Disodium Cromoglycate

Efficacy, cost-effectiveness, and tolerability of mometasone furoate, levocabastine, and disodium cromoglycate nasal sprays in the treatment of seasonal allergic rhinitis

Background: Current guidelines recommend intranasal glucocorticosteroids as first-line therapy for seasonal allergic rhinitis.
Objective: To compare the efficacy, cost-effectiveness, and tolerability of the topical glucocorticosteroid mometasone furoate, the topical antihistamine levocabastine hydrochloride, and the cromone disodium cromoglycate in seasonal allergic rhinitis.

Methods: This study was performed during the 2003 grass pollen season as an open, randomized, parallel-group, single-center study of 123 patients assigned to receive mometasone furoate (200 µg once daily), levocabastine hydrochloride (200 µg twice daily), or disodium cromoglycate (5.6 mg 4 times daily). Symptom scores and nasal inspiratory peak flow measurements were recorded in a patient diary. The global efficacy of the study medication was evaluated by patients after treatment. Eosinophil cationic protein concentrations were measured in nasal secretions before and after treatment. Cost-effectiveness was evaluated as medication cost per treatment success.

Results: Mometasone furoate therapy was significantly superior to the use of levocabastine or disodium cromoglycate with respect to all nasal symptoms, the global evaluation of efficacy, and eosinophil cationic protein concentration. Furthermore, mometasone furoate therapy was significantly superior to disodium cromoglycate therapy with respect to nasal inspiratory peak flow. Medication cost per treatment success was lowest with mometasone furoate use and highest with levocabastine use.

Conclusion: This is the first study to compare mometasone furoate nasal spray with nonsteroidal topical treatments for seasonal allergic rhinitis. Mometasone furoate nasal spray was confirmed as a first-choice topical treatment option for seasonal allergic rhinitis.

INTRODUCTION

Allergic rhinitis (AR) is the most common atopic disease, with a worldwide prevalence of up to 40%.1 It has an inflam- matory pathogenesis that involves the liberation of mast cell mediators after an allergenic stimulus, liberation of proin- flammatory TH2-associated cytokines and chemokines, mu- cosal infiltration with inflammatory cells, and up-regulation of specific IgE production and IgE receptors.

Systemic interactions with the immune system and the bone marrow mediated via cytokines are assumed to play a role in the development of asthma.2 This inflammatory patho- genesis provides the rationale for an anti-inflammatory treat- ment of AR. Among the treatment options for AR, intranasal glucocorticosteroids show the broadest anti-inflammatory effects and the greatest clinical efficacy. Systematic reviews with meta-analyses have shown that intranasal glucocortico- steroids are more effective in AR than are oral3 and intrana- sal4,5 antihistamines and intranasal cromones.4 Furthermore, it has been shown that intranasal glucocorticosteroids are more cost-effective than oral antihistamines in the United States.6,7 Accordingly, the guidelines of Allergic Rhinitis and its Impact on Asthma1 and the European Academy of Allergol- ogy and Clinical Immunology8 recommend topical glucocor- ticosteroids as first-line therapy for patients with AR who have moderate-to-severe or long-lasting symptoms. In Ger- many, however, these recommendations are not reflected in prescription data. Topical glucocorticosteroids are underrep- resented in prescriptions for seasonal AR (SAR). They do not match the prescription volume of oral antihistamines and are not prescribed more frequently than the other topical medi- cations. Indeed, in Germany during 2003, topical glucocorti- costeroids were prescribed approximately as frequently as cromones, with intranasal glucocorticosteroids comprising 10.3% of all SAR prescriptions and disodium cromoglycate comprising 13.2%.

These data are surprising because, according to a multina- tional European study,9 85% of patients who consulted their general practitioner because of SAR had moderate-to-severs SAR according to Allergic Rhinitis and its Impact on Asthma guidelines (and hence could be treated with topical glucocor- ticosteroids as a first-line therapy). Reasons for this discrep- ancy may include the overestimation of adverse reactions associated with intranasal glucocorticosteroids, the underes- timation of their efficacy relative to other treatment options, or incorrect perceptions with respect to cost.

Reliable ranking of relative cost-effectiveness can only be determined using data from clinical studies. Currently, stud- ies that compare mometasone furoate with nonsteroidal top- ical AR medications are lacking. This study was designed to compare the efficacy, cost-effectiveness, and safety of the topical nasal glucocorticosteroid mometasone furoate, the topical nasal antihistamine levocabastine hydrochloride, and the nasal cromone disodium cromoglycate in a randomized, parallel-group trial in patients with SAR. The selected drugs are the most frequently prescribed representatives of their respective classes in Germany.

METHODS

This study was performed between May 15, 2003, and July 1, 2003, at the Institut fu¨r Atemwegsforschung GmbH in Du¨s- seldorf, Germany, and was approved by the ethics committee of the Physicians Chamber of Nordrhein, Du¨sseldorf, Ger- many. The study was performed in accordance with German Drug Law, the Declaration of Helsinki (Edinburgh 2000), and the International Conference on Harmonisation Guidance for Good Clinical Practice. All the patients gave written in- formed consent before any study-related procedures com- menced.

Study Design and Patients

This was an open, randomized, single-center study with 3 parallel groups. For technical reasons (different application frequencies, number of sprays per application, spray vol- umes, formulations, and smells or tastes and overall spray volumes that would have been too high in a triple-dummy design), a masked design was not feasible. After a 4- to 14-day run-in period (at the end of May 2003), patients
received mometasone furoate (200 µg once daily), levoca- bastine hydrochloride (200 µg twice daily), or disodium cromoglycate (5.6 mg 4 times daily) nasal spray for 28 ± 3 days (during June 2003, covering the relevant grass pollen season in the region according to historical pollen counts). The selected dosages were those approved and recommended for adults.

Data regarding airborne grass pollen load were provided by the Stiftung Deutscher Polleninformationsdienst, Bad Lipp- springe, Germany. Pollen was collected using a Burkhard pollen trap at the sampling station nearest to the study site (Mo¨nchengladbach, Germany).
Patients were chronologically randomly allocated in a 1:1:1 ratio to the 3 treatment groups following a randomiza- tion list not accessible to the investigators. Closed medication boxes were indistinguishable, and their dispensing was organized in a way that the contents became apparent to investi- gators only after documentation of the assignment to each patient. Nedocromil eyedrops were provided as rescue med- ication. No further antiallergy and intranasal medications were allowed during the study. Patients visited the study center 4 times: at the beginning of the run-in period, at the beginning of the treatment period, after 1 week of treatment, and after 4 weeks of treatment. One week after the end of treatment, a final telephone conversation took place to iden- tify any further adverse events (AEs) (defined as any unto- ward medical events different from the condition studied and beginning after the end of the run-in period) and to follow up any existing AEs.

To be eligible for study inclusion, patients had to be aged 18 to 65 years with at least a 2-year history of moderate-to- severe SAR caused by grass pollen. Further criteria included positive skin prick test reactions (wheal diameter ≥3 mm larger than with saline) or radioallergosorbent test findings of class 2 or greater to grass pollen. Female patients of child- bearing potential had to use an acceptable method of contra- ception (hormonal, intrauterine device, or double-barrier method).

The exclusion criteria consisted of a history of hypersen- sitivity to any of the study drugs, lack of adherence to washout periods for antiallergy medications,10 and long-term therapy with nonsteroidal anti-inflammatory drugs or tricy- clic antidepressants. Further exclusion criteria were upper respiratory tract infection, acute or chronic sinusitis, rhinitis medicamentosa, nasal polyps, clinically relevant deviations of the nasal septum, active or inactive tuberculosis of the airways, asthma other than mild intermittent asthma treated
with short-acting β2-agonists on an “as-needed” basis, nasal or paranasal surgery in the previous 6 months, ocular herpes
simplex, cataract, history of glaucoma, any untreated infec- tion, and skin diseases requiring treatment with oral glucocor- ticosteroids or antihistamines currently or in the past.

Efficacy, Cost-effectiveness, and Safety Assessments

During the run-in and treatment periods, in the morning and in the evening patients evaluated and recorded in patient diaries the severity of the nasal symptoms obstruction, rhi- norrhea, sneezing, and itching and the severity of eye com- plaints on a 4-point scale (0 = absent to 3 = severe) for the previous 12 hours. Each morning and each evening the pa- tients performed 3 measurements of nasal peak inspiratory flow rate (nPIFR) using a peak inspiratory flow meter (In- check; Clement Clarke International Ltd, Harlow, England) and documented the results in their diaries. The nPIFR de- pends on nasal patency and nasal obstruction and has been shown to correlate with nasal symptoms and to significantly improve with treatment of AR.11 The consumption of rescue medication (nedocromil eyedrops) was determined by weigh- ing the bottles at dispensation and return.

At the end of the 4-week treatment period, patients eval- uated the global efficacy of the study medication on a 4-point scale (1 indicates very good; 2, good; 3, slight; and 4, insufficient). Nasal secretion samples were collected from the patients before and after treatment using the paper-disc meth- od.12 Eosinophil cationic protein (ECP) levels in nasal secre- tions were measured in duplicate as a marker of nasal inflam- mation using the UniCAP system (Pharmacia, Uppsala, Sweden) in the laboratory of the Ear, Nose, and Throat Department of the University of Ghent. For specimens with ECP concentrations below the detection limit of 2 µg/L, half of the detection limit (1 µg/L) was inserted as the value included for analysis.

Daily medication costs were calculated from mean phar- macy prices of available packages, as given in the Rote Liste 2003 (the German equivalent of the US Physician’s Desk Reference), and the dosage regimens applied in the study. Tolerability of the study medication was evaluated by docu- mentation of AEs and physical examination at visits 1 and 4 and by rhinoscopy and vital signs at each visit.

End Points, Statistical Analysis, and Sample Size

The total nasal symptom score (TNSS) was defined as the mean of the scores of the single nasal symptoms (obstruction, rhinorrhea, sneezing, and nasal itching). The total symptom score (TSS) was defined as the mean of the scores of the single nasal symptoms and eye complaints. Efficacy end points for group comparison were the average daytime (cal- culated from evening entries), nighttime (calculated from morning entries), and all-day (ie, mean of morning and evening entries) TNSSs, TSSs, and single symptom scores during a 23-day period when all patients received treatment and were exposed to the same pollen load conditions. The comparison of the average all-day TNSSs of the mometasone furoate and disodium cromoglycate groups was defined as the primary end point.

Additional efficacy end points were the average proportion of symptom-free days (ie, all diary entries = 0 for nasal and all symptoms); the average use of rescue medication (nedocromil eyedrops); the number of patients evaluating the global efficacy of the study medication as “very good,” “good,” “slight,” or “insufficient”; and the mean difference in ECP concentrations of nasal secretions obtained before and after treatment. Of the 3 measurements of nPIFR performed every morning and evening, the lowest daily values of the morning maximum and evening maximum were averaged across time.

Homogeneity between groups before treatment was de- scriptively evaluated using y2 or Mann-Whitney U tests at α = .10. During and after treatment, data were compared using pairwise y2 tests (global efficacy) or Mann-Whitney U tests (all other end points). The primary end point was subject to confirmatory analysis. With a significance level of P = .05 and an SD of 0.6 (maximum SD observed at the study site for the primary end point in similar SAR studies), applying the formula of Machin and Campbell13 required a sample size of 39 per group to detect a difference of 0.45 in the average all-day TNSS, with a power of 90%. Because the levocabas- tine group was intended to include the same number of patients as the other 2 groups, and the assumed dropout rate was 5%, it was determined that 123 patients should be ran- domized.

All other group comparisons were of an exploratory nature and were performed without α adjustment at α = .05. The term statistically significant is used for all results where P ≤ .05. This article reports the results of the intent-to-treat analysis for each variable. This analysis used data from all ran- domized patients who took study medication at least once and for whom a reasonable number of efficacy values was avail- able for the variable being investigated.

Cost-effectiveness was calculated as follows to provide the cost per treatment success in each group: [Daily Medication Costs × Treatment Duration × No. of Patients] / No. of Treatment Successes. Treatment successes were defined as patients who evaluated the global efficacy of the study med- ication as “very good” or “good.” Tolerability of the study medication was evaluated by recording AEs and by analyzing data from the physical examinations outlined.

RESULTS

Patient Characteristics

To randomize 123 eligible patients, 145 were screened. All randomized patients received at least 1 dose of study medi- cation. One hundred twenty patients completed the study (Fig 1). The mean age of the patients was 34.6 years (range, 18.9 –58.9 years), and most were women (59.4%). Treatment groups did not differ significantly with respect to sex, age, proportion of smokers, or proportion of patients with con- comitant perennial AR (overall proportion, 19.5%) (Table 1).

Efficacy End Points

Treatment groups were homogeneous with respect to all symptom scores on the last 4 days of the run-in phase, when all patients were included in the study (see all-day TSS in Table 1 as an example). Results for the efficacy variables are summarized in Tables 2, 3, and 4. During the evaluation period, the average all-day, daytime, and nighttime TNSSs were significantly lower in the mometasone furoate group
compared with the disodium cromoglycate group (P ≤ .001) (Table 2). The average all-day, daytime, and nighttime TSSs (including eye complaints) were also significantly lower in the mometasone furoate group compared with the disodium cromoglycate group (P = .001) (Table 2). These significant differences were also seen when comparing the mometasone furoate and disodium cromoglycate groups for each of the all-day, daytime, and nighttime individual nasal symptom scores (Table 3).

The average all-day, daytime, and nighttime TNSSs and TSSs were also significantly lower in the mometasone furoate group compared with the levocabastine group (Table 2). Furthermore, mometasone furoate was superior to levocabas- tine with respect to the all-day, daytime, and nighttime indi- vidual nasal symptom scores for sneezing and nasal itching and the daytime score for rhinorrhea (the all-day score ap- proached significance, P = .051) and the all-day and night- time scores for obstruction (Table 3). No significant differences in average all-day, daytime, or nighttime symptom scores were observed for the comparison of the levocabastine and disodium cromoglycate groups except for a significant superiority of levocabastine in the daytime sneezing score (P = .04). However, levocabastine approached superiority for several variables (Table 3).

Figure 1. Flow of patients in the study design. Asterisk indicates patient applied the study medication only once and was not included in the intent-to-treat sample.

No significant differences were observed with respect to eye complaints or consumption of rescue medication for any between-treatment group comparisons, although the scores for eye complaints decreased with mometasone furoate treat- ment (Table 3). Significantly more symptom-free days (TNSS and TSS) were observed in the mometasone furoate group compared with the levocabastine and disodium cromo- glycate groups, whereas no significant differences were found between patients treated with levocabastine vs diso- dium cromoglycate (Table 2).
The average nPIFR was significantly higher in the mo- metasone furoate group than in the disodium cromoglycate group (P = .005) (Table 4), indicating better nasal patency in patients treated with mometasone furoate. With respect to this variable, mometasone furoate showed some evi- dence of numerical superiority over levocabastine,whereas levocabastine showed a trend toward superiority compared with disodium cromoglycate. At the last visit, patients were asked to evaluate the global efficacy of the study medication (Fig 2). According to these assessments, the efficacy of mometasone furoate was significantly su- perior to that of levocabastine (P = .02) and disodium cromoglycate (P < .001). The concentration of ECP as a marker of eosinophil activ- ity and inflammation was measured in the patients’ nasal secretions before and after the treatment period. Before treat- ment, no differences between the groups were observed with respect to the number of specimens with ECP concentrations below the detection limit (32% of all specimens). After the treatment period, however, significantly more specimens with ECP concentrations below the detection limit were observed in the mometasone furoate group (49%) than in the levoca- bastine (15%; P = .003) and disodium cromoglycate (19%; P = .009) groups (Fig 3). The ECP concentrations in the disodium cromoglycate group at baseline were higher than those in both other groups, and the mometasone furoate and disodium cromoglycate groups were not homogeneous (U test: P = .10 for disodium cromoglycate vs mometasone furoate; P = .13 for disodium cromoglycate vs levocabas- tine). The absolute change from visit 2 to visit 4 was com- pared between groups using the Mann-Whitney U test, which yielded no significant difference between the mometasone furoate and disodium cromoglycate groups but demonstrated significant superiority for mometasone furoate and disodium cromoglycate compared with levocabastine (P = .003 for mometasone furoate vs levocabastine; P < .001 for disodium cromoglycate vs levocabastine) (Table 4). Cost-effectiveness The cost-effectiveness of each study medication was descrip- tively evaluated as medication cost per treatment success (defined as a global evaluation of “very good ” or “good”). Although the mean daily medication costs of mometasone furoate and disodium cromoglycate nasal sprays were almost identical, costs per treatment success were approximately 33% lower with mometasone furoate compared with diso- dium cromoglycate and 272% higher with levocabastine compared with mometasone furoate (Table 5). Tolerability All 3 study medications were equally well tolerated in this study. The percentages of patients with at least 1 AE were 44%, 45%, and 48% in the mometasone furoate, levocabastine, and disodium cromoglycate groups, respectively (Table 6). Except for headache or migraine, the incidence of AEs was low. Of 117 AEs reported, only 9 were regarded as possibly being related to the study medication: 7 local complaints in the nose or pharynx (2, 2, and 3 in the mometasone furoate, levocabastine, and disodium cromoglycate groups, respectively), 1 episode of fatigue (in the levocabastine group), and 1 episode of vertigo (in the mometasone furoate group). No serious AEs occurred. One pregnancy was re- ported in the levocabastine group, but it was not considered to be related to study medication. No significant treatment group differences were observed with respect to vital vari- ables or weight. Physical examinations before and after treat- ment showed no relevant changes in any of the treatment groups. Rhinoscopic findings were consistent with the local AEs observed. DISCUSSION The results obtained from patient diaries in this study show that the topical glucocorticosteroid mometasone furoate has superior efficacy in reducing the nasal symptoms of AR compared with the topical antihistamine levocabastine and the cromone disodium cromoglycate. Comparing levocabas- tine and disodium cromoglycate, only a trend in favor of levocabastine was observed, except for a significant differ- ence for daytime sneezing. The diary results are supported by the significantly better global evaluation of treatment efficacy recorded by the patients in the mometasone furoate group compared with those in the other treatment groups. Furthermore, nPIFR measurements showed better nasal patency with mometasone furoate treatment than with disodium cromogly- cate nasal spray. With respect to ocular symptoms, no sig- nificant differences between treatment groups were observed. These results correspond well to those of a recently pub- lished meta-analysis4 that compared topical corticosteroids, topical antihistamines, and cromones in AR. The meta-anal- ysis confirmed the superiority of nasal corticosteroids over topical antihistamines and cromones with respect to all nasal symptoms and the global evaluation of treatment efficacy, with only marginal superiority for topical antihistamines compared with cromones. A further meta-analysis,5 which compared only topical corticosteroids and topical antihista- mines in AR, produced similar results. However, a meta- analysis by Weiner et al3 found no superiority of systemic antihistamines over topical corticosteroids with respect to ocular symptoms. This led to the assumption of substantial efficacy for topical corticosteroids for ocular symptoms, for example, in the European Academy of Allergology and Clin- ical Immunology treatment guidelines.8 However, data from the present study, in agreement with the meta-analyses out- lined previously herein, showed no significant superiority of any topical treatment with respect to eye complaints, al- though a tendency in favor of mometasone furoate nasal spray was detectable. The lack of a placebo group in this clinical study prevents further speculation about the magni- tude of possible treatment effects on ocular symptoms. How- ever, a meta-analysis4 of placebo-controlled trials suggested that topical nasal medications may be effective for treating these symptoms. Figure 2. Global evaluation of efficacy by the patients. y2 Tests yielded P < .001 for mometasone furoate vs disodium cromoglycate (DSCG); P = .02 for mometasone furoate vs levocabastine hydrochloride; and P = .11 for levocabastine vs DSCG. Figure 3. Nasal secretion specimens with eosinophil cationic protein (ECP) concentrations below the detection limit (DL) of 2 µg/L in each group before (visit 2) and after (visit 4) treatment. DSCG indicates disodium cromoglycate. The pattern of symptom scores during the grass pollen season showed divergent courses for the mometasone furoate group compared with the levocabastine and disodium cromo- glycate groups. The course of the mean all-day TNSSs, for example, is depicted in Figure 4. After increasing until the beginning of the pollen season, TNSSs remained more or less constant in the levocabastine and disodium cromoglycate groups. In contrast, TNSSs steadily decreased in the mometa- sone furoate group. Under the assumption of a gradual dif- ference in efficacy, a curve parallel to the other 2 but on a lower score level could have been expected for mometasone furoate. Instead, the divergent courses may reflect fundamen- tal differences in the way these medications act. Whereas levocabastine and disodium cromoglycate are not really con- sidered to be anti-inflammatory, the corticosteroid mometa- sone furoate exerts a broad range of anti-inflammatory activities via the regulation of gene expression (eg, of inflam- matory mediators).1 These nontachyphylactic effects on the chronic inflammation underlying AR are probably the reason for the favorable decrease in symptoms during the entire pollen season with mometasone furoate therapy. Of note, the overall relatively low symptom scores observed for all 3 treatment groups may in part have resulted from the compar- atively low grass pollen counts in 2003 in the study region. In the present study, concentrations of ECP in nasal secre- tions were measured at the beginning of the study (before treatment) and at the end of the season (after treatment) as markers of eosinophil, and thus inflammatory, activity in the nasal mucosa. Mometasone furoate was superior to levoca- bastine and disodium cromoglycate with respect to the num- ber of samples with ECP levels below the detection limit after treatment. However, a Mann-Whitney U test of ECP concen- trations revealed superiority of mometasone furoate over levocabastine only and not over disodium cromoglycate,which was itself superior to levocabastine. The mometasone furoate and disodium cromoglycate groups were not homo- geneous with respect to ECP concentration at the beginning of the study, with clearly higher mean and median values in the disodium cromoglycate group. Whereas a reduction of eosinophils in nasal scrapings has been reported in 1 study with disodium cromoglycate,14 the decrease in mean ECP concentration observed with disodium cromoglycate proba- bly resulted from a few extreme baseline values and a regres- sion to the mean effect rather than from true anti-inflamma- tory activity. This view is supported by the significantly higher proportion of ECP concentrations below the detection limit in the mometasone furoate group after treatment and a nearly unchanged median value in the disodium cromogly- cate group. Figure 4. Course of pollen load and mean total nasal symptom scores (TNSSs) in the treatment groups during the 2003 grass pollen season. Vertical bars represent the beginning and end of the evaluation period. Direct medication costs are the largest cost component in expenditures for AR.15 Medication costs per treatment suc- cess (as defined and calculated herein) show that mometasone furoate nasal spray was the most cost-effective topical treat- ment in the study. Using the same method, Nash et al16 found that the topical corticosteroid fluticasone was more cost- effective than the oral antihistamine loratadine or combined fluticasone and loratadine in a randomized clinical study. The safety profiles were similar among all 3 treatment groups, with essentially only a few minor local irritation reactions attributed to study medications. The open design of this study could be criticized; however, masking was techni- cally not possible because, for example, a triple-dummy design would have required an extremely high daily treatment volume. Double-masked studies are the gold standard of clinical research, but open trials can also provide valuable results; indeed, it has been shown that an open vs a double- masked study design has no effect on the results of objective measurements in hypertension trials.17 Even in trials that assess neuroleptics, which use psychological rating scales, no differences were detectable in the reduction of scores and response rates between open and double-masked trials.18 In conclusion, mometasone furoate nasal spray is more effective in reducing nasal symptoms and inflammation, results in greater patient satisfaction, and is more cost-effec- tive in patients with SAR than is the topical antihistamine levocabastine or the cromone disodium cromoglycate. Fur- thermore, mometasone furoate had the same favorable toler- ability profile as the nonsteroidal topical treatments. The demonstrated efficacy, cost-effectiveness, and good tolerabil- ity observed in this study suggest that mometasone furoate nasal spray should be considered as a first-choice option for SAR treatment. This suggestion is supported by its low systemic bioavailability relative
to other intranasal cortico- steroids and, hence, the reduced probability of causing systemic adverse effects.

The underrepresentation of intranasal corticosteroids in prescriptions for AR observed in many countries, including Germany,4 is probably the result of a “corticosteroid phobia,” even among physicians. To optimize SAR treatment and to achieve compliance with treatment recommendations, guide- lines need to be reinforced in communication with medical societies. Health care decisions at a political level, such as reimbursement, should be based on pharmacologic and clin- ical evidence, accepting that AR is a widespread, impairing disease and a risk factor for asthma, a disease that has substantially higher treatment costs than AR.