Supplementary Appendix

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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:

2 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Rescue Use of Inhaled Beclomethasone and Albuterol in a Single Inhaler in Mild Asthma. Alberto Papi MD, Giorgio W. Canonica MD, Piero Maestrelli MD, Pierluigi Paggiaro MD, Dario Olivieri MD, Ernesto Pozzi MD, Nunzio Crimi MD, Antonio M. Vignola MD, Paolo Morelli PhD, Gabriele Nicolini PharmD, and Leonardo M. Fabbri MD on behalf of the BEclomethasone plus Salbutamol Treatment (BEST) Study Group.

3 INTRODUCTION The rationale for including the four groups considered in the study is as follows: 1. The group treated with the as-needed beclomethasone/albuterol combination was the experimental group. 2. The group treated with as-needed albuterol alone was included as a control, to determine whether patients with a diagnosis of mild persistent asthma, who were controlled during the run-in period with a dose of 500 μg/day of inhaled beclomethasone, became symptomatic after withdrawal of inhaled beclomethasone suggesting that they indeed required additional treatment. 3. The group treated with the regular beclomethasone twice daily was included as the reference group treated according to guidelines The group treated with the regular beclomethasone/albuterol combination twice daily was included to investigate whether the effect of the beclomethasone/albuterol combination was equivalent if used as-needed or regularly. PATIENTS AND METHODS 1

4 The study was performed in accordance with the good clinical-practice guidelines recommended by the International Conference on Harmonization of Technical Requirements. The protocol was registered on the website of the National Library of Medicine ( no. NCT ). Patients We screened patients with functional and clinical characteristics of mild persistent asthma at the time of recruitment according to the 1997 EPR2 guidelines, as well as patients already treated by their physician with inhaled corticosteroids below the daily dose of 500 μg/day because of a historical diagnosis of mild persistent asthma 1. Exclusion criteria were current smoking or ex-smoking habits (>10 packs/year), COPD as defined by the European Respiratory Society (ERS)-Consensus Statement 2, history of near-fatal asthma and/or admission to emergency room/intensive care unit because of asthma, 3 or more courses of oral corticosteroids or hospitalization for asthma during the previous year, or regular treatment for >6 months with 500 μg/day of beclomethasone or equivalent. 2

5 Protocol Drugs used in the 4-week run-in period were 250 μg inhaled beclomethasone twice daily (Clenil 250 metered dose inhaler [MDI], Chiesi Farmaceutici, Parma, Italy) plus rescue albuterol 100 μg (Butovent MDI, Chiesi Farmaceutici, Parma, Italy). Drugs used during treatment period were: (i) twice-daily inhaled placebo and as-needed inhaled 250 μg beclomethasone/100 μg albuterol combination (Clenil Compositum 250 MDI, Chiesi Farmaceutici, Parma, Italy); (ii) twice-daily inhaled placebo and as-needed inhaled 100 μg albuterol (Butovent MDI, Chiesi Farmaceutici, Parma, Italy); (iii) twice-daily inhaled 250 μg beclomethasone alone (Clenil 250 MDI, Chiesi Farmaceutici, Parma, Italy) and as-needed inhaled 100 μg albuterol; or (iv) twice-daily inhaled 250 μg beclomethasone/100 μg albuterol combination and as-needed 100 μg albuterol. MDI devices were identical in shape and used in all groups to ensure a double-blind design. The inhalation devices containing regular treatment (beclomethasone, beclomethasone/albuterol combination or placebo) were blue, whereas those for as-needed treatment (albuterol or 3

6 beclomethasone/albuterol combination) were green. A package insert written in the local language containing the instructions for use was included in each test treatment. Patients were instructed to take 1 puff in the morning and 1 puff in the evening from the blue device, and one or more puffs when needed for symptoms relief from the green device. Patients were individually instructed to use the MDIs with the support of the package insert. Patients were instructed to measure their PEF morning and evening before taking the study medication; three values were to be recorded each time on diary cards, and the highest value was used for assessment. Patients were also instructed to record daily asthma symptoms, number of nocturnal awakenings, study drug intake and number of rescue puffs. Daytime symptoms were evaluated in the evening on a 4-point 3 scale ranging from 0 (no symptoms) to 4 (symptoms for most of the day which affected normal daily activities), whereas nighttime symptoms were evaluated in the morning on a 4- point scale ranging from 0 (no symptoms during the night) to 4 (symptoms so severe that they did not allow the patient to sleep at all). At each visit, a physical examination was performed, blood pressure, heart rate, and pulmonary function were measured, and asthma symptoms, asthma exacerbations, and adverse events were 4

7 reported. Pulmonary function tests were given and measured according to ERS guidelines 4, at least 8 hours after the patient s last rescue medication and before study drug morning dose. Outcome Variables Secondary outcomes were (i) the mean value of evening PEF measured during the last 2 weeks of treatment, (ii) daily variability of PEF measured during the last 2 weeks of treatment; (iii) the percentage of days without the use of albuterol and/or without asthma symptoms during the last 2 weeks of treatment; (iv) the asthma symptom score during the last 2 weeks of treatment; (v) the number of exacerbations; (vi) the time to first exacerbation; (vii) changes from baseline lung function parameters and (viii) changes from baseline asthma clinical/symptoms scores. Patients with 2 severe exacerbations were withdrawn from the study. A 10-day course of oral corticosteroids (30 mg of prednisone or prednisolone or 24 mg of methyl-prednisolone) plus as-needed use of albuterol was prescribed for treatment of severe exacerbations. Safety parameters were the number of adverse events, adverse drug reactions and serious adverse events, and the change from baseline in heart rate and blood pressure. 5

8 Statistical Analysis A posteriori, with the actual sample size of 455 examined subjects, adjusting the morning PEF standard deviation for baseline (SD=55 L/min), we found that the actual power of our study with a hypothesis of equivalence, α=0.05 (2-sided), was >80% to detect a difference of 23 L/min between treatment groups, and with a hypothesis of non-inferiority, α =0.05 (2-sided), was >80% to detect a clinical difference of 20 L/min between treatment groups. These values are similar to the value of 25 L/min used to power previous studies in mild persistent asthma 5, 6. No formal adjustment of the type I error was performed because the comparisons were a priori ordered according to clinical relevance. The alpha levels for the three primary tests were controlled for multiplicity using a prioritization method of adjustment for multiple testing. Under this method of statistical testing, the tests were prospectively prioritized, and each subsequent test was conducted only if the preceding test was significant at the α=0.05. Specifically, the initial test was the superiority of as-needed beclomethasone/albuterol combination vs. as-needed albuterol. If the initial test showed the superiority, then the equivalence of the investigational treatment vs. regular beclomethasone was conducted. Finally, if the second test confirmed the equivalence, then the equivalence between the investigational treatment and regular beclomethasone/albuterol combination was conducted. This 6

9 prioritization method of adjustment for multiple testing regarded only the primary outcome morning PEF and not the secondary outcomes. Statistical Methods Regarding the primary variable (i.e. the mean value of the highest of the three values of morning PEF on a 2-week basis from the patient s diary card), a minimum of 10 measurements were required in each 2-week period. In the case of fewer than 10 measurements, the entire 2-week period was excluded from analysis. As Last Observation Carried Forward (LOCF) analysis might inflate the apparent sample size and spuriously increase the precision of estimates of treatment effect, we report the results obtained by using either the LOCF or the Maximum Likelihood (ML) analyses. Demographic and baseline characteristics were summarized by means of descriptive statistics (number of subjects, mean, standard deviation, median, minimum and maximum) or frequency distributions (number and percent), as appropriate. For parameters recorded on diary cards, the mean values of the last week of the run-in period were considered for baseline. For parameters measured at clinic visits, values recorded at visit 2 were considered for baseline. 7

10 For the primary efficacy analysis, a 2-sided 95% confidence interval for the difference in final PEF recorded by patients on diary cards for the investigational treatment minus regular beclomethasone and for the investigational treatment minus regular beclomethasone/albuterol combination was used to demonstrate the equivalence. A margin of equivalence was chosen in the protocol by defining the largest difference that is clinically acceptable and was equal to 40 L/min, i.e., 10% of the expected average morning PEF at the end of treatment, which was hypothesized to be 400 L/min. The two treatments were declared equivalent if the 2-sided 95% confidence interval lay entirely within the interval to +. A preliminary test for treatment by geographic region interaction was planned at 0.10 significance level. The ANCOVA model was used to verify the superiority of the investigational treatment compared to as-needed albuterol. For the secondary efficacy variables, missing data was replaced using the LOCF and LM techniques. The ANCOVA model was also used and the 2-sided 95% confidence interval was evaluated, although no predefined criteria for determining equivalence were stated. The number of patients experiencing adverse events, adverse drug reactions and serious adverse events during the treatment period were evaluated by means of frequency distributions. Differences 8

11 between treatment groups of patients who experienced adverse events, adverse drug reactions and serious adverse events were evaluated using the χ 2 test or 2-tailed Fisher exact test. The number of exacerbations and the number of patients experiencing exacerbations were evaluated by means of frequency distributions. The number of exacerbations per patient/year was calculated as (total number of exacerbations/number of patients) x /mean of extent of exposure. Times to the first exacerbation were compared by means of Kaplan-Meier curves. Statistical analysis was performed using SAS, version 8.2, on a Windows 2000 operating system. RESULTS About 30% of the patients were receiving low-dose inhaled corticosteroids at screening, while the remaining 70% of the patients were not on inhaled corticosteroids. At run-in, patients were treated for 4 weeks with 250 μg BDP twice daily, and only those patients adequately controlled at the end of the run-in period were randomized to the treatment study phase. Thus, according to guidelines 1, 7 severity 9

12 can be defined as mild persistent even if some subjects have characteristics that border on moderate persistent asthma. Population Groups were well matched for demographic and clinical parameters (Table 1 of the manuscript): (i) mean morning PEF recorded during the last week of the run-in period, as well as all laboratory lung function tests measured during the same time, and (ii) daytime and nighttime symptom scores, use of rescue medication, nocturnal awakenings, and symptom-free days during the run-in period. Furthermore, adherence to regular study medication regimens, estimated from diary cards (>97%), was no different between groups. Exacerbations Although not specifically instructed to do so, all patients referred to the investigator when they experienced severe exacerbations. Thus, all the courses of oral corticosteroids were prescribed by an investigator physician involved in the study. 10

13 Safety The safety results of the present study showed that the number of adverse events reported during the treatment phase and the proportion of patients with adverse events were similar in all treatment groups. The number of adverse drug reactions (i.e., those events having a certain/definite, probable/likely, or possible correlation with study drug) was also low and similar across all treatment groups. Serious adverse events were reported in the main manuscript. Two cases of oral candidiasis were reported in the two groups of patients taking regular beclomethasone treatment. One patient in the regular beclomethasone/albuterol combination group left the study prematurely because of adverse events (acute tonsillitis). Events likely to be due to potential lack of efficacy consisted of uncontrolled asthma and were reported in 1 patient (0.8%) in the as-needed beclomethasone/albuterol combination group, 5 patients (4.2%) in the as-needed albuterol group, 3 patients (2.8%) in the regular beclomethasone group, and none in the regular beclomethasone/albuterol combination group. No changes of systolic or diastolic blood pressure were observed in any group, whereas a nonclinically significant increase of heart rate, likely to be due to the use of rescue albuterol, was observed 11

14 in all groups. Palpitation and tachycardia were reported in only 1 patient in the as-needed beclomethasone/albuterol combination group and 1 patient in the regular beclomethasone/albuterol combination group. 12

15 References 1. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma:expert panel report 2. Bethesda (MD): National Institutes of Health, National Heart, Lung and Blood Institute.; Siafakas NM, Vermeire P, Pride NB, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J 1995;8(8): Ringdal N, Chuchalin A, Chovan L, Tudoric N, Maggi E, Whitehead PJ. Evaluation of different inhaled combination therapies (EDICT): a randomised, double-blind comparison of Seretide (50/250 microg bd Diskus vs. formoterol (12 microg bd) and budesonide (800 microg bd) given concurrently (both via Turbuhaler) in patients with moderate-to-severe asthma. Respir Med 2002;96(11): Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 1993;16: Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352(15): Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996;335(12): Global initiative for asthma. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Updated Bethesda, MD: National Heart, Lung and Blood Institute;

16 Figure 1 Supplementary Appendix Figure 1: Estimated number of exacerbations per patient per year in the four study groups.. As-needed combination therapy consisted of placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; as-needed albuterol therapy, placebo twice daily plus 100 μg of albuterol as needed; regular beclomethasone therapy, 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed; and regular combination therapy, 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. 14

17 Figure 2 Supplementary Appendix Figure 2: Cumulative doses of beclomethasone inhaled during the entire 6-month treatment period. Data are expressed as mean (SD). As-needed combination therapy consisted of placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; as-needed albuterol therapy, placebo twice daily plus 100 μg of albuterol as needed; regular beclomethasone therapy, 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed; and regular combination therapy, 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. ** P <

18 Table A Supplementary Appendix Table A. Changes versus baseline at the end of the 6-month study. Missing values replaced by Last Observation Carried Forward (LOCF) technique. As-needed combination therapy consisted of placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; asneeded albuterol therapy, placebo twice daily plus 100 μg of albuterol as needed; regular beclomethasone therapy, 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed; and regular combination therapy, 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. As-needed combination Mean p (SE) value Morning PEF 1.23 L/min (2.8) Evening PEF 1.44 L/min (3.1) PEF variability % (0.44) FEV 1 L 0.12 (0.03) FEV 1 % of 3.70 predicted value (0.89) FVC L 0.10 (0.04) FVC % of 2.77 predicted value (0.92) Daytime asthma symptoms (0.13) Night-time asthma 0.09 symptoms (0.15) Nocturnal awakenings (0.04) Symptom-free 6.21 days, % Rescue medication puffs/day (2.8) 0.08 (0.06) (3.6) (3.5) (0.40) < (0.03) < (1.2) (0.03) (1.2) (0.14) (0.12) (0.04) (3.7) (0.09) As-needed albuterol p Mean (SE) value Regular beclomethasone p Mean (SE) value (3.3) (3.5) (0.49) (0.03) (0.94) (0.03) (0.92) (0.19) (0.17) (0.03) (2.9) (0.07) < (2.9) (0.06) Regular combination p Mean (SE) value (3.0) (2.9) (0.36) (0.04) (0.98) (0.04) (1.03) (0.11) (0.10) (0.03) < Values reflect mean (± SE) change from baseline to the end of the treatment period. Abbreviations: FEV 1, forced expiratory volume volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow. 16

19 Table B Supplementary Appendix Table B. Changes versus baseline at the end of the 6-month study Missing values replaced by Maximum Likelihood (ML) technique. As-needed combination therapy consisted of placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; as-needed albuterol therapy, placebo twice daily plus 100 μg of albuterol as needed; regular beclomethasone therapy, 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed; and regular combination therapy, 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. As-needed combination Mean (SE) Morning PEF L/min 1.80 (2.38) Evening PEF L/min 2.41 (2.32) PEF variability % (0.33) FEV 1 L 0.11 (0.28) FEV 1 % of predicted 3.53 value (0.84) FVC L 0.10 (0.03) FVC % of predicted value 2.71 (0.93) Daytime asthma symptoms (0.09) Night-time asthma symptoms (0.10) Nocturnal awakenings (0.02) Symptom-free days, % 7.69 (2.50) Rescue medication 0.04 puffs/day (0.06) As-needed albuterol p Mean (SE) value (2.40) (2.36) (0.34) < (0.28) < (0.85) (0.03) (0.93) (0.10) (0.10) (0.02) (2.53) (0.06) p value Regular beclomethasone Mean (SE) (2.53) (2.45) (0.35) (0.30) (0.89) (0.04) (0.98) (0.10) (0.10) (0.02) (2.65) (0.06) p value Regular combination Mean (SE) (2.46) (2.42) (0.35) (0.29) (0.87) (0.04) (0.97) < (0.10) (0.10) (0.02) < (2.60) (0.06) p value < Values reflect adjusted mean (SE) change from baseline to the end of the treatment period. Covariates included geografic region, treatment effect and baseline values. Abbreviations: FEV 1, forced expiratory volume volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow. 17

20 Table C Supplementary Appendix Table C. Asthma exacerbations. As-needed combination therapy consisted of placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; as-needed albuterol therapy, placebo twice daily plus 100 μg of albuterol as needed; regular beclomethasone therapy, 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed; and regular combination therapy, 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. No. of exacerbations No. of exacerbations per patient per year No. (%) of patients with exacerbations No. (%) of patients with severe exacerbations As-needed combination (n= 122) As-needed albuterol (n=118) Regular beclomethasone (n=106) Regular combination (n=109) (4.92%) 21 (17.80%) 6 (5.66%) 11 (10.09%) 0 (0.0%) 4 (3.4%) 3 (2.8%) 3 (2.8%) p value as-needed combination vs asneeded albuterol regular beclomethasone vs asneeded albuterol 0.80 as-needed combination vs regular beclomethasone 0.13 as-needed combination vs regular combination as-needed combination vs asneeded albuterol regular beclomethasone vs asneeded albuterol as-needed combination vs regular beclomethasone as-needed combination vs regular combination Abbreviations: FEV 1, forced expiratory volume volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow. 18