Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma

Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma Anjuli S Nayak, MD*; Charles Banov, MD†; Jonathan Corren, MD‡; Barry K Feinstein, MD§; Anthony Floreani, MD㛳; Bruce F Friedman, MD**; Alan Goldsobel, MD††; Gregory M Gottschlich, MD‡‡; Paul J Hannaway, MD§§; Kathy L Lampl, MD¶¶; Robert J Lapidus, MD㛳㛳; Michael Lawrence, MD***; William Lumry, MD†††; Zev Munk, MD‡‡‡; David Pearlman, MD§§§; Anthony T Scardella, MD¶¶¶; Eric J Schenkel, MD㛳㛳㛳; Allen T Segal, MD****; Nathan Segall, MD††††; Bernard Silverman, MD‡‡‡‡; Lucy Shneyer, MS§§§§; Keith B Nolop, MD§§§§; and Judy E Harrison, MD§§§§

Background: Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. Objective: To compare the efficacy and safety of once-daily (AM) administration of mometasone furoate dry powder inhaler (MF DPI) 200 ␮g and 400 ␮g with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. Methods: This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV1 was the primary efficacy variable. Results: At endpoint, both doses of MF DPI were significantly more effective than placebo (P ⱕ .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 ␮g was more effective than placebo (P ⱕ .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 ␮g provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. Conclusions: The results of this study indicate that once-daily (AM) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma. Ann Allergy Asthma Immunol 2000;84:417– 424.

INTRODUCTION Since their introduction more than 20 years ago, inhaled glucocorticoidshave

become central to the management of patients with chronic asthma.1 Their potent anti-inflammatory activity pro-

* Asthma & Allergy Research Associates, SC, Normal, IL and Dept. of Pediatrics, Peoria School of Medicine, Peoria, IL. † Allergy & Asthma Ctrs of Charleston, PA, Charleston, SC; ‡ Allergy Research Foundation, Inc., Los Angeles, CA; § Virginia Allergy & Pulmonary Associates, PC, Richmond, VA; 㛳 University of Nebraska Medical Center, Omaha, NE; ** Allergy, Asthma, Bronchitis and Immunology Associates, Fountain-Valley, CA;

†† Allergy & Asthma Associates, San Jose, CA; ‡‡ Allergy & Asthma Affiliates Research Center, Cincinnati, OH; §§ Allergy Affiliates Inc., Salem, MA; ¶¶ Asthma & Allergy Associates, Rockville, MD; 㛳㛳 Rocky Mountain Pulm. Medical Clinical Research, Wheat Ridge, CO; *** Center for Clinical Research, Taunton, MA; ††† Allergy & Asthma Research Associates, Dallas, TX ‡‡‡ Breco Research, Houston, TX; §§§ Rockland Pulmonary Associates, PC, Denver, CO;

VOLUME 84, APRIL, 2000

vides control of asthma symptoms, improves pulmonary function, decreases bronchial hyperresponsiveness, and may help to prevent airway remodeling.2 Clinical studies have repeatedly shown that the use of inhaled corticosteroids improves control of persistent asthma in all stages of severity.2 Inhaled glucocorticoid therapy is so effective that it is recommended in asthma management guidelines endorsed by such international groups as the United States National Heart, Lung and Blood Institute and the World Health Organization.3,4 Inhaled glucocorticoids are most frequently administered with multiple daily dose regimes in the long-term control of asthma. Although the reasons for patient noncompliance are complex and multifactorial, simplification of the treatment regimen tends to promote improved adherence.5 For example, a study of inhaled medication use in children with asthma found 71% compliance with twice-daily dosing, which decreased to 34% with threetimes-a-day and 18% with four-times-

¶¶¶ Asthma & Allergy Center at St. Peter’s Medical Center, New Brunswick, NJ; 㛳㛳㛳 Valley Clinical Research Center, Easton, PA; **** Allergy Associates Research, Dallas, TX; †††† Georgia Allergy & Respiratory Institute, Atlanta, GA; ‡‡‡‡ Long Island College Hospital, Brooklyn, NY; §§§§ Schering-Plough Research Institute, Kenilworth, NJ. Received for publication February 14, 1999. Accepted for publication in revised form November 22, 1999.

417

a-day dosing.6 These findings are consistent with compliance studies in other chronic diseases, such as epilepsy and hypertension, which have shown consistently greater adherence with once-daily dosing than with multiple daily dose regimens.7–9 Mometasone furoate (MF) is a highly potent topical steroid that has been shown to be effective and well tolerated when administered once daily as an aqueous nasal spray for the treatment of seasonal allergic and perennial rhinitis.10 –12 Mometasone furoate had negligible systemic bioavailability when administered orally or intranasally, and no hypothalamic-pituitaryadrenal axis suppression was reported with single intranasal doses up to 4,000 ␮g, which is 20 times the recommended daily dose.13 Mometasone furoate also is a potent inhibitor of the factors associated with inflammation. In vitro studies have shown MF to be either as potent as or more potent than fluticasone propionate and more potent than beclomethasone dipropionate, budesonide (BUD), and triamcinolone acetonide (TAA) in inhibiting cytokine production.14 –16 Another in vitro study found MF to be more effective than beclomethasone in inhibiting sulfidileukotrine production by primed basophils.17 Mometasone furoate was also the most potent glucocorticoid analyzed in an in vitro study that assessed relative binding affinity for the glucocorticoid receptor and stimulation of receptormediated transactivation of gene expression.18 Because of its high topical potency, low systemic bioavailability, and demonstrated efficacy as a once-daily treatment in allergic rhinitis, MF has been developed as an inhaled formulation for the treatment of asthma. This formulation consists of a pure powderlactose mixture (one part mometasone furoate to 5.8 parts lactose) administered by a novel breath-actuated dry powder inhaler (DPI). The MF-DPI is a multiple-dose inhaler containing the powdered MF-lactose agglomerate in a central reservoir. Removal of the in-

418

haler’s cap automatically releases a single, metered dose of MF into the inhalation channel. Closure of the cap reloads the next dose and simultaneously advances a numerical counter mechanism, displaying the number of doses remaining in the inhaler. The present study was conducted to compare the efficacy and safety of oncedaily administration of MF DPI 200 ␮g, MF DPI 400 ␮g, and placebo in patients with persistent asthma who were not previously taking inhaled glucocorticoids. METHODS Patients Male and female patients aged 12 years or older who had a history of asthma for at least 6 months and had used only a short-acting inhaled betaadrenergic agonist to control their asthma in the previous 2 weeks were eligible to participate in the study. Patients were excluded if they used inhaled glucocorticoids for 3 months prior to screening. All patients were nonsmokers or had stopped smoking for more than 6 months prior to screening. Patients had to demonstrate a baseline forced expiratory volume in 1 second (FEV1) ⱖ55% to ⱕ85% of predicted normal values after all restricted medications had been withheld for the specified intervals. They also had to demonstrate reversibility of airways disease at screening or within the previous 12 months, by an increase in absolute FEV1 of ⱖ12%, with an absolute volume increase of 200 mL, within 30 minutes after bronchodilator administration. The patients must have been using albuterol for acute relief of symptoms of bronchospasm for at least three times per week prior to the baseline visit. Patients were also excluded for any of the following reasons: premenarche, pregnancy, or lactation; immunotherapy, unless on a stable maintenance; treatment with oral glucocorticoids for ⬎14 days in the 6 months before screening, methotrexate, cyclosporine, or gold within 3 months, or oral, inhalation, intramuscular, intra-articular, or

systemic steroids within 3 months, or another investigational drug in the month before screening; daily use of nebulized beta-adrenergic agonists; the need for ventilator support in the previous 5 years; hospitalization for asthma in the previous 3 months; requirement of ⬎12 puffs/day of albuterol on 2 consecutive days between the screening and baseline visits; an upper or lower respiratory tract infection (viral or bacterial) in the 2 weeks prior to screening; or evidence of clinically significant oropharyngeal candidiasis. Women of child-bearing potential were required to use an acceptable method of birth control. Study Design This double-blind, randomized, parallel group study compared the efficacy and safety of once-daily administration in the morning of MF DPI 200 ␮g, MF DPI 400 ␮g, and placebo at 21 study centers in the United States. The protocol was approved by the institutional review boards, and written informed consent was obtained from each patient and from the parent or guardian of patients under 18 years of age. A 1- to 2-week run-in period prior to baseline preceded a 3-month treatment phase. During the run-in period, each patient was provided with an albuterol inhaler (Proventil) to be used as needed or could continue the use of the previously prescribed nebulized betaadrenergic agonist. Each patient received a history, physical examination, hematologic and blood chemistry determinations, urinalysis, EKG, and chest x-ray; all female patients were given a pregnancy test. Topical and oral antihistamines, nasal or ocular decongestants, nasal cromolyn, nasal ipratropium bromide, albuterol and nebulized beta-adrenergic agonists (with a 6-hour hold prior to treatment visits), and immunotherapy (not oral) were permitted after the screening visit and for the remainder of the study. Medications prohibited after the screening visit included those linked with clinically significant hepatotoxicity (eg, methotrexate, 17-alkylsteroids), or induction of liver enzymes (eg, barbitu-

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

Table 1. Summary of Demographic Characteristics

Age (yr) Mean (Range) Sex Male/female Race White/African American/other Body weight (kg) Mean (Range) Smoking history Never/not in past 6 mo

MF DPI 200 ␮g QD (n ⴝ 72)

MF DPI 400 ␮g QD (n ⴝ 77)

Placebo (n ⴝ 87)

33 (14–65)

31 (12–62)

35 (12–72)

34/38

35/42

41/46

62/6/4

65/8/4

76/7/4

79 (49–129)

76 (41–124)

80 (36–136)

56/16

64/13

70/17

Table 2. Asthma-Related Baseline Characteristics. Values Are Indicated as the Mean, Mean (range), or Mean ⫾ SEM MF DPI 200 ␮g QD MF DPI 400 ␮g QD (n ⴝ 72) (n ⴝ 77) Duration of asthma in years Mean (range) FEV1, (%) predicted at baseline Mean (range) FEV1 (L) FVC (L) at baseline FEF25%–75% (L/sec)* AM PEFR (L/min)* Albuterol use (puffs/day)*

Placebo (n ⴝ 87)

17 (1–40)

15 (1–40)

15 (1–48)

72 (54–95) 2.60 ⫾ 0.08 3.56 ⫾ 0.12 2.09 373 ⫾ 12 4.02

72 (46–91) 2.57 ⫾ 0.07 3.40 ⫾ 0.10 2.23 370 ⫾ 11 4.18

73 (53–90) 2.61 ⫾ 0.06 3.55 ⫾ 0.10 2.18 377 ⫾ 11 4.09

* Not determined for one patient in the MF DPI 400 ␮g QD group and one in the placebo group because they were lost to follow-up and had no post-baseline data.

rates), beta-adrenergic blockers (oral or non-selective ophthalmic preparations), ocular, intramuscular, nasal, intra-articular, oral, intravenous and inhaled glucocorticoids, high potency topical corticosteroids for dermatological use, oral decongestants, and astemizole. Oral beta-adrenergic receptor agonists, salmeterol, theophylline and inhaled cromolyn and nedocromil, inhaled anticholinergics, zafirlukast (Accolate), and leukotriene modifiers were also prohibited during the study. At all study visits, spirometry was performed to measure FEV1, forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of vital capacity (FEF25%–75%). Eligible patients were randomized according to a computer-generated

VOLUME 84, APRIL, 2000

code to once-daily treatment each morning with MF DPI 200 ␮g, MF DPI 400 ␮g, or placebo. All patients completed a daily diary card to document morning and evening peak expiratory flow rate (PEFR), asthma symptoms, number of albuterol inhalations, adverse events, and the use of study drug and concomitant medications. The patients reported to the study centers for treatment visits after 1, 2, 4, 8, and 12 weeks of treatment. Efficacy Evaluation The primary efficacy variable was the change from baseline to endpoint (the last evaluative treatment visit) in FEV1. Secondary efficacy variables included mean changes from baseline in FVC, FEF25%–75%, and PEFR; asthma symptom scores; albuterol use; and

physician assessments of response to therapy. Severity of asthma symptoms (wheezing, difficulty breathing, and cough) was rated on a 4-point scale (0 ⫽ none, 1 ⫽ noticeable, 2 ⫽ annoying, 3 ⫽ very uncomfortable). The physicians numerically rated the response to therapy (1 ⫽ much improved, 2 ⫽ improved, 3 ⫽ no change, 4 ⫽ worse, or 5 ⫽ much worse) compared with the level of symptoms at baseline. Quality of Life Determinations The quality of life data in this study were measured with the widely used and validated general health questionnaire (SF-3619) and an asthma-specific module20 that evaluated breathlessness, mood, social impact, asthma concerns, psychosocial impact, and physical symptoms. Both the SF-36 and the asthma-specific questionnaires use the past week as the reference period for assessment. The questionnaire was administered at the baseline visit and at the 12-week visit (or last visit if discontinued early). Time to Worsening of Asthma Time to worsening of asthma was recorded and was defined as the first occurrence of any of the following: 20% or greater decrease in FEV1 from baseline; clinical asthma exacerbation requiring emergency treatment, hospital admission, or treatment with asthma medications in addition to those permitted in the protocol; 25% or greater decrease on two consecutive days in AM or PM peak flow from the mean baseline AM value; more than 12 puffs per day for two consecutive days of use of a rescue bronchodilator (Proventil); or more than two treatments with nebulized beta-adrenergic receptor agonists on two consecutive days. Results were analyzed using a log rank assessment. Safety Assessments All patients were monitored for adverse events and changes in physical examination, including oropharyngeal examination, vital signs, hematologic and blood chemistry profiles, and EKG

419

cance. If the comparison of MF DPI 400 ␮g to placebo was significant, the other two pairwise comparisons were made without adjustment to the alphalevel. The same two-way ANOVA was used to analyze the change in FEV1 from baseline at each treatment visit, as well as the other secondary efficacy variable.

Figure 1. The effects of MF DPI QD on the mean change in FEV1 over the course of the study and at endpoint. (A) The mean change for placebo (circles), MF DPI 200 ␮g QD (triangles) and MF DPI 400 ␮g QD (squares) are indicated at weeks 1, 2, 4, 8, and 12. (B) The change from baseline to endpoint includes the last evaluative treatment visit for all subjects and accounts for those subjects discontinuing over time. The number of subjects for each mean is indicated in parentheses for both panels with the SEM bars. *P ⱕ. 01 versus placebo; †P ⫽ .01 versus MF DPI 400 ␮g QD.

during the 12-week, double-blind treatment period. Statistical Analysis A sample size of 70 patients per treatment group was chosen to detect a clinically meaningful difference in the mean change from baseline in FEV1 of 0.25 L (10% of baseline) between any paired treatment group, with 90% power and a two-sided level of significance, ␣ ⫽ 0.05. The primary efficacy analyses were based on all randomized patients who received at least one dose

420

of study medication and who had postbaseline data (intent-to-treat principle). To account for expected discontinuance, especially in the placebo group, endpoint was defined as the last observation for a given subject. The primary efficacy variable was analyzed for all patients using a two-way analysis of variance (ANOVA) model, extracting sources of variation due to treatment and center. Pairwise comparisons were based on least square means from the ANOVA using a 5% level of signifi-

RESULTS Patient Population A total of 236 patients, 12 to 72 years old, was randomized to one of the three treatment groups, and all received at least one dose of study medication. The comparability of the treatment groups at baseline was assessed by comparing the three groups with respect to sex, age, weight, race, and disease characteristics (baseline FEV1 and PEFR). The three treatment groups were found to be comparable at baseline with respect to demographics (Table 1) and asthma-related characteristics (Table 2). Analysis at endpoint showed no age, sex, or race related differential response to therapy. Overall, 81% of the patients completed the study. A total of 44 patients discontinued treatment before the end of the 12-week treatment period, including 7 patients in the once-daily MF DPI 200 ␮g group (10%), 15 patients in the once-daily MF DPI 400 ␮g group (19%), and 22 patients in the placebo group (25%). The major reason for discontinuation was adverse events, and the distribution was comparable among the groups: 8% for MF DPI 200 ␮g QD, 12% for MF DPI 400 ␮g QD, and 10% for placebo. Only one patient in each of the MF DPI groups discontinued due to treatment failure, while seven patients in the placebo group did so. Evaluation of Efficacy: Pulmonary Function There was a consistent improvement in FEV1 observed with MF DPI relative to placebo throughout the study (Fig 1A) and at endpoint (Fig 1B). The increases in both MF DPI groups were of comparable magnitude and not statistically different from one another, ex-

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

Table 3. Summary of Efficacy Results by Endpoint Analysis*

Pulmonary Function FEV1 (L) FVC (L) FEF25%–75% (L/sec) Patients’ self-reports (scale 0–4; none to very uncomfortable) AM wheezing scores AM difficulty breathing scores AM cough scores Albuterol (No. of puffs per day) Physician evaluated response to therapy scores (scale 1–5; much improved to much worse)

MF DPI 200 ␮g QD (n ⴝ 72)

MF DPI 400 ␮g QD (n ⴝ 76)

Placebo (n ⴝ 86)

0.35† ⫾ 0.05 0.23 ⫾ 0.08‡ 0.65 ⫾ 0.09†

0.35† ⫾ 0.04 0.38 ⫾ 0.06† 0.37 ⫾ 0.07§

0.06 ⫾ 0.05 0.02 ⫾ 0.08 0.08 ⫾ 0.08

⫺0.40¶ ⫺0.44¶ (n⫽71) ⫺0.06 (n⫽71) ⫺1.58† 2.28†

⫺0.39¶ ⫺0.48¶ ⫺0.20 ⫺2.23† 2.17†

⫺0.14 ⫺0.20 ⫺0.05 ⫺0.47 2.60

* The change from baseline to endpoint includes the last evaluative treatment visit for all treated subjects and accounts for those subjects discontinuing over time. Values are expressed as the mean change in value and include the SEM for FEV1, FVC, and FEF25%–75%. † P ⱕ .01 versus placebo (change from baseline). ‡ P ⫽ .05 versus placebo (change from baseline). § P ⫽ .02 versus MF DPI 200 ␮g QD (change from baseline). ¶ P ⱕ .05 versus placebo (absolute score; change from baseline).

cept at week 8. The percentage change at endpoint was 14.8% (MF DPI 200 ␮g), 14.2% (MF DPI 400 ␮g), and 2.5% (placebo). Analyses of improvements in FVC and FEF25%–75% at endpoint also indicated that once-daily treatment with MF DPI 200 or 400 ␮g was superior to placebo (Table 3). Throughout the study, the FVC values were numerically greater for the MF DPI groups relative to the placebo; they were statistically significant at 1, 4, and 12 weeks for the MF DPI 400 ␮g group (P ⱕ .05) and at 4, 8, and 12 weeks for the MF DPI 200 ␮g group (P ⫽ .05; time course data not shown). The FEF25%–75% was significantly improved (P ⱕ .01) for the MF DPI 200 ␮g group compared with placebo group from week 1 onward (P ⱕ .01; time course data not shown). Peak expiratory flow rate was measured each day in the morning (before dosing) and approximately 12 hours later by the patient and prior to the use of albuterol (if required); the results were recorded in the patient diaries. Mean values for AM PEFR were significantly higher for patients in the oncedaily MF DPI 400 ␮g group than those

VOLUME 84, APRIL, 2000

for the placebo group as early as the fourth day (P ⱕ .05) and remained higher throughout the study (P ⱕ .01; Fig 2A) and at endpoint (P ⱕ .01; Fig. 2B). The greatest improvement in AM PEFR occurred over the first 2 weeks (Fig 2A). The once-daily MF DPI 200 ␮g group was numerically improved (7.5% increase at endpoint) but not statistically different from placebo at any point throughout the study. Time to Worsening of Asthma Kaplan-Meier estimates of time to worsening of asthma showed that both MF DPI groups were clearly better than placebo (Fig 3). Because fewer than 50% of patients in each of the three groups had met the criteria for worsening by the time of their last visit, median time to worsening could not be determined during the 12-week treatment period. However, this measure of efficacy further supported the other variables in demonstrating that both MF DPI 200 ␮g and 400 ␮g were superior to placebo and provided effective control of asthma. More patients (26 patients) in the placebo group experienced asthma worsening than in either the MF DPI 400 ␮g (9 patients)

or the MF DPI 200 ␮g (13 patient) groups. A log rank assessment showed that both MF DPI treatment groups were significantly different from placebo (P ⱕ .01; Fig 3). Evaluation of Asthma Symptoms Asthma symptom scores were in the mild to moderate range at baseline. Improvements in the scores for wheezing and difficulty breathing for the MF DPI groups (Table 3) indicated that active treatment was superior to placebo. At endpoint, AM wheezing scores had improved significantly in both MF DPI groups compared with placebo (Table 3). The difference between the two MF DPI groups was not significant (P ⫽ .88). Significantly greater improvement in AM difficulty breathing scores was also observed for the MF DPI 200 and 400 ␮g groups over placebo (Table 3) with no significant difference between the MF DPI groups. Similar results were observed in the scores for PM wheezing, difficulty breathing, and cough (data not shown). At endpoint, albuterol use had decreased significantly for both MF DPI groups compared with the placebo group (Table 3). Physicians’ Evaluation of Response to Therapy The physicians evaluated the patient’s response to therapy at each treatment visit, comparing the level of symptoms with baseline. Statistical analysis confirmed the difference between the physicians’ numerical scores at endpoint between placebo and the active treatment groups (P ⱕ .01: Table 3). The percentage of patients considered much improved or improved was similar in the MF DPI 200 ␮g (64%) and 400 ␮g (66%) treatment groups and both were higher than the placebo group (50%) at endpoint. Symptoms worsened in only 5% (MF DPI 200 ␮g) and 8% (MF DPI 400 ␮g) of the active treatment groups as compared with 21% for the placebo group. Health-Related Quality of Life Of the 236 patients enrolled in the study, 221 (94%) completed the quality of life questionnaires at both the

421

Only five patients reported one or more severe adverse events considered by the investigator to be related to treatment. There were no life-threatening adverse events considered related to treatment. Severe treatment related events were reported in one patient in the placebo group (coughing), three patients in the MF DPI 200 ␮g QD group (dysphonia and coughing in one patient, nausea in another, and bronchitis in the third), and one patient in the MF DPI 400 ␮g QD group (weight increase). No clinically relevant changes in vital signs, results of physical examinations, or clinical laboratory tests were observed from baseline to endpoint for any treatment group. No ECG abnormalities reported during the study were considered to be clinically significant.

Figure 2. The effects of MF DPI QD on the mean change in morning peak expiratory flow rate (AM PEFR) over the course of the study and at endpoint. (A) The mean change for placebo (circles), MF DPI 200 ␮g QD (triangles) and MF DPI 400 ␮g QD (squares) are indicated at weeks 1, 2, 4, 6, 8, 10, and 12. (B) The change from baseline to endpoint includes the last evaluative treatment visit for all subjects and accounts for those subjects discontinuing over time. The number of subjects for each mean is indicated in parentheses for both panels with the SEM bars. *P ⱕ .05 versus placebo; †P ⱕ .05 versus MF DPI 200 ␮g QD.

baseline and endpoint of the study. The patients had a low burden of disease, based on baseline scores and the published values for the United States population.20,21 Evaluation of Safety Analysis of safety data showed that both doses of MF DPI were well tolerated. Treatment-related adverse events occurred at a similar incidence among the three groups (Table 4). The

422

most frequently reported events were headache, oral candidiasis, and pharyngitis. Treatment-related headache and pharyngitis occurred at a similar incidence in all treatment groups. The incidence of treatment-related oral candidiasis was low (3% to 4%) for all treatment groups and did not lead to study discontinuation for any patient. Treatment-related adverse events were mild or moderate in severity.

DISCUSSION This 12-week, multicenter study demonstrated that once-daily (QD) MF DPI was an effective and well-tolerated treatment for patients with mildto-moderate persistent asthma. These patients had a minor burden of disease at the beginning of the study, as reflected by the quality of life questionnaire. Once-daily (AM) treatment with either dosage of MF DPI (200 ␮g or 400 ␮g) significantly increased FEV1 at endpoint, the primary efficacy variable. Both active treatments were more effective than placebo at improving asthma symptoms and physician-evaluated response to therapy, as well as reducing the use of rescue medication. Significant improvement for most parameters occurred within the first week of treatment. Although both regimens of MF DPI QD demonstrated excellent efficacy overall, improvement in morning PEFR was greater in the MF DPI 400 ␮g group than in the 200 ␮g group. These results indicate that MF DPI 400 ␮g QD was the optimal single daily dosage, as administered in the morning, for the overall population of patients examined; however, treatment with MF DPI 200 ␮g QD likely provides adequate control for many of these patients.

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY

Figure 3. The effects of MF DPI QD on the Kaplan-Meier estimates of time to worsening of asthma. Both active treatment groups were significantly different from placebo (P ⱕ .01).

Table 4. Incidence of Frequently Reported Treatment-Related Adverse Events*

Any adverse event Headache Pharyngitis Dysphonia Oral candidiasis Weight increase Tremor

MF DPI 200 ␮g QD (n ⴝ 72)

MF DPI 400 ␮g QD (n ⴝ 77)

Placebo (n ⴝ 87)

14 (19%) 6 (8%) 2 (3%) 1 (1%) 2 (3%) 0 (0%) 0 (0%)

19 (25%) 5 (6%) 4 (5%) 2 (3%) 3 (4%) 2 (3%) 2 (3%)

19 (22%) 5 (6%) 5 (6%) 2 (2%) 1 (1%) 0 (0%) 0 (0%)

When first introduced more than 20 years ago, inhaled glucocorticoids were administered in fixed doses four times a day. Since then, newer and more potent agents have been developed, allowing for more flexible dosing regimens that can be tailored to the disease state of the individual patient.22 The efficacy of twice-daily doses for the treatment of mild-or-moderate asthma has been shown in studies with FP in doses up to 500 ␮g twice daily,23–26 BUD in doses up to 800 ␮g twice daily,27,28 and TAA at 400 ␮g twice daily.29,30 A number of investigators have compared once-daily to twice-daily regimens of inhaled FP and BUD in the treatment of adults with asthma, but the results have been mixed.31–33 For example, once-daily FP 200 ␮g was less effective than twice-daily FP

VOLUME 84, APRIL, 2000

100 ␮g in improving morning and evening PEFR in a 12-week study.32 On the other hand, once-daily BUD 200 ␮g was found to be as effective as twice-daily BUD 100 ␮g in adults with mild-to-moderate asthma, although this study was not placebo-controlled.31 In another study, which also lacked a placebo group, once-daily BUD 800 ␮g was less effective than twice-daily BUD 400 ␮g for long-term management of PEF, asthma symptoms, and rescue medication use.33 Studies have found that simplifying the treatment regimen tends to improve asthma compliance.5,6 In general, the less complicated the dosing regimen, the better patients adhere to long-term therapy; therefore, once-daily administration of an effective inhaled glucocorticoid may be the most desirable dosing option for most patients with

persistent asthma. In the present placebo-controlled study in which only once daily dosing was examined, 12 weeks of MF DPI provided consistent and substantial improvements in efficacy, as measured by pulmonary function (FEV1, PEFR, FVC, FEF25%–75%), asthma symptoms, physician-evaluated response to therapy and use of rescue medication. Further, statistically significant improvements in FEV1 and PEFR were noted after 1 week of therapy in the MF DPI 400 ␮g group, suggesting that this dosage afforded a more rapid onset of action. In summary, this 12-week study demonstrated that once-daily administration of inhaled MF via a novel dry powder inhaler was significantly more effective than placebo in the treatment of patients with mild-to-moderate persistent asthma. Although both MF DPI QD dosages (200 ␮g and 400 ␮g) were efficacious, MF DPI 400 ␮g QD, as administered in the morning, resulted in greater overall improvement in these patients; therefore, 400 ␮g would be the suggested starting dose, with a reduction to 200 ␮g likely possible in many patients. Given that the majority of patients with persistent asthma have a mild or moderate form of the disease, this study indicates that once-daily MF DPI can provide a convenient and effective option for most patients who require inhaled glucocorticoid therapy. REFERENCES 1. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995;332: 868 – 875. 2. Pedersen S, O’Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997;52:1–34. 3. National Heart Lung and Blood Institute. National Asthma Education Program, Expert Panel Report 2. Guidelines for the diagnosis and management of asthma. Bethesda, MD: US Department of Health and Human Services; 1997. Report No.: 97-4051. 4. Global Initiative for Asthma. Global strategy for asthma management and prevention NHLBI/WHO workshop report. Bethesda, MD: National Institutes of Health, National Heart, Lung

423

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

424

and Blood Institute; 1995. Report No.: 95-3659. Bender B, Milgrom H, Rand C. Nonadherence in asthmatic patients: is there a solution to the problem? Ann Allergy Asthma Immunol 1997;79: 177–186. Coutts JA, Gibson NA, Paton JY. Measuring compliance with inhaled medication in asthma. Arch Dis Child 1992;67:332–333. Farmer KC, Jacobs EW, Phillips CR. Long-term patient compliance with prescribed regimens of calcium channel blockers. Clin Ther 1994;16: 316 –326. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150:1881–1884. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. Jama 1989;261:3273–3277. Drouin M, Yang WH, Bertrand B, et al. Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclomethasone dipropionate for treating perennial allergic rhinitis patients. Ann Allergy Asthma Immunol 1996;77:153–160. Graft D, Aaronson D, Chervinsky P, et al. A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray. J Allergy Clin Immunol 1996; 98:724 –731. Hebert JR, Nolop K, Lutsky BN. Once-daily mometasone furoate aqueous nasal spray (Nasonex) in seasonal allergic rhinitis: an active- and placebo-controlled study. Allergy 1996;51: 569 –576. Brannan MD, Seiberling M, Cutler DL, et al. Lack of systemic activity with intranasal mometasone furoate. J Allergy Clin Immunol 1996;97:198. Barton BE, Jakway JP, Smith SR, Siegel MI. Cytokine inhibition by a novel steroid, mometasone furoate. Immunopharmacol Immunotoxicol 1991;13: 251–261. Crocker IC, Church MK, Newton S,

16.

17.

18.

19.

20.

21. 22.

23.

24.

25.

Townley RG. Glucocorticoids inhibit proliferation and interleukin-4 and interleukin-5 secretion by aeroallergenspecific T-helper type 2 cell lines. Ann Allergy Asthma Immunol 1998;80: 509 –516. Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effects of topically active glucocorticoids on IL-4, IL-5, and interferon-gamma production by cultured primary CD4⫹ T cells. J Allergy Clin Immunol 1997;100: 511–519. Crocker IC, Zhou CY, Bewtra AK, et al. Glucocorticosteroids inhibit leukotriene production. Ann Allergy Asthma Immunol 1997;78:497–505. Smith CL, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Arzneimittelforschung 1998;48:956 –960. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30: 473– 483. Marks GB, Dunn SM, Woolcock AJ. A scale for the measurement of quality of life in adults with asthma. J Clin Epidemiol 1992;45:461– 472. Schering-Plough Research Institute; 1992. Report No.: P92-240. Data on file. Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998;157:S1–53. Katz Y, Lebas FX, Medley HV, Robson R. Fluticasone propionate 50 micrograms BID versus 100 micrograms BID in the treatment of children with persistent asthma. Fluticasone Propionate Study Group. Clin Ther 1998;20: 424 – 437. Pearlman DS, Noonan MJ, Tashkin DP, et al. Comparative efficacy and safety of twice daily fluticasone propionate powder versus placebo in the treatment of moderate asthma. Ann Allergy Asthma Immunol 1997;78: 356 –362. Wasserman SI, Gross GN, Schoenwetter WF, et al. A 12-week dose-ranging study of fluticasone propionate powder

26.

27.

28.

29.

30.

31.

32.

33.

in the treatment of asthma. J Asthma 1996;33:265–274. Wolfe JD, Selner JC, Mendelson LM, et al. Effectiveness of fluticasone propionate in patients with moderate asthma: a dose-ranging study. Clin Ther 1996;18:635– 646. Busse WW, Chervinsky P, Condemi J, et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998;101: 457– 463. Osterman K, Carlholm M, Ekelund J, et al. Effect of 1 year daily treatment with 400 microg budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics. Eur Respir J 1997;10: 2210 –2215. Bernstein DI, Cohen R, Ginchansky E, et al. A multicenter, placebo-controlled study of twice daily triamcinolone acetonide (800 microg per day) for the treatment of patients with mildto-moderate asthma. J Allergy Clin Immunol 1998;101:433– 438. Ramsdell JW, Fish L, Graft D, et al. A controlled trial of twice daily triamcinolone oral inhaler in patients with mild-to-moderate asthma. Ann Allergy Asthma Immunol 1998;80:385–390. Chisholm SL, Dekker FW, Knuistingh, et al. Once-daily budesonide in mild asthma. Respir Med 1998;92: 421– 425. Johansson L-O. A comparison of oncedaily regimen of fluticasone propionate (FP) 200 mg and budesonide (BUD) 400 mg and twice-daily regimine of fluticasone propionate 100 mg. Eur Respir J 1998;12:38S. Weiner P, Weiner M, Azgad Y. Long term clinical comparison of single versus twice daily administration of inhaled budesonide in moderate asthma. Thorax 1995;50:1270 –1273.

Request for reprints should be addressed to: Anjuli S. Nayak, MD Asthma & Allergy Research Associates, SC 1300 Franklin Avenue, Suite 180 Normal, IL 61761-3588.

ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY