Comparison of inhaled albuterol powder and aerosol in asthma

Edwin Bronsky, M.D., Gerald A. Buchrdte, M.D., wiltsam W. Buslpe, MD,, Paul Chervinsky, M.D., John Condemi, M.D., Mohammed A. Ghafouri, Ph.D., Leonard Hudson, M.D., S. Lakshminarayan, M.D., Richard Lackey, M.D., lU&s#mM E. , Ph.D., Stephen I. Rennard, M.D., Ailen S8gal, M.D., Law8m8 §m#ey, W.D., Sh8Mon Spector, M.D., John J. Stablei, M.D., Andre Van As, M.D., and Archi Wilson, M.D., Ph.D. Salt Lake City, Utah, Madison, Wis., Tampa and Miami, Fla., New Bedford, Mass., Rochester, N. Y., Omaha, Neb., Seattle, Wash., Research Triangle Park, N. C., Dallas, Texas, Los Angeles and Orange, Calif., and Albuquerque, N. M. In this multicenter, randomized, double-blind study comparing the eficacy and saj&y oj aerosolized albuterol with the dry powder formulation, 231 patients with chronic reversible obstructive airway disease were randomly allocated to receive either placebo aibuterol aerosoi followed immediately by active albuterol powder (200 Fg) or active albuterol aerosol (two puffs, I80 pg) followed immediately by placebo lactose powder four times a day for a period oj‘ 12 weeks. No statistically significant differences were found between the powder and aerosol formulations with respect to pulmonary function, length of time mean FEV, remained ~=I58 above baseline, physicians’ assessments of patients’ clinical response, or patients’ subjective Jymptom scores. There were also no significant dzserences between treatment groups in cardiovascular effects, laboratory values, or adverse events. Among patients who expressed a preference for one of the delivery systems, half preferred using the powder. Results of this study demonstrate that 200 l.~g of albuterol powder is as safe and effective as 180 pg of alhuterol aerosol. (J ALLERGY CLIN~MUNOL 1987:79:741-7.1

Albuterol is well established as a relatively selective p+drenergic bronchodilator. Aerosolized albuterol has been widely used in Europe since 1969 and in the United States since 1981 for the treatment of bronchospasm. The drug is well tolerated with few adverse effects, and the incidence of cardiovascular changes is lower than with other P-agonists such as isoproterenol.“” A dry powder formulation of albuterol has also been available in the United Kingdom and other countries since 197 1. The powdered form has been particularly useful in patients who are unable to properly use the pressurized aerosol“, 5 or who prefer an alternative delivery system. A capsule containing albuterol pow-

~1

From Glaxo Inc., Research Triangle Park, N. C. Supported in part by Glaxo Inc. Received for publication May 7, 1986. Accepted for publication Oct. 21, 1986. Reprint requests: Marshall E. Reese, Ph.D., Associate Director, Clinical Investigation. Glaxo Inc., Research Triangle Park, NC 27709.

METHUDS Patient selection

FEVZ5.+ Forced expuatory flow between 25% and

der is inserted into a flow-activated device (Rotabaler, Glaxo Inc., Research Triar@e Park, N. C.) th& b4p.s the patient avoid the difficulty of s~b~jz~~~ release of medication with the start of ins~~~~. This article summarizes the results of a mt;zlticenter study comparing the efficacy and safety of ~~~4dized albuterol with the dry powder formulation in patk:rrts with chronic reversible obstructive airway disease.

A 12-week multicenter, randomized, doubk-b&d study was conducted to compare the efficacy and safety of albuterol powder with afbuteroi aerosol. Pat&r&swere required at screening to have FEV, of =3X0% of predicted 741

742

J. ALLERGY CLIN. IMMUNOL. MAY 1987

Bronsky et al.

TABLE I. Background treatment

characteristics

of

groups Powder Variable

No. of patients Age (yr) Mean Range Sex (M) Ethnic origin White Black Other Smoking None ~1 pk/day >I pkiday Cigar/pipe Asthma duration (yr) <1 l-5 >5 Classification of asthma* Extrinsic Intrinsic Mixed Diseasehistory None Pulmonary Endocrine Gastrointestinal

N

(%)

115

Aerosol N

(%I

116

33.7 12-76 54 (47)

33.2 12-67 53 (46)

100 (87) 3( 3) 12 (10)

102 (88) 6( 5) 8( 7)

100 (87) 10 ( 9) 4 ( 4) I( 1)

95 (82) lot 9) 11 (IO) O( 0)

I( 1) 11 (10) 103 (90)

5 ( 4) 19 (16) 92 (79)

37 (32) 8( 7) 70 (61)

37 (32) 9( 8) 70 (W

72 (63) O( 0) 8( 7) 7 ( 6)

61 (53) 6 ( 3t 3( 3) 9( 8)

*Extrinsic:asthmasymptomsresultingfrom outsidethe body(e.g., p&en, dust,andanimalhair)andIgEmediated;intrinsic:asthma symptomsresultingfrom factorswithin the body (non-IgEmediated), externalfactorsnot identified;mixed:asthmaprovoked or inducedby combinationof extrinsicand intrinsicfactors. ?p < 0.01, Fisher’sexacttest.

values when all bronchodilator medication had been withheld for at least. 12 hours. In addition, reversibility of the patient’s condition was documented by a 3 15% increasein FEV, within 15 minutes after inhalation of a standard dose of isoproterenol (two puffs, 262 p.g). Patients receiving inhaled steroidscould be ,admitted to the study provided the dose remained constant for the duration of the trial and reversibility of their condition had been established. Pregnant women were excludedfrom the study. Informed written consentwas obtained from each participant, and the protocol was approved by the institutional review boards at each clinical center.

Study design A medical history was taken at the screeningvisit, and a complete physical examination, in&ding a 12-lead elec@ocardiogramand a seriesof clinical laboratory tests, was performed. A chest x-ray film was taken before entry into

the study, if a normal chest film had not been obtained in the previous 12 months. The treatment phaseof the study consistedof sevenvisits at 2-week intervals. Patients were assigned according to a randomly generated code to receive one of the following regimens four times a day: (1) placebo albuterol aerosol (two puffs) followed immediately by active albuterol powder (200 +g) administered by Rotahaler or (2) active albuterol aerosol (two puffs, 180 pg) followed immediately by placebo lactose powder administered by Rotahaler. The double placebo method of dispensing medication was used to ensure that both the patients and the physicians were blinded to the treatment assignments.Patientswere required to abstain from any theophylline preparations during the treatment phase but were provided with a metered-doseinhaler of metaproterenol for limited use to alleviate acute exacerbationsof bronchospasm. At visit 1 each patient received a mini-Wright peak flow meter and was instructed to record the best of three successivepeak expiratory flow measurementsevery morning before taking medication and every evening before taking the last dose of medication. In addition, patients were asked to record on a diary card their assessmentof their symptom severity(wheezing, breathlessness,coughing, and tightness in chest), number of attacks, use of study medication, and use of metaproterenol. Instructions for use of the inhalersincluded the following: (for metered-dose inhaler) shake inhaler, exhale fully, and place mouthpiece in mouth, depress top of canister while the patient is inhaling deeply, hold breath for as long as possible, repeat procedure for second puff (for the Rotabaler), place powder capsuleinto the inhaler and turn inhaler to open the capsule, exhale fully, grip mouthpiece between the teeth and lips and tilt the head slightly backwards, inhale deeply, and hold breath for as long as possible. PFIs (FEY,, FVC, and FEF,,.,,), pulse rate, and blood pressurereadings were obtained at visit 1 before study drug administration and at 30 minutes, 1,2,3,4,5, and 6 hours after drug administration. These procedures were repeated at visits 3, 5, and 7. At visit 4 and 7, each patient took the first dose of medication for that day, and 1 hour later, a 12-lead ECG was obtained. Complete physical examinations and laboratory tests were repeated at visit 7. As each patient completed the study, the physician was asked to evaluate the patient’s overall responseto therapy and compliance. Patientswere rated as clinically improved, unchanged, worse, or not evaluable. Any patients requiring medical intervention (i.e., burst of steroids) were placed in the worse (failure) category. Patientswere also askedwhich delivery system they preferred using: aerosol, powder, or no preference. Safety of the study drugs was evaluated through observation of adverse experiences and the monitoring of cardiovascular changesand laboratory tests.

Statistical

analysis

Efficacy analyseswere based on the following variables: PFl’s( FBV, , FEFn.,j, and FVC), length of time mean FEV, remained 215% above baseline, physician’s evaluation of

VOLUME 79 NUMBER 5

Inhaled

albuterol

powder

TABLE II. Mean pulmonary function status at screening .-

and

aeromi

in asthma

---After bronchodiktor --II_-

Before bronchodiletor Treatment group/PFT

Value

% Predicted

Value

X Predicted

Albuterol powder Fl-1

2.00

60

2.59

-7

1.41 3.02

31 12

2.16 3.57

56 ss

2.08 1.51 3.14

62 40 76

2.65 2.13 3.70

X0 56 x9

FEFZS.75 FVC Albuterol aerosol FEV, FJS5.75

FVC

743

FEV, and FEFa.,5 measured in liters per second and FVC in liters.

response, patient’s preference, and diary data. Analysis of continuous data was by two-sided analysis of variance or by independent sample t tests. Categoric data were analyzed by chi-square or Fisher’s exact test.

fUZU.TS Thirteen clinical centers recruited 231 men and

women, with each center enrolling between eight and 33 patients. Randomization produced two comparable treatment groups with no statistically significant differences , except for prior incidence of pulmonary disease (Table I). A positive pulmonary disease history usually meant the prior occurrence of pneumonia or bronchitis and did not reflect active disease at the time of the study. Ninety-seven percent of the powdertreated group and 9 1% of the aerosol-treated group had a history of antiasthma medication use, including bronchodilators , cromolyn sodium, and corticosteroids. Pretreatment pulmonary function status at screening was similar between groups (Table II) and confirmed that the patients had mild to moderate obstructive airway disease with a largely reversible component.

Forty-eight of the 231 patients (26 in the powdertreated group and 22 in the aerosol-treated group) were unable to complete the entire 1Zweek study (Table III). No significant differences were observed between treatment groups in the dropout rate or reasons for not completing the study. Efficacy and safety analyses were based on al1 patients enrolled in the study. PFTs after administration of the study drug revealed no significant differences between treatment groups at any of the study visits. Mean PFlY values at weeks 0 and 12 are presented in Table IV. Both treatment groups demonstrated a gradual but nonsignificant decrease during the IZweek period in the length of time mean FEV, remained 2 15% above baseline,

TABLE BL Patients not completing 1P-week study

entire

Al f%mon

Required medical intervention for acute asthma* Study drug ineffective Adverse event Excessiveuse of rnetaproterenol Became pregnant Personal, scheduling problems, etc.

powrtsr-

12

11

3 f

3 3

I I 8

0 0 5

-*Two additionalpatientsin the powder-treatedgroup and ow in the aerosol-tnxted graup required medical intervention and withdrew from the study temporarily but later completed all visits.

a possible reflection of the gradual increase in baseline values during the study as demonstrated at week 12. The peak bronchodilating effect (i.e., maximum increase), however, remained relativeiy constant throughout the study for both treatment regimens (Figs. 1 and 2). The average weekly morning peak cxpiratory flow rates were consistently lower than the eve&ng values for both formulations, reflecting the lower ~1~s obtained during the nocturnal period (Fig. 3). These data also illustrate the gradual imp~ve~~t in pact function during the la-week period. Wng the study there was little variability within each group and no significant differences between t tPwsResults of the physicians’ as~sa~~~ of evalmble patients’ clinical responses revealad t&g the percentage of patients improved or &tained with the powder formulation was nearly the same as w&b the aerosol formulation (Fig. 4). Similarly, there was no significant difference between groups in the number of

744

Bronsky

J. ALLERGY CLIN. IMMUNOL. MAY 1987

et al.

WEEK 0 o Aerosol Powder

l

0

i0

6b

li0 Time

FIG. 1. Percent

change

from

baseline

160

2io

360

360

(Minutum)

in mean

FEV,

after

drug

treatment

at study

visit

TABLE IV. Mean pulmonary function values at selected time points after administration study drugs Visit 1 (week 0)

1.

of

Visit 7 (week 12)

Powder (N = 115)

Aerosol (N = 116)

Powder (N = 66)

Aerosol (N = 64)

2.20 2.12 2.50 2.40

2.25 2.77 2.59 2.52

2.25 2.12 2.46 2.40

2.32 2.19 2.55 2.53

1.65 2.39

1.70

1.69

1.80

1

2.42

2.43

2.45

4 6

1.98 1.87

2.16

2.07

1.99 1.96

2.13 2.10

3.31

3.27

3.75 3.55 3.52

3.61

3.34 3.14 3.57

Pm/time

(hr)

Fl-1 0.4 0 1 4 6

f=F,,.,, Wet) 0

FVC (L) 0 1 4 6

3.25 3.65 3.50 3.42

patients who could not be adequately maintained (10% versus 13%). Since every patient used both the aerosol and powder delivery systems as part of the blinding procedure, patients were asked at the completion of the study which formulation they preferred. Among those who expressed a preference, there was no significant difference between treatment groups in the desirability of one formulation over the other: 5 1% preferred, the aerosol and 49% preferred the powder. Thirty percent of the patients in each treatment group stated that they had no preference.

3.43 3.36

3.51

Symptom scores recorded on patients’ diary cards revealed no significant differences between treatment groups in wheezing, breathlessness, coughing, or tightness in the chest. In general, symptom scores, like the peak flow readings, were slightly higher in the mornings, reflecting the interval from the last evening dose to the next morning dose. No significant differences were observed between treatment groups in use of metaproterenol for acute exacerbations of bronchospasm. Average weekly use amoag patients was generally limited to between two and three doses throughout the 12-week period.

VOLUME 79 NUMBER 5

Inhaled

FIG. 2. Percent

0

30

60

120

change

from

baseline

in mean

FIG. 3. Average

weekly

peak

flow

Adverse events were reported by 18 of 115 patients (16%) in the powder-treated group and 26 of 116 patients (22%) in the aerosol-treated group. Fortyseven of the 59 adverse events in the powder-treated group (HI%) were characterized as mild by the patients, nine (15%) as moderate, and three events (5%) as severe. These more severe events included headache, bronchospasm, and pruritus. The patient reporting bronchospasm attributed the event to the placebo aerosoi formuknion and withdrew from the study after two visits. This was the only patient to withdraw from the powder-treated group because of an adverse event (Table III). In the aerosol group, 35 of the 57 adverse events (61%) were considered mild, 17 (29%) moderate, and five events (9%) severe. The adverse

160 FEV,

readings

after

albuterol

powder

240 1

300

drug

treatment

(powder

A; aerosol

and

aerom:

in zvsthrna

745

360 at study

visit

‘7

0).

events considered severe by the patients in&&d headache, tremor, and coughing. Two aerosol-treated group withdrew cause of tremor and one because of wall pain. Symptoms ended in both study medicativn was stopped. No significant differences treatment groups in electmcardi oratory tests, mean pulse stok blood pressures. N diographic or laboratory abnvrmaiitie

The results of this cont.roIkd clinic4 trial clearly demonstrate that 200 pg of aIbutervl powder four times a day produces similar improvements in pul-

746

J. ALLERGY CLIN. IMMUNOL. MAY 1987

Bronsky et al.

60 8

EJ Powder n Aerosol

50

N = 110 N = 109

s

g

40

‘s E 8 t p

30

P

20 10 0 Improved

Maintained

WorSe

Status FIG. 4. Physicians’

assessments

of clinical efficacy after 12 weeks of therapy.

monary function to those observed following two puffs (180 p,g) of albuterol aerosol four times a day. The two formulations were also found to be comparable in terms of cardiovascular changes and incidence of adverse events and laboratory abnormalities. Our findings confirm results of other investigators who have compared the efficacy of dry powder albuterol with the aerosol formulation and found no statistically significant differences between the two formulations. 6g Caution must be exercised in interpreting the data from these previous studies, however, since sample sizes were quite small (between IO and 20) and may have been insufficient to detect clinically important differences because of lack of statistical power. The present study, with its study population of 231, provides the strongest evidence to date to support the equivalence in efficacy of the two dosing forms of albuterol. Although the subjective data obtained from the diary cards in the study were recorded by patients in an unsupervised fashion, the trends observed from the symptom scores, peak expiratory flow measurements, and use of ancillary medication substantiate the spirometry data collected during the 1Zweek study. Patient preference is an additional factor that must be considered when the two drug formulations are compared because efficacy alone may be insufficient to promote compliance. In a long-term comparison of albuterol powder with albuterol aerosol, Hartley et al.” found that patients preferred the aerosol to the powder 2: 1. In our study, patients were equally divided in their preference for one formulation or the other. Why the powder method appears to have increased in popularity in the present study can only be

speculated. Perhaps there is a greater‘concern over fluorocarbon propellants or there may be increased confidence in new methods of medication delivery. In either case, a large proportion of patients who participated in our study did not consider the slight inconvenience involved in loading the inhaler with powder capsules as an inconvenience or impediment to usage. In summary, the results of this study demonstrate that albuterol powder is as safe and effective as albuterol aerosol and that it provides a highly acceptable and therapeutic alternative for patients unable to properly use the aerosol inhaler or who prefer an alternative delivery system. We thank Helen Bhattacharyya, Ph.D., for the statistical analyses, and Rose Mills, M.P.H., for editorial assistance. REFERENCES 1. Spector SL, Garxa-Gomez M. Dose-response effect of albuterol aerosol compared with isoproterenol and placebo aerosol. J ALLERGY CLIN IM~OL 1977;59:280-6. 2. McFadden ER Jr. Betarreceptor agonist: metabolism and pharmacology. 3 ALLERav CLW Irmmo~ 1981;68(2):91-7. 3. Littner MR, Tashkin DP, Siegel SC, et al. Double-blind comparison of acute effects of inhaled albuterol, isoproterenol, and placebo on cardiopulmonary function and gas exchange in asthmatic children. Ann Allergy 1983;50:309-16. 4. Paterson IC, Crompton SK. Use of pressurized aerosols by asthmatic patients. Br Med J 1976;1:76-7. 5. Epstein SW, Manning CPR, Ashley MJ, Corey PN. Survey of the clinical use of pressurized aerosol inhalers. Can Med Assoc J 1979;120813-6. 6. Duncan D, Paterson IC, Harris D, Crompton GK. Comparison of the bronchodilator effects of saibutamol inhaled as a dry powder and by conventional pressurized aerosol. Br J Clin Pharmacol 1977;4:669-71. I. Hartley JPR, Nogrady SG, Gibby GM, Seaton A. Broncho-

VOLUME 79 NUMBER 5

Inhaled albuterol

dilator effects of dry salbutamol powder administered by Rotahaler. Br J Clin Pharmacol1977;4:673-5.

8. HetzelMR, ClarkTJH. Comparisonof salbutamolRotahaler with conventional pressurized aerosol. Clin Allergy 1977;7: 563-8. 9. Latimer KM, Roberts R, Dolovich J, Hargreave FE. Salbu-

powder

and a~osol

in asthma

tamol: comparison of bronchodilating effect of inhaled powder and aerosol in asthmatic subjects. Can Med 4ssts J 1982: 127(9):857-9. 10. Hartley JPR, Nogrady SG, Seaton A. Long-term comparison of salbutamol powder with salbutamol acr~col in asthmatic outpatients. Br J Dis Chest 1979:‘?3:17 I-6

Sabrima Awaaoli, M.D., Antonio Fomd, M.D., Giu M. Cbbo, M.D., SalvarkM! Vahte, M.D., and Oiuliano C&pi, M.D. Rome and Milan, Ital) Weselectedjve atopic children with asthma with previously documented late asthmatic respunse (LAR) associated with increasedhyperresponsivenessto methacholine after the inhalation of Dermatophagoides pteronyssinus.The children hadfour allergen inhalation tests on 4 diRerent days, at least 14 days apart. On days I and 4, saline placebo was inhaled I hour hejke the expected onset of LM, and FEV, was measured hourly until FEV, returned within 10% qf baseline value; then methacholine challenge was performed. On days 2 and 3, 20 and 40 mg of cromolyn was inhaled double blind 1 hour before the expected onset of LRR. FEV, und methachoh’neresponsivenesswere measured as on &ys I and 4. The two doses (J crumdyn significantly delayed the L.AR onset without altering the overall L&Z magnitude and prevented the allergen-induced increase in methacholine responsiveness. Both these eflects were greater at the maximal dose used. We conclude that cromolyn can prevent the allergen-induced increase in methacholine responsivenessand that this effect is not due to alteration in the magnitude of LAhB.Our findings reveal a possible explanation of the effectivenessof this drug in the treatment of allergic asthma. (J ALLERGY CLIN IMMUNOL 1987;79:747-54. )

Atopic subjects with asthma respond to inhalation of the relevant allergens with an immediate bronchoconstriction that resolves spontaneously in most cases and that is reversible by inhalation of P,-adrenergic agonists.’ Some sub&ts also demonstrate a further spontaneous increase in airflow resistance that is longer lasting and that responds poorly to inhaled p,-adreflergic agonists. I4 LAR, but not isolated EAR, can be associated with an increase in nonspecific bronFrom the Istituto di Clinica Medica, Servizio di Fisiopatologia Reapimtoria, Policlinico A. Gemelli, Univeraiti Cattolica de1 Sacro Cuore, Roma, and Divisione di Pneumologia Pediatrica, Centro Auxologico Itaiiano di Piancavallo, Milano, Italy. Received for publication Oct. 21, 1986. Accepted for publication Dec. 13, 1986. Reprint requests: Sabrina Mattoli, M.D., Servizio di Fisiopatologia Respiratoria, Policlmico A. GemeUi, Universith Cattolica de1 S Cuore, Large S. Vito 8, 00168 Roma, Italy.

Abbreviations used EAR: Early asthmatic response LAR: Late asthmatic response PC,M: Concentration of methachoiinc provoking a 20% fall in FEV,

chial responsiveness to histamiue,5, ’ rneth~h~~i~e,’ and ultrasonically nebulized distilkd water. 7 The magnitude and duration of increased hyperrespo&veness closely relate to the magnitude of the LAR itself,6. ’ suggesting that the same mechanism(s) might be responsible for these two phenomena. ln~~~n, mucosal edema, and secretion, in addition to smdoth

muscle contraction, appear to be involved. There is now a considerable body of evidence on the relevance of processes involved in LAR. In fact. 747