Albuterol treatment for children with asthma: A comparison of inhaled powder and aerosol

uterol treatment for children omparison of inhaled powder

and aer

1 P. Kemp, MD,” C. T. Furukawa, MD,” E. A. Bronsky, MD, J. Grossman, MD,d R. F. Lemanske, MD,” L. E. Mansfield, MD,‘S. Murp atner, MDrh M. E. Reese, PhD, P. R. Rogenes, PhD, S. L. Spec and D. G. Tinkelman, MD San Diego, Calif.; Seattle, Wash.; Murray, Utah; Albany, N.Y.; Madison, Wis.; El Paso, Texas; Albuquerque, NM.; San Antonio, Texas; Research Triangle Park, N.C.; Los Angeles, Calif.; and Atlanta, Ca. A dose-ranging study and a 12-week treatment study were conducted in children with asthma, aged 4 to 12 years, to assess the ejj?cacy and safety of albuterol inhaled as either an aerosol or as dry powder. Both studies were double-blind and placebo-controlled with randomized assignment to treatment. The dose-ranging study in 30 patients indicated that similar single doses of albuterol aerosol and powder had comparable effects with the intermediate doses (i.e., 180 pg of aerosol and 200 p.g of powder) providing effective bronchodilation with minimal adverse effects. In the subsequent 12-week, parallel-group study, 204 children received albuterol as either aerosol, 180 pg. or powder, 200 pg four times a day. Both formulations were equally effective with no untoward cardiovascular effects and only one incident of mild tremor. Among those children who expressed a preference for one of the delivery systems, signi$cantly more children preferred the powder (44% versus 26%, p <: 0.01). hlbuterol taken four times a day as either aerosol or dry powder is both effective and well tolerated in children with asthma. {.I ALLERGY

CLINIMMUN~L1989$3x597-702.)

The beneficial effects of the P,-adrenergic bronchodilator albuterol in the treatment of children with asthma is widely recognized.‘-sNot all dosageforms of the drug, however, are available for pediatric use. Albuterol tablets are indicated for children 6 years and older, whereasthe syrup may be administeredto patients as young as 2 years of age. The aerosol and powder formulations are currently under regula-

From the Allergy and Asthma MedicaI Group and ResearchCenter, San Diego, Calif. Received for publication May 23, 1988. Accepted for publication Sept. 13, 1988. Reprint requests:J. P. Kemp, MD, Allergy and Asthma Medical Group and ResearchCenter, 3444 Kearny Villa Road, Suite 100, San Diego, CA 92123. Coinvestigators: “E. 0. Meltzer, MD, “H. A. Orgel, MD, PhD, “M. J. Welch, MD, “L. C. Altman, MD, bC. W. Bierman, MD, %. Marshall, MD, ‘W. E. Pierson, MD, bG. G. Shapiro, MD, ‘M. .I. Sharpe, RN, 5. Walker, MD, ‘D. P. Burkley, MD, ‘L. T. Christensen,MD, ‘C. M. Rogers,MD, dM. R. Ball, MD, “D. Shulan, MD, “W. W. Busse, MD, ‘M-M Logvinoff, MD, *R. W. Katz, MD, %I. W. Kelly, PharmD, gB. C. McWiIliams, MD, “S. Syring, RN, ‘R. M. Katz, MD, ‘G. S. Rachelefsky, MD, ‘A. S. Robr, MD, and ‘S. C. Siegel, MD.

Abbreviations used

PFT: Pulmonaryfunctiontest FVC: Forcedvital capacity f=L-z: Forcedexpiratoryflow between25%and 75% of Fvc

ECG: Electrocardiogram MIX: Metered-dose inhaler

tory consideration for pediatric use in the United States. We present the results of two inde~~mde~tdot blind studiesevaluating the effectsof albuterol aerosol and powder in children with reversible obstructive airway disease. Dosages and regimens in previous studies of thesetwo formulations have varied greatly. Typically, 90 to 800 p.ghasbeenadministered,usually as single doses,but in one study,3100TV200 kg doses were administered up to six times a day. Bnview of this variability, a dose-ranging study was conducted at two centers (San Diego and Seattle) to assessthe cardiopulmonary effects and safety profile of single doses of the aerosol and powder in children aged 4

Kemp et al.

tcr 12 years. Results of this study enabled the selection of dosages for a subsequent IZweek, multicenter study comparing safety profiles, clinical responses, n’s preferences during albuterol treatment

with inhaled powder or aerosol. Children aged 4 to 12 years with asthmawere enrolled in the dose-rangingand 12-weekstudies. Short-acting bronchodilators were withheld for 12 hours, and sustainedrelease theophylline products, for 48 hours before the screening visit of each study. edical histories were obtained, and complete physical examinations were performed at the screeningvisit of each study. Baseline PFTs, a 12-lead ECG, and specimensfor hematology, biochemistry, and urinalysis tests were obtained. Reversibility of bronchospasmwas demonstrated. we-ranging

study

A lO-way crossover design basedon Latin squareswas used. During visits 1 to 4, each child received, according to a computer-generatedrandom code, a single dose of albuterol aerosol (90 pg), albuterol powder (100 pg), placebo aerosol, or placebo powder. At visits 5 to 8, children similarly receivedalbuterol aerosol(180 pg), albuterol powder (200 pg), placebo aerosol, or placebopowder. At visits 9 to 10, each child received albuterol powder (400 pg) or placebo powder. Active and placebo powder were administered by Rotahaler (Glaxo Inc., ResearchTriangle Park, W.C.), a breath-activated device that is twisted to release powder from a capsule;the active and placeboaerosolswere administeredby MDI. Intervals betweenvisits rangedfrom 1 to 10 days. After each dose, patients were evaluated for changesin pulmonary function, heart rate, blood pressure, ECG, and untoward effects, such as tremor. Patientswere not allowed to progressto the next higher dose if there was evidence of an increasein heart rate 240%, increasein systolic pressure 220%, decreasein diastolic pressure 220%, or any significant ECG abnormalities or adverseexperiences. PFTs (FEV,, FVC, and FEF,,.,,) were performed at 5, 15, and 30 minutes, and at 1, 1.5, 2, 3, 4, 5, and 6 hours after drug administration. Vital signs were recordedat these times. An ECG was obtained at baselineand at 15 minutes, 1, 2, and 4 hours after dosing. A discharge examination, including clinical laboratory tests and an ECG, was performed within 10 days of the final visit.

The treatment phase of the 12-week study consisted of seven visits at 2-week intervals. Patients enrolled at 10 clinical centers were randomly assignedto receive one of the following regimens four times a day: (1) placebo albuterol aerosol (two puffs) followed 1 to 3 minutes later by one capsuleof active albuterol powder (200 kg) or (2) active albuterol aerosol (two puffs, 180 pg) followed 1 to 3 minutes later by placebo lactosepowder. Patientswere required to abstain from any theophylline preparations during the

treatmentphasebut were provided with an NlDI of isoproterenol to use as necessaryto alleviate symptomswhen the study drug appearedinadequate. At visit 1, each patient or parent received a pe& flow meter. The best of three successivepeak expiratory flow rates were recorded every morning before the first dose of medication and every evening before the last dose. In addition, patients (parents) were asked to record symptom severity (wheezing, breathlessness,coughing, and tightness in chest), number of attacks, use of study medication and use of isoproterenol. Serial PFTs (FEV,, FVC, and FEF,,.,,) and vital signs were recorded at visits 1, 3, 5, and 7 (before study drug administration and at 0.5, 1, 2, 3, 4, 5, 6, and X hours after drug administration). An ECG was obtained at each of the seven visits 1 hour after drug administration. Complete physical examinations and laboratory testswere repeatedat visit 7. Any adverseexperiencesreportedor observedduring the course of the study were recorded. Efficacy analyseswere basedon the following variables: spirometry values FEV,, FEF,,,,, and FVC; the number of patients with FEV, >15%, FEF,,.,* 220% above baseline, and the duration of response at these levels; physician’s evaluation of response (i.e., clinically improved, nnchanged,or worse); incidence of asthmaexacerbations;patients’ delivery systempreference;and diary data(i.e., peak expiratory flow rates, symptoms,and use of isoproterenol). Safety analyseswere basedon adverseevents, vital signs, and laboratory and ECG abnormalities. Statistical

analysis

Analysis of continuous data was by two-way analysis of variance or by independent sample Student’s t tests. Categoric data were analyzed by Co&ran-Mantel-Naenszel, chi-square,rank sum, sign, or Fisher’s exact test. Statistical significance was defined asp =S 0.05. RESULTS Dose-ranging Twenty-five

study boys and five girls (mean age, 9.4

years) with reversible obstructive airway disease participated in the dose-ranging study. Albuterol powder and aerosol at all three dosing levels produced significantly better FEV, and FEF25-75 results than placebo at most time points. For FVC, however, the lowest doses of aerosol (30 lag) and powder (100 p,g) had little effect compared with placebo, whereasthe intermediate doses(180 pg an 200 pg, respectively) produced significantly better responsesthan placebo. The mean percent change from baseline in FEV, for all treatmentsis illustrated in Fig. 1. improvement in FEV, was evident 5 minutes after adrni~~s~atio~of either albuterol aerosol or powder at all doses. No significant differences were observed betweenthe responsesto aerosol and powder at either the low or intermediate doses. The mean percent change frc3m

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Minutes Fig. 1. Mean percent

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baseline was 215% for l’/z hours after the low dose of powder, 3 hours for the low dose of aerosol, 2 to 3 hours after the intermediate dosesof either the powder or aerosol, and nearly 4 hours after the 400 kg dose of albuterol powder. Changesin mean pulse rates and systolic and diastolic blood pressurewere minimal after each of the dosestested with no clinically significant changesin ECGs or laboratory values. Four adverseeventswere associatedwith the 400 pg dose of albuterol powder: tremor in two patients and headacheand vomiting in another.Qne of thesepatientsexperiencedtremor with aerosol, 180 p,g, as well as with the high dose of powder, and another patient experienced headache with both the placebo powder and the 400 p,g dose of active powder. No patient was withdrawn from the study becauseof an adverseevent. A total of 204 children with mild to moderate asthma were enrolled at 10 clinical centers. At least half the children enrolled were 4 to’ 8 years of age, and the rest of the children were 9 to 11 years of age. Randomization produced two comparable treatment groups with no statistically significant differences in demographicor diseasecharacteristics(Table I). Baseline PFTs were not significantly different between

versus

aerosol

verses

placebo

treatment groups at the screening visit ( on any subsequentstudy day. Nineteen of the 204 children dropped out of the study before the last scheduledvisit for the following reasons:protocol violations (9), asthmaexacerbations (.5), adverse experiences (3), and development of a concurrent illness (2). There was no statistical difference in the number of dropouts from the alb~~erol aerosol and powder groups (12 versus seven, respectively) . Analysis of pulmonary function data obtained during an 8-hour period at each of four visits demonstrated that, with the exception of only a few time points, there were no statistically significant differences between albuterol powder or aerosol with respectto FEVI, FEF25.75r or FVC responsesduring the 1Zweek period. The similarities of the responsesare illustrated in Figs. 2 and 3) which depict the mean percent change from baseline in FEV, and FEE,,.,,. Between 47% and 65% of children achieved an increasein FEV, of 215% above baseline during the four study visits, whereas 72% to 95% of children achievedan increasein FEF,,,, of 220% abovebaseline. Mean duration of these increasesranged from 192 to 242 minutes. Both the mean improvements above baseline and the duration of ~roncl~od~atio~ were greater for FEFZSFY5 than for FEV,. There were

Visit 1

30

25 .g jjj

0) g

e Albuterol Aerosol (n = 98) A Albvterol Powder (n = 104)

20 15 10 5 0

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8 Albuterol Aerosol (n = 91)

A Albuterol Powder (n= 93)

0 30 60

120

160

300

240

460

360

Minutes Fig.

2. FEV,, mean percent change 1.7% to 2.2% for the aerosol, and

TABLE 1. Demographic

from

baseline;

1.7% to 2.4%

and disease characteristics

standard errors for the powder.

of patients

of the

means

ranged

in the 12-week comparative

from

stu

Albuterol aerosol IN = 104)

Albuterol pamper (N = 100)

8.1 (YkO.2) 4-11

8.4 (CQ.2) 4-11

70134

70/30

Age W

Mean(f SEM) Range Sex M/F Screening visit PFT data Mean baseline l%V,* (k SEM) Percent of predicted Mean baseline FEF,,,,* (k SEM) Percent of predicted

1.25 (+0&q 76 1.18 (r0.05) 60

1.38 (~0.049 81 1.35 (+-0.06) 65

*FEV, measuredin liters, and FEF25.75, in liters per second.

no significant differences between treatment groups in any PET variables at any visit or among visits. Furthermore, the younger children (4 to 8 years of age) respondedas well as the older children to either formulation. Analysis of the physicians’ clinical evaluations revealed no significant differences between the two treatment groups; among patients receiving the albuterol aerosol or powder, 56% and 58% of the patients were considered improved, 35% and 36% remained unchanged, and 6% and 1% worsened, respectively, while patients were receiving the study rugs. There were also no treatment differences with respect to symptom scores recorded on the patients’ diary cards. Average weekly scores in both groups

were low at baseline and declined t~ougRo~t the 12 week treatment period, whereas peak flow rea steadily increasedover the sameperiod. ~o~i~~ peak flow readings were consistently lower than evening values for both formulations, with no si~ni~car~tdifferencesbetween treatment groups. During the study, 26 (25%) patients in the albuterof aerosol-treatedgroup and 13 (13%) in the a~b~tero~ powder-treated group (p < 0.05) experienced asthma exacerbationsthat required medical i~terve~t~o~ (usually steroid therapy) other than iso~rot~re~o~~ which was allowed during the study to control breakthrough symptoms. Of these patients, four in the aerosol-treatedgroup and one in the powder~~~ated group were required to stop participation in the study, There were few adverseexperiences, and no clin-

VOLUME 83 NUMBER 3

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70 60 50 40 30 20 10 0 0 30 60

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@ Ahterol Aerosol (n = 31) A Albuterol Powder (n = 93)

300

360

48Q

Minutes Fig. 3. Midexpiratory flow rate (FEF 25-75),mean percent change from baseline; standard errora of the means ranged from 3.2% to 5.0% for the aerosol, and 2.7% to 6.7% for the powder.

ically significant laboratory abnormalities occurred. Three children dropped out of the study: one child complained of a sore throat, swollen inner cheeks, and increased nervousness, one disliked the taste of the medication, and one complained of lung pain after treatment. At the completion of the study, significantly more patients expressed a preference for the powder formulation (44% versus 26%; p = 0.003). Approximately 30% in each treatment group expressed no preference. DISCUSSION In the past, dosagesof albuterol aerosol or powder in pediatric studies were basedon adult responsesto the drug6z7and on precedent rather than on specific studies in children. The dose-ranging study reported here is the first to document that 180 pg of albuterol aerosol and 200 kg of albuterol powder, the same dosagesas those recommendedfor adults, also produce effective bronchodilation with the least potential for side effects in children. The results of the 1Zweek comparison study in children closely match results of a simifar study in adults,’ which also demonstrated at improvement in pulmonary function and control of symptomsafter albuterol aerosol, 180 pg four times daily, was equivalent to improvement produced by albuterol powder, 200 pg four times daily. As in the adult study, both the mean bronchodilating response and duration remained relatively constant throughout the 12 weeks, indicating that tachyphylaxis was not a problem associatedwith long-term or repetitive use of albuterol by the pediatric population examined in

this study. We areunableto explain why more children receiving albuterol aerosol experienced an exacerbation of asthmacomparedwith children receiving the powder formulation. In the absenceof other significant differences, it is most likely a chance effect. Improvement in pulmonary function during the study was more evident when it was expressed as 320% increase in FEZF,,.,,than as 315% in FEV,, especially among the younger children (4 to 8 years of age). Although FEV, is a widely acceptedmeasure of bronchodilator activity in adults, FEF,,,, is also a useful index for monitoring asthma,and evaluation of both variables is warranted in the assessmentof bronchodilator activity. There remains some controversy over what is measuredby various spirometric tests. Whether or not FEFzSeY5 is less effort dependentthan FEV, is debatable, but it has been demonstratedthat even modestencouragementto do better during serial PFTs resulted in significant increasesin FEV, but not =%.wg Adverse events were also consistent with events previously reported for children’ and adult? with only three of 204 children dropping out of the l&week study becauseof an adverseexperience. One clear difference that did emergefrom the present study, in contrast to studies i~voIvi~g adults, was the children’s preferencefor the powder delivery system over the aerosol. Hartley et al.” found that adults preferred the aerosolto powder 2: I, whereas et al.* found patients equally divided in their preference. Among those children in our study who expresseda preference,44% said that they preferred the powder comparedwith 26% who preferred the aero-

J.WLLERGYCLiW.IMMUNQL.

Kemp et al.

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sol. Previous studies have demonstrated that some children have difficulty with metered-dose aerosols ‘I-j3 becausethey are unable to fully synchronize releaseof the medication with the start of inspiration. This difficulty was not directly observedin the present study, but it may have accountedfor the greater preference for albuterol powder. Although it is not believed to be an influencing factor in terms of preference in this study, it should be noted that the powder formulation, unlike the aerosol, contains no Freon propellants. Despite assurancesthat the MD1 is safe and effective when it is used in the recommended manner, some patients may still prefer an alternative delivery system. The novelty of the powder delivery systemfor use with a P-agonist, a device not currently available in the United States, may also have influencedsomechildren’s choices. We can only speculate on the reasons for their preference, since this information was not directly solicited. In summary, the results of both the dose-ranging study and the 12-week treatment study demonstrate that albuterol aerosoland albuterol powder are equally effective and well tolerated in children with reversible obstructive airway disease. Rapid bronchodilation with little or no extrapulmonary effects was achieved with both formulations, and albuterol as either aerosol or powder can be used successfully in children as young as 4 years. thank Rose Mills, MPH, for editorial assistance, and Nguyen V. Dat, PhD, for the statistical analyses.

REFERENCES 1. Lenney W, Milner AD, Hiller EJ. Use of salbutamol powder in childhood asthma. Arch Dis Child 1978;53:958-61. 2. Francis PW, Krastins IR, Levinson H. Qral and inhaled safbutamol in the prevention of exercise-induced~r~nc~ospas~. Pediatrics 1980;66:103-8. 3. Croner S, HedenskogS, Kjellman NI, Odelram H. Salbutamol by powder or spray inhalation in childhood asthma. Allergy 1980;35:589-92. 4. Lee HS, Evans HE. Albuterol by aerosol and orally administered theophylline in asthmatic children. J Pediatr 1982; 101632-5. 5. Berg IM, Berg T, Ringqvist I. Salbutamol in the treatment of asthmaticchildren: a comparisonof oral andinhalation therapy alone and in combination. Eur J Respir Dis 1982;63:305-9. 6. Nelson HS, Spector SL, Whitsett TL, George RB, Dwek JH. The bronchodilator responseof inhalation of increasing doses of aerosolized albuterol. J ALLERGYCLLVIMMUNOL 1983; 72:311-5. 7. Orgel HA, Meltzer EO, Welch MJ, Kemp JP. Inhaled albuterol powder for the treatment of asthma-a dose-responsestudy. J ALLERCVCL~ IMMUNOL1985;75:468-71. 8. Bronsky E, Bucholtz GA, Busse WW, et al. Comparison of inhaled albuterol powder and aerosol in asthma. J ALLERGY CLM IMMUNOL1987;79:741-7. 9. Harm DL, Marion RJ, Kotses H, Creer TL. Effect of subject effort on pulmonary function measures:a preliminary investigation. J Asthma 1984;21(5):295-8. 10. Hartley JPR, Nogrady SG, Gibby OM, Seaton A. Bronchodilator effects of dry salbutamol powder administeredby rotahaler. Br J Clin Pharmacol 1977;4:673. 11. Crompton GK. Problemspatients have using pressurizedaerosol inhalers. Eur J Respir Dis 1982;(Suppl 119)63:101-4. 12. Paterson IC, Crompton GK. Use of pressurisedaerosols by asthmaticpatients. Br Med J 1976;1:76-7. 13. SaundersKB. Misuseof inhaledbronchodilatoragents.Br Med J 1965;1:1037-9.