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(Chest. 1999;116:65-72.)
© 1999 American College of Chest Physicians

Controlled Trial of Two Formulations of Cromolyn Sodium in the Treatment of Asthmatic Patients >= 12 Years of Age*

Clifton Furukawa, MD; Dean Atkinson, MD; Terrence J. Forster, MD; Kristine Nazzario, RPh; Brandon Simpson; Thomas Uryniak, MS; Frank E. Casty, MD, FCCP and for the Intal Study Group

* From the Department of Pediatrics (Dr. Furukawa), University of Washington, School of Medicine, Seattle, WA; Oklahoma Allergy and Asthma Clinic (Dr. Atkinson), Oklahoma City, OK; Allergy, Asthma and Arthritis Associates, P.C. (Dr. Forster), Doylestown, PA; and Rhône-Poulenc Rorer (Ms. Nazzario, Messrs. Simpson and Uryniak, and Dr. Casty), Collegeville, PA.

Correspondence to: Frank E. Casty, MD, FCCP, 324 Glad Way, Collegeville, PA 19426; e-mail: frank.casty{at}rp-rorer.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Study objectives: This multicenter, randomized, double-blind, placebo-controlled, parallel study compared the efficacy and safety of the hydrofluoroalkane (HFA) formulation of cromolyn sodium metered-dose inhaler (MDI) with the chlorofluorocarbon (CFC) formulation in asthmatic patients >= 12 years old over a 12-week period.

Design: Stable asthmatics using only currently marketed cromolyn sodium and as-needed inhaled ß2-agonists were randomly assigned to treatment with HFA cromolyn sodium, CFC cromolyn sodium, or placebo, administered as two inhalations (2 mg) qid for 12 weeks. Prior to randomization, all patients were required to meet minimum symptom and/or pulmonary function test criteria after discontinuation of cromolyn sodium. Efficacy was assessed by changes in daily symptom scores, albuterol use, peak expiratory flow, pulmonary function measurements, and overall opinions of effectiveness.

Results: A total of 280 patients in 29 centers were randomly assigned to treatment with HFA cromolyn sodium (n = 94), CFC cromolyn sodium (n = 91), or placebo (n = 95). Patients treated with the HFA formulation of cromolyn sodium demonstrated a 28 to 33% improvement over placebo for all symptom scores (p < 0.05) and a 35% improvement over placebo in the use of albuterol MDI (p < 0.05). The patients' opinions of overall effectiveness favored HFA cromolyn sodium (p = 0.011) and CFC cromolyn sodium (p = 0.006) over placebo. The investigators' opinions indicated a statistically significant difference favoring CFC cromolyn sodium compared with both placebo (p < 0.001) and HFA cromolyn sodium (p = 0.042). No statistically significant differences existed among groups in the incidence of treatment-related adverse events.

Conclusion: The HFA formulation of cromolyn sodium MDI is a well-tolerated and effective treatment for asthma patients >= 12 years old. The safety and efficacy profile of the HFA formulation is comparable to that of the CFC formulation.

Key Words: chlorofluorocarbon • cromolyn sodium • hydrofluoroalkane • metered-dose inhaler • Montreal Protocol • ozone


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Cromolyn sodium, an inhaled anti-inflammatory agent for the treatment of asthma, has been available for > 30 years. Clinical studies have shown this nonsteroid medication, available as a nebulizer solution and as a metered-dose inhaler (MDI), to control the symptoms and bronchial hyperresponsiveness associated with asthma and to reduce the number of acute exacerbations, with an acceptable safety profile.1 2 3 4 Like other pressurized aerosol medications, the MDI formulation of cromolyn sodium currently contains chlorofluorocarbon (CFC) propellants. During recent years, CFCs have been criticized for their harmful effects on the environment, especially the depletion of the stratospheric ozone layer. The production and use of CFCs were banned by international treaty (the Montreal Protocol) in 1987. Exemptions to the national and international bans were made for MDIs to allow time for comparative clinical trials of alternative propellants, as required by worldwide regulatory agencies including the US Food and Drug Administration.

Thus far, the most promising alternative propellants for MDIs are derivatives of hydrofluoroalkane (HFA). Rhône-Poulenc Rorer has developed a formulation of cromolyn sodium MDI with HFA-227 as the propellant, polyvinylpyrrolidone as a lubricant, and polyethylene glycol as a surfactant. The HFA formulation of cromolyn sodium was developed to have similar in vitro and in vivo performance to the CFC formulation. The HFA agents lack chlorine, and thus have zero ozone depletion potential.5 6 7 Preclinical studies have demonstrated the acceptability of these propellants in terms of pharmacology, toxicology, and safety.8

The study reported here was intended to evaluate the efficacy and safety of HFA cromolyn sodium compared with placebo, and to compare HFA cromolyn sodium with CFC cromolyn sodium, in asthmatic patients >= 12 years old.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
Study Population
The patients in the study were >= 12 years old and had a documented history of bronchial asthma. All patients had maintained daily therapy with the currently marketed cromolyn sodium MDI for at least 2 months prior to the screening visit (visit 1) and were using inhaled ß2-agonists to control asthma symptoms for at least 1 month preceding visit 1. Patients had an FEV1 of at least 60% of predicted normal at screening.

Excluded from the study were patients with other clinically significant respiratory disorders, current or recent smokers, patients with a history of life-threatening asthma exacerbations, and patients with seasonal allergic asthma. Also excluded were patients who used any of the following: inhaled corticosteroids within 4 weeks of visit 1; oral or parenteral steroids for > 10 days within 3 months of visit 1; immediate-release theophylline; ipratropium bromide; oral or nebulized ß2-agonists; salmeterol within 12 h of visit 1; sustained-release theophylline within 48 h of visit 1; or nedocromil sodium within 2 weeks of visit 1.

Signed informed consent was obtained from each patient prior to performance of study procedures.

Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 29 sites in the United States. Eligible patients were >= 12 years old, they had an FEV1 of at least 60% predicted normal, and they had maintained daily therapy with CFC cromolyn sodium for at least 2 months prior to the screening visit, plus inhaled ß2-agonists for acute relief of symptoms for at least 1 month prior to screening. After screening, the patients entered a 2-week baseline period to confirm that they were well controlled on combination therapy of CFC cromolyn sodium and inhaled ß2-agonists. This was followed by a 2- to 4-week single-blind period during which all patients discontinued use of CFC cromolyn sodium and were treated with placebo. During this time, all patients maintained daily diary records of their daytime and nighttime asthma symptoms; their use of albuterol and other medications; their morning and evening peak expiratory flow (PEF), as measured with a hand-held peak flowmeter (Assess Peak Flow Meter; Healthscan; Cedar Grove, NJ); and a description of any adverse events. Nighttime symptoms (cough, wheeze, chest tightness, breathlessness) were recorded each morning on awakening, as follows: 0 = no symptoms; 1 = symptoms on awakening only; 2 = symptoms causing one awakening during the night or causing patient to awaken early; 3 = symptoms causing two or more awakenings during the night and causing patient to awaken early; 4 = symptoms kept patient awake most of the night; and 5 = symptoms kept patient awake all night. Daytime symptoms (cough, wheeze, chest tightness, breathlessness) were recorded each evening, as follows: 0 = no symptoms; 1 = symptoms for one short period during the day; 2 = symptoms for two or more short periods during the day; 3 = symptoms for most of the day, but not affecting normal activities; 4 = symptoms for most of the day and affecting normal activities; and 5 = symptoms so severe that the patient could not perform normal activities. Clinic visits were scheduled at regular 2-week intervals and included review of diary cards and measurements of pulmonary function by spirometry: FEV1; FVC; forced expiratory flow during midportion of FVC (FEF25–75%); and PEF. Blood and urine samples were taken for laboratory evaluation of blood chemistry, hematology, and urinalysis prior to the baseline period and at the end of the double-blind treatment period.

Patients whose asthma was well controlled on CFC cromolyn sodium and inhaled ß2-agonists during the baseline period were eligible for randomization provided that they demonstrated either (1) a 15% decrease in FEV1 or a 25% decrease in FEF25–75% compared with the screening value; or (2) a total asthma symptom score of at least 28 (out of a possible 140), with an increase of at least 14 in comparison with the baseline period and an increase in albuterol use of >= 14 puffs during the single-blind treatment period. Eligible patients were randomized to one of three treatment groups: HFA cromolyn sodium, CFC cromolyn sodium, or placebo, two puffs (2 mg) qid for 12 weeks. Patients continued using albuterol MDI on an as-needed basis for the duration of the study.

Medications
Patients in each of the three groups were instructed to take two inhalations of the study drug qid: early morning, lunchtime, dinnertime, and bedtime. Each actuation of cromolyn sodium MDI (HFA or CFC formulation) delivered 1 mg of drug through the mouthpiece. Therefore, patients in the active treatment groups received a total daily dose of 8 mg cromolyn sodium. The placebo MDI contained only HFA propellant, HFA-227, and excipients in the same concentrations as the active treatment of HFA cromolyn sodium.

During the study, in addition to their study medications, the patients were permitted to take the following drugs: inhaled albuterol in response to asthma symptoms; antibiotics for bacterial infections; antihistamines; topical cromolyn sodium and/or nasal and ocular vasoconstrictor agents for allergies; nasal corticosteroids for allergies if the daily dose was stable throughout the study or if taken as a 14-day regimen by patients who developed allergic nasal symptoms during the study; continued immunotherapy for patients who had been on a stable maintenance dose for at least 3 months prior to screening; mucolytics and expectorants as needed; and topical corticosteroids for ophthalmic and dermal use.

Efficacy Variables
The primary efficacy variable was the symptom summary score (defined as the sum of daytime asthma and nighttime asthma scores). Secondary variables included pulmonary function test results at biweekly clinic visits, use of as-needed albuterol, daytime and nighttime asthma symptom scores, and morning and evening PEFs recorded in patients' diaries. The primary time period was the entire 12-week treatment period. Data from diary variables or each visit were also examined at 2-week intervals to assess the time course of response.

Opinions of Treatment Effectiveness
At the end of the treatment period, the patient and physician independently rated their opinions of the overall effectiveness of the treatment in controlling the patient's asthma symptoms using the following scale: 1 = very effective; 2 = moderately effective; 3 = slightly effective; 4 = had no effect; and 5 = made condition worse.

Statistical Methods
The study was designed to have 100 evaluable patients per treatment group. This estimate was based on detecting a difference of 0.3 points in the mean symptom score assuming an SD of 0.65 points, a type I error of 0.05, and a power of 90%.

The three treatment groups were assessed for demographic and baseline comparability using the Cochran-Mantel-Haenszel test (categorical data) and an analysis of variance (continuous data) with treatment as the stratifying variable. Efficacy measures were analyzed using a parametric analysis of covariance with the treatment value as the response variable and the baseline value as the covariate. If the overall three-treatment group test was statistically significant (p < 0.05), then pairwise comparisons were made. Patient and physician opinions of treatment efficacy were assessed using the Cochran-Mantel-Haenszel test.

Adverse events were categorized according to the Coding Symbols for Thesaurus of Adverse Reactions Terms, or COSTART, coding dictionary. The association between the adverse event rates and treatment was assessed using Fisher's Exact Test.

Patients were classified as treatment failures if they required disallowed concomitant medications or if they withdrew for any reason involving the worsening of their asthma symptoms or lack of treatment effect. Data from patients who withdrew from the trial as a result of treatment failure were included up to the time of withdrawal; after withdrawal, data were carried forward using either the individual's score on the day the patient was designated a treatment failure or the last nonmissing score recorded before that. Data from patients who withdrew from the trial due to reasons other than treatment failure were included in the statistical analysis to the point of withdrawal; after withdrawal, data were carried forward with an average of the data collected during treatment prior to withdrawal, for each visit and each day after the last recorded data point.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Demographics and Screening Characteristics
A total of 280 patients at 29 centers were randomized to treatment. The demographics of the study population and baseline measurements are shown in Table 1 . Asthma severity at the start of the study was similar among the three treatment groups, as reflected by the use of antiasthma medications during the 3 months prior to the screening visit and by baseline measurements (Table 1) .


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  		Table 1. Characteristics of Study Population

 
A total of 256 patients completed the entire 12 weeks of treatment (HFA cromolyn sodium, n = 88; CFC cromolyn sodium, n = 84; placebo, n = 84). Twenty-four patients withdrew after randomization; of these, 16 patients withdrew because of an adverse event (3 in the HFA cromolyn sodium group, 5 in the CFC cromolyn sodium group, and 8 in the placebo group). A total of 40 patients were classified as treatment failures (11 in the HFA cromolyn sodium group, 5 in the CFC cromolyn sodium group, and 24 in the placebo group).

Diary Card Variables
Over the 12-week treatment period, patients treated with either formulation of cromolyn sodium experienced a marked improvement in symptoms. Differences between each cromolyn sodium group and the placebo group for the symptom summary score were statistically significant at all biweekly treatment periods (Fig 1 ), and no statistically significant differences were observed between the symptom scores for the two active treatment groups. The overall reduction in symptom summary scores during the 12-week treatment period is shown in Figure 2 . During the primary treatment period, mean symptom summary scores in both the HFA and CFC cromolyn sodium-treated groups decreased by approximately 27% and 22%, respectively (HFA: baseline, 3.11; weeks 1 to 12, 2.28; p < 0.001 vs placebo; CFC: baseline, 2.86; weeks 1 to 12, 2.23; p = 0.001 vs placebo), compared with an increase of approximately 4% in the placebo group (baseline, 2.51; weeks 1 to 12, 2.60). These changes were consistent with improvements in daytime and nighttime asthma symptoms (Fig 2) .



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  		Figure 1. Biweekly mean symptom summary scores (daytime + nighttime symptom scores: 0 = no symptoms, 10 = symptoms interfered with sleep and daytime activities) for the three treatment groups. {circ} = placebo; x = HFA cromolyn sodium; {diamondsuit} = CFC cromolyn sodium. Differences between both formulations of cromolyn sodium, compared to placebo, were statistically significant at all time points. *p <= 0.05.

 


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  		Figure 2. Mean percent changes from baseline for the three treatment groups over the 12-week treatment period for the symptom summary score, daytime symptoms, nighttime symptoms, and albuterol use. Open squares = placebo; shaded squares = HFA cromolyn sodium; filled squares = CFC cromolyn sodium. *p <= 0.05 compared to placebo.

 
Differences in daytime asthma scores between each active treatment group and placebo were also statistically significant at all time points. A 23% reduction from baseline in daytime asthma scores was reached at treatment weeks 1 to 2 in patients treated with HFA cromolyn sodium (baseline, 1.80; weeks 1 to 2, 1.38; p < 0.001 vs placebo) and maintained throughout the 12-week treatment period. During the first 2-week treatment period, daytime symptom scores in the placebo group decreased by approximately 1% (baseline, 1.41; weeks 1 to 2, 1.39). Overall, during the 12 weeks of treatment, mean daytime asthma scores in the HFA and CFC cromolyn sodium groups decreased by 29% (weeks 1 to 12: HFA, 1.27; p < 0.001 vs placebo) and 25% (weeks 1 to 12: CFC, 1.25; p = 0.002 vs placebo), respectively, compared with a 1% reduction in the placebo group (weeks 1 to 12: placebo, 1.39).

Patients using HFA cromolyn sodium also reported statistically significant fewer nighttime symptoms at all time points compared with placebo. The pattern of reduction for nighttime scores was similar to the daytime scores, with a 21% reduction from baseline reached at treatment weeks 1 to 2 in patients treated with HFA cromolyn sodium (baseline, 1.31; weeks 1 to 2, 1.03; p = 0.001 vs placebo); the reduction was maintained throughout the 12-week treatment period. Patients in the placebo group experienced a steady increase of nighttime symptoms throughout the treatment period. During the first 2-week treatment period, nighttime symptom scores in the placebo group increased by approximately 2% (baseline, 1.08; weeks 1 to 2, 1.10). Overall, during the 12 weeks of treatment, mean nighttime scores in the HFA and CFC cromolyn sodium groups decreased by 23% (HFA: weeks 1 to 12, 1.02; p < 0.001 vs placebo) and 18% (CFC: weeks 1 to 12, 0.99; p = 0.003 vs placebo), respectively, compared with a 10% increase in the placebo group (weeks 1 to 12, 1.19).

The patients in the HFA cromolyn sodium group experienced an increase in both morning and evening PEF during the 12-week treatment period. PEF increased slightly for patients in the CFC cromolyn sodium group and decreased for placebo patients during the same period. The differences in morning PEF between the HFA cromolyn sodium and placebo groups reached statistical significance for all biweekly time periods except treatment weeks 5 to 6. Over the 12-week treatment period, the mean change from baseline PEF was 21.9 L/min in the HFA cromolyn sodium group (5.3% increase: baseline, 409.4; weeks 1 to 12, 431.3), 5.7 L/min in the CFC cromolyn sodium group (1.3% increase: baseline, 433.6; weeks 1 to 12, 439.3), and -4.1 L/min in the placebo group (1.0% decrease: baseline, 411.0; weeks 1 to 12, 406.9). Similar results were seen with the evening PEF; the mean change from baseline was 20.2 L/min in the HFA cromolyn sodium group (4.7% increase: baseline, 426.8; weeks 1 to 12, 447.0), 0.7 L/min in the CFC cromolyn sodium group (0.1% increase: baseline, 454.6; weeks 1 to 12, 455.2), and -7.7 L/min in the placebo group (1.8% decrease: baseline, 432.1; weeks 1 to 12, 424.4). As with the morning PEF, evening PEF differences between HFA cromolyn sodium and placebo were statistically significant at all biweekly time periods except treatment weeks 5 to 6.

The improvements in asthma symptoms and PEF in the two active treatment groups were paralleled by decreased use of rescue albuterol. Between-treatment differences in albuterol use were statistically significant for treatment weeks 1 to 2, 3 to 4, 9 to 10, and 11 to 12 for HFA cromolyn sodium, and treatment weeks 1 to 2 for CFC cromolyn sodium (Fig 3 ), compared with placebo. There were no statistically significant differences between the HFA and CFC cromolyn sodium groups. During the overall treatment period, mean albuterol use decreased by approximately 27% in the HFA cromolyn sodium group (baseline, 1.95; weeks 1 to 12, 1.43; p = 0.005 vs placebo) and 13% in the CFC cromolyn sodium group (baseline, 1.90; weeks 1 to 12, 1.66; p = 0.173 vs placebo; Fig 2 ), compared with an increase of approximately 8% in the placebo group (baseline, 1.54; weeks 1 to 12, 1.66).



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  		Figure 3. Biweekly mean scores for albuterol use (times per day) for the three treatment groups. The unit "times/day" refers to the number of times a patient's individualized unit dose (typically two puffs) was taken. {circ} = placebo; x = HFA cromolyn sodium; {diamondsuit} = CFC cromolyn sodium *p <= 0.05 compared to placebo. **p <= 0.01 compared to placebo.

 
Spirometry at Clinic Visits
Pulmonary function measurements at baseline are shown in Table 2 . All treatment groups experienced an improvement in pulmonary function from baseline. Differences between CFC cromolyn sodium and placebo treatment groups reached statistical significance for percentage predicted FEV1 (a 15.1% increase in the CFC cromolyn sodium group vs a 10.8% increase in the placebo group) and FVC (a 10% increase in the CFC cromolyn sodium group vs a 5.5% increase in the placebo group) for treatment weeks 1 to 12. Statistically significant differences were also seen between CFC cromolyn sodium and placebo at the last clinic visit (treatment week 12) for all variables except FEF25–75%. Although the differences between the HFA cromolyn sodium and placebo groups did not reach statistical significance, there were no statistically significant differences between the HFA and CFC cromolyn sodium groups.


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  		Table 2. Pulmonary Function Variables at Baseline and During the Primary Time Period (Treatment Weeks 1 to 12)

 
Opinions of Treatment Effectiveness
Physicians rated the treatment as moderately or very effective for 56% of the patients treated with HFA cromolyn sodium, 43% of the placebo-treated patients, and 63% of the patients treated with CFC cromolyn sodium. The mean scores for treatment effectiveness among physicians were 2.62, 2.21, and 2.96, respectively, for patients treated with HFA cromolyn sodium, CFC cromolyn sodium, and placebo. The difference between the CFC cromolyn sodium and placebo groups was statistically significant (p < 0.001); however, the difference between the HFA cromolyn sodium and placebo groups was not significant (p = 0.129). The CFC cromolyn sodium formulation was rated as effective for more patients than HFA cromolyn sodium, with a statistically significant difference (p = 0.042) between the two active groups.

Approximately 77% of the patients in the HFA cromolyn sodium group rated their treatment as moderately or very effective, compared with 73% of patients in the CFC cromolyn sodium group and 54% of placebo-treated patients. The mean scores for opinions of treatment effectiveness were 2.16 and 2.07 for the HFA and CFC cromolyn sodium groups, respectively, compared with 2.78 for the placebo group. Comparisons of the active treatments to placebo were statistically significant for both groups (p = 0.011, HFA cromolyn sodium vs placebo; p = 0.006, CFC cromolyn sodium vs placebo). Between-treatment differences were not statistically significant for the two active groups (p = 0.989).

Adverse Events
Seventy-five percent of the patients reported at least one adverse event during the treatment period, and event rates were similar among the three treatment groups (HFA cromolyn sodium, 71 patients [76%] reporting events; CFC cromolyn sodium, 67 patients [74%] reporting events; placebo, 71 patients [75%] reporting events). Approximately 5% of patients reporting adverse events had at least one event that was judged as probably treatment related. The three most common treatment-related events were asthma (HFA cromolyn sodium, n = 4 [4%]; CFC cromolyn sodium, n = 0 [0%]; placebo, n = 1 [1%]), taste perversion (HFA cromolyn sodium, n = 2 [2%]; CFC cromolyn sodium, n = 0 [0%]; placebo, n = 0 [0%]), and pharyngitis (HFA cromolyn sodium, n = 1 [1%]; CFC cromolyn sodium, n = 0 [0%]; placebo, n = 1 [1%]). There were no statistically significant differences among the three treatment groups in the incidence of treatment-related events.

Of the 16 withdrawals attributed to adverse events (HFA cromolyn sodium, n = 3; CFC cromolyn sodium, n = 5; placebo, n = 8), only four were judged to be treatment related. Two patients in the HFA cromolyn sodium group withdrew due to worsening asthma after 55 and 82 days of treatment. One patient in the CFC cromolyn sodium group had a prior history of persistent headaches and withdrew after 19 days of treatment because of an increase in their intensity and frequency. One patient in the placebo group withdrew after 42 days of treatment due to an asthma exacerbation related to physical exertion, and considered possibly related to the study drug.

There were no clinically significant changes from baseline for laboratory variables in any treatment group, nor was there a difference among treatments in the incidence of clinically significant laboratory values. A total of seven laboratory adverse events were reported by six patients during the study. None of these events was considered by the investigators to be related to study medication. There was no statistical difference among the treatment groups for any of these events.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
In this placebo-controlled study, the patients' asthma had been well controlled by a combination of inhaled ß2-agonists and CFC cromolyn sodium during the 2-week screening period, and they demonstrated deterioration in symptom scores and/or pulmonary function on discontinuation of CFC cromolyn sodium during the subsequent baseline period. The target population for this study was mild to moderate asthmatics as indicated by a documented history of asthma and a screening FEV1 of at least 60% predicted normal. The population studied had a baseline severity of summary symptoms of approximately 2.8 on a scale from 0 to 10, and albuterol use of approximately two times or four puffs per day at randomization. The results of this study showed that HFA cromolyn sodium inhalation aerosol reduced asthma symptoms, decreased rescue medication use, and increased morning and evening PEFs in asthmatic patients previously maintained with CFC cromolyn sodium. Symptoms were improved by >= 23% in the HFA cromolyn sodium group, while at the same time rescue albuterol use was reduced by 27%. Morning and evening PEF also improved by approximately 21 L/min (5%) from baseline in the HFA cromolyn sodium group. Differences between HFA cromolyn sodium and placebo were statistically significant at all biweekly time points for the symptom summary score and for daytime and nighttime asthma symptom scores, at all but two time points for rescue albuterol use, and at all but one time point for morning and evening PEFs.

The Guidelines for the Diagnosis and Management of Asthma recommend treatment with cromolyn sodium for patients with mild persistent asthma.9 10 11 12 This is defined generally on symptom scores (symptoms > 2/wk but < 1/d) and use of inhaled short-acting ß2-agonists < 1/d. Although the guidelines included in the Expert Panel Report 2 were not available12 at the initiation of the study, the patients included in this study generally met the criteria for mild to moderate persistent asthma. The inclusion criteria for this study were designed to include patients with moderate asthma so that a discernible difference in improvement could be demonstrated by the reduction in albuterol use and overall symptom scores. Considering that patients meeting the criteria for mild persistent asthma were also included in the study, minimal improvement in reduction of albuterol use would be expected because of the infrequent albuterol use in this population.

As shown in this study, the mean overall symptom scores and albuterol use were both reduced by 27% from baseline in the HFA cromolyn sodium group, while mean symptom scores and albuterol use were reduced by 22% and 13%, respectively, in the CFC cromolyn sodium group. These results are precisely the treatment goals for mild to moderate asthma that are described in both national and international guidelines: fewer symptoms and less reliance on inhaled rescue medications. In addition, there was a statistically significant difference in the patients' opinion of efficacy between HFA cromolyn sodium and placebo. Finally, the safety profile of the groups treated with HFA and CFC cromolyn sodium were similar to those treated with placebo.

In summary, HFA cromolyn sodium can provide clinical benefit similar to that provided by the currently used CFC formulation, and it has a comparable safety and tolerability profile. These findings confirm the clinical history of the CFC formulation of cromolyn sodium as a well-tolerated and effective therapy for treating patients with mild to moderate asthma.1 2 3 4 5 6


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
We would like to acknowledge the following investigators for their time and participation in this study: Rafeul Alam, MD (Galveston, TX); Dean Atkinson, MD (Oklahoma City, OK); Mary Anne Bartoszek-Scott, MD and Robert M. Biondi, MD (Norwalk, CT); Morris Beck, MD (Miami, FL); George Bensch, MD (Stockton, CA); William E. Berger, MD (Mission Viejo, CA); John D. Bray, MD (Midland, TX); John Condemi, MD (Rochester, NY); Bradley Cromar, MD (Wenatchee, WA); Albert F. Finn, MD (Charleston, SC); Terrence J. Forster, MD (Doylestown, PA); Clifton Furukawa, MD (Seattle, WA); John Georgitis, MD (Winston-Salem, NC); Pinkus Goldberg, MD (Indianapolis, IN); Marc F. Goldstein, MD (Mt. Laurel, NJ); Margaret Guill, MD (Augusta, GA); Michael Kraemer, MD (Spokane, WA); Joel M. Karlin, MD and Jeffrey Rumbyrt, MD (Denver, CO); Craig LaForce, MD (Raleigh, NC); Michael Lawrence, MD (Taunton, MA); Donald McNeil, MD (Worthington, OH); Michael Mellon, MD (San Diego, CA); Zev M. Munk, MD (Houston, TX); Anjuli S. Nayak, MD (Normal, IL); Gerardo D. Neuwirth, MD (Fridley, MN); James H. Ransom, MD (Topeka, KS); David Skoner, MD (Pittsburgh, PA); Willard F. Washburne, MD (Shreveport, LA); Steven Weiss, MD (Safety Harbor, FL); and Robert Wood, MD (Lutherville, MD). We also acknowledge Deborah Birdsall (FIRSTATS, Inc, Rochester, NY) for her technical support.


   Footnotes
 
Supported by a grant from Rhône-Poulenc Rorer Pharmaceuticals.

Abbreviations: CFC = chlorofluorocarbon; FEF25–75% = forced expiratory flow during midportion of FVC; HFA = hydrofluoroalkane; MDI = metered-dose inhaler; PEF = peak expiratory flow

Received for publication October 1, 1998. Accepted for publication January 12, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

  1. Schwartz, HJ, Blumenthal, M, Brady, R, et al (1996) A comparative study of the clinical efficacy of nedocromil sodium and placebo: how does cromolyn sodium compare as an active control treatment? Chest 109,945-952[Abstract/Free Full Text]
  2. Furukawa, CT, Shapiro, GG, Bierman, CW, et al (1984) A double-blind study comparing the effectiveness of cromolyn sodium and sustained release theophylline in childhood asthma. Pediatrics 74,453-459[Abstract/Free Full Text]
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