historic. The incorporation of electrocardiogram recording in clinical trials provides direct information relating to prolongation of QT interval corrected for heart rate.
Although administered at low doses, intranasal steroids still have the potential for systemic absorption and adverse consequences. However, it is appreciated that meaningful differences exist in the bioavailability of different steroid molecules, and although a small but statistically significant effect on growth in children has been identified with the long-term use of intranasal beclomethasone when administered twice daily for 1 year, this is not evident with all intranasal steroids. In addition, twice-daily intranasal steroid administration may have more effect—from the endocrinologic perspective—than once-daily administration in the morning, which coincides better with the natural diurnal variation in cortisol. Thus, once-daily intranasal steroid administration is preferable, and when used in studies in children, measurement of height change during the study period is an important outcome variable together with other indices of systemic steroid bioavailability (eg, tests of hypothalamic-pituitary-adrenal axis function). These considerations have even greater relevance if children are concurrently also receiving inhaled steroids for asthma, because the total steroid load will be greater.
Objective monitoring of nasal airway inflammation in rhinitis
2005, Journal of Allergy and Clinical Immunology
Citation Excerpt :
In a prospective study of infants with a strong family history of allergic disease, it has been shown that both eosinophils and basophilic cells increase in number in nasal scrapings of allergic children between birth and 4 years of age but are uncommon in children with no allergic disease.92 In adults with SAR, using the Rhino-probe scraping technique, the following cytologic patterns have been reported: eosinophils in 81%, basophilic cells in 42%, neutrophils in 64%, and bacteria in 28% of those with at least a 1+ grading.93 The frequency of neutrophil-positive and bacteria-positive specimens in patients with allergy is noteworthy.
Allergic rhinitis is an inflammatory nasal disorder in which a range of different cells participates. A variety of approaches has been used to monitor nasal inflammation objectively to investigate disease processes and to evaluate the effect of therapeutic intervention. These approaches include nasal lavage, nasal cytology, and nasal biopsy, together with the more recently established measurement of nasal nitric oxide (NO) concentration. Although all provide information about nasal mucosal inflammation, the extent of information that can be obtained by each approach, the ease of sampling, and the complexity of sample handling differ. Such considerations influence the choice of approach when measurement of nasal inflammation is to be an objective outcome parameter in a clinical trial. In addition, the choice of approach is also determined by the questions or hypotheses that are to be addressed.
Nasal lavage is simple and rapid to perform, is well tolerated, and provides a sample that can provide information about luminal cell recruitment, cell activation, and plasma protein extravasation. Nasal cytology involves sampling and recovering mucosal surface cells. It is also easy to perform and is well tolerated in general, although some find that the procedure causes a transient unpleasant sensation. A differential cell count from the sample provides information about relative cell populations. Both nasal lavage and nasal cytology are readily applicable to clinical trials. Nasal cytology sample handling is easier, but nasal lavage offers the advantage of providing considerably greater information from the sample.
Nasal biopsy is a considerably more invasive procedure and requires expertise not only in tissue sampling but also in biopsy processing. Therefore, it is applicable only in specialist centers. However, nasal biopsy is the only sampling technique that directly informs about tissue cellular events, although these may be implied, in part from the other sampling approaches. Tissue specimens can be used to evaluate both protein and gene expression.
Measurement of nasal NO involves expensive equipment but provides an instantaneous result, unlike the other approaches, all of which require sample processing and analysis. Recommendations for standardization of measurement have been made, and measures are considered in part to reflect allergic inflammation within the nasal mucosa. The limitations of nasal NO are that it reflects only a certain aspect of allergic mucosal inflammation, and that because a proportion of nasally measured NO is derived from the sinuses under normal circumstances, nasal NO is not specific for nasal disease. The high contribution from the sinus mucosa limits the discriminatory ability of nasal NO to reflect nasal tissue–specific alterations.
The incorporation of measures of nasal inflammation in clinical trials has distinguished anti-inflammatory therapy from symptomatic therapy and has the potential to provide information about the efficacy of novel therapies for allergic rhinitis.

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^*: Supported in part by Glaxo, Inc., Research Triangle Park, N.C. Presented in part at the Annual Meeting of the American Academy of Allergy and Immunology, San Antonio, Texas, Feb. 24–March 1, 1989.

¹: From the Allergy and Asthma Medical Group and Research Center, San Diego, Calif.

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A dose-ranging study of fluticasone propionate aqueous nasal spray for seasonal allergic rhinitis assessed by symptoms, rhinomanometry, and nasal cytology*

Immunol Allergy Clin North Am

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Topical steroid treatment for allergic rhinitis and allied conditions

Clin Otolaryngol

A dose-tolerance study of intranasal fluticasone propionate aqueous nasal spray in the treatment of seasonal allergic rhinitis

J Allergy Clin Immunol

Rhinomanometry: measurement of nasal patency

Ann Allergy

Nasal cytology in clinical practice

Am J Rhinol

Treatment of seasonal allergic rhinitis with triamcinolone acetonide nasal aerosol

Ann Allergy