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Eur Resplr J
1991, 4, 175--179
Bricanyl Turbuhaler® in the treatment of asthma: a six week
multi-centre study carried out in Sweden, the United Kingdom,
Denmark, Norway and Finland
K. Osterman*, E. StAhl**, A. Kallent
Bricanyl Turbuhaler* in the treatment of asthma: a six week multi-centre study
carried out in Sweden, the United Kingdom, Denmark, Norway and Finland.
K. Osterman, E. Stdhl, A. Kiillen.
ABSTRACT: Two hundred and fifty eight adult patients with bronchial
asthma participated In an open, parallel group study of 8 wks duration.
During a 2 wk run-in period the 8 3-agonlst terbutaline (0.5 mg q.i.d) was
delivered via a pressurized freon aerosol, Bricanyl metered dose inhaler
(MDI). During the following 6 wks, one third of the patients continued
with MDI and two thirds with the same dose of terbutallne in the form
of dry powder, Bricanyl Turbuhaler. There were no statistically significant differences in the increases in peak expiratory flow rate (PEFR)
after inhalation between the two treatment groups. The asthma
symptom scores decreased in the Turbuhaler group during the study
but remained the same in the MDI group. No difference in use of extra
trial medication during the day was found. During the night, the
difference was statistically significant in favour of Turbuhaler (p<O.OS).
Turbuhaler was well accepted and easy to use. As compared with the
MDI used during run-in, SO% of the patients in the Turbubaler group
preferred to use Turbubaler and 26% MDI, whilst 24% had no preference. In conclusion, Turbuhaler was at least as effective as MDI during
the whole Turbuhaler life-span (6 wks).
Eur Respir J., 1991, 4, 175-179.
Several anti-asthmatic drugs, such as 13 2-agonists,
corticosteroids and ipratropium bromide, are available
as inhalation therapy. The most commonly used
inhalation device is the pressurized metered dose inhaler
(MDI). However, many patients have problems with
MDis due to difficulties in co-ordinating actuation of
the inhaler with inhalation [1]. MDis also contain freons
and lubricants which may further irritate the
hyperreactive airways of asthmatic patients [2]. In order
to reduce these problems alternative devices, such as
Turbuhaler [3], have been developed.
Bricanyl Turbuhaler is a breath-actuated dry powder
inhaler which delivers pure terbutaline sulphate. It is
preloaded with 200 doses of 0.5 mg terbutaline sulphate
and contains no additives. Since there is a steady
increase in pollution, the absence of freons will be an
advantage for the environment.
Previous studies have shown that Bricanyl Turbuhaler
treatment is equipotent to Bricanyl MDI [4-6].
The aim of this study was to evaluate the acceptability and efficacy of Bricanyl Turbuhaler in the course of
its life-span in regular treatment of asthma.
• Dept of Allergology, Karolinska sjukhuset,
Stockholm, Sweden.
• • Medical Dept, AB Draco, Lund, Sweden.
t
Dept of Biostatistics, AB Draco, Lund, Sweden.
Correspondence: K. Osterman, Dept of Allergy,
Karolinska sjukhuset, S-104 01 Stockholm, Sweden.
Keywords: Acceptance; asthma; powder inhaler;
preference; terbutaline; Turbuhaler.
Received: November 30, 1989; accepted after revision August 27, 1990.
Participating investigators: R. Dahl, J. Fredriksen,
E.R. Weeke (Denamrk); K. Kiviranta, K. Lehtonen,
(Finland); C.H. Hagelund, N. Ringdal, (Norway);
G. Malmer, H. Matsols, A-M. Norborg, J. Perk, G.
Svensson, (Sweden); M. Bone, M.G. Britton, A.J.
Johnson, R.L. Joshi, F. Moran, P.R. Studdy, (UK).
Patients and methods
Two hundred and fifty eight patients (145 females)
with stable asthma and forced expiratory volume in one
second (FEV 1) of 1 l or more entered the study. All
patients required inhaled 13 2-agonists daily. Twenty
seven patients did not complete the study according to
the protocol: six patients did not return to the clinic and
21 patients dropped out because of deterioration of
asthma or concurrent illness (17 patients in the
Turbuhaler group and four in the MDI group). The
mean age of the patients was 48 yrs (range 17-77 yrs).
Demographic data are shown in table t and maintenance therapy in table 2.
The study was of an open, parallel group design, with
a total duration of 8 wks, including a two week run-in
period in which Bricanyl MDI was used (2 x 0.25 mg
terbutaline sulphate q. i.d. ). The patients measured peak
expiratory flow rate (PEFR) every morning and evening
before and after the inhalation. During week 2, the
patients had to show an increase in PEFR after
inhalation of 0.5 mg terbutaline sulphate of at least 15%
K. OSTERMAN, E. STAHL, A. KALIEN
176
Table 1. - Demographic data for each treatment group
Turbuhaler
n=177
Age yrs
Duration of
disease yrs
Reversibility
MDI
n=81
48 (17-74)
16 (1-60)
47 (19-77)
15 (1-45)
27 (15-79)
26 (15-78)
Data are mean and range in parenthesis. MDI: pressurized
metered dose inhaler.
Table 2. - Maintenance therapy for each treatment group
Concomitant medication
Oral j3 -agonists
Inhaled steroids
Oral steroids
Anticholinergics
Theophylline
Turbuhaler
n=177
MDI
n=81
27%
82%
16%
4%
56%
22%
74%
11%
0%
53%
Number of patients in %. MDI: pressurized metered dose
inhaler.
on at least one occasion at home using a mini Wright
peak flow meter in order to be included in the study.
After the run-in period, the patients were randomly
divided into two groups. One third of the patients
continued with MDI treatment and two thirds with the
same dose of Bricanyl Turbuhaler, i.e. 0.5 mg of
terbutaline sulphate q.i.d. (on waking, at midday, late
afternoon and before going to bed). The patients
received the instruction leaflet provided by the
manufacturers and were also instructed verbally.
Extra inhalations of terbutaline were allowed and were
recorded every morning and evening in diary cards,
together with PEFR and asthma symptoms according to
the following scoring system: 0 = none; 1 = mild; 2 =
moderate; and 3 =severe. The patients in the Turbuhaler
group were also given a standard questionnaire about
inhaler use. The question about preference was: "Which
inhaler do you prefer to use?"
The patients were informed verbally and in writing
and their informed consent was obtained. The study was
approved by the local Ethics Committees.
Efficacy variables (PEFR, asthma symptom score
(0--3) and number of extra inhalations) were defined as
the mean during the treatment period minus the mean
during the run-in period.
Table 3. - PEFR morning values
Weekly means
MDI group
Turbuhaler group
Run-in:
Treatment:
Week
Before
After
1
2
1
2
3
4
5
6
322
322
329
331
334
329
328
331
377
377
381
384
387
382
382
383
Increase Before After
+55
+56
+53
+53
+53
+54
+54
+52
336
340
341
340
339
338
337
336
390
398
397
394
392
394
394
391
Period mean
Run-in
Turbuhaler group
MDI group
Before
After
Increase
Before
After
Increase
321
377
+56
339
395
+56
Within-group
analysis
Turbuhaler
p-value
0.026
MDI
0.80
MDI: pressurized metered dose inhaler.
Treatment
327
380
+53
338
393
+55
Between-group
analysis
Turb.-MDI
0.48
Increase
+54
+58
+56
+54
+53
+56
+57
+55
177
A SIX WEEK TREATMENT WITII BRICANYL TURBUHALER
PEFR
Run-In
Treatment
350
325
300
275
8
15
22
29
36
43
50
Daya
Fig. 1. - Mean PEFR values in the morning (before inhalation). : Turbuhaler group (n=177); - - : MDI group (n=Sl). Note that
both groups used MDI during the run-in period. MDI: pressurized metered dose inhaler; PEFR: peak expiratory flow rate.
Statistical methods
PEFR were analysed using multivariate techniques
(Hotelling's T2) on the two variables: measurement
before inhalation and measurement after inhalation. In
addition to the between-group comparison, the
temporal behaviour of PEFR was analysed using a
non-parametric trend test (Page's test). The distribution
of asthma scores 0, 1, 2, 3 on an arbitrary day
was estimated for descriptive purposes. These analyses
were conducted for the run-in period and for the
treatment period using a stationary Markov chain model
[7].
Results
increases in PEFR were 56 lmin· 1 and 55 lmin· 1 after
run-in and treatment, respectively. No statistically
significant differences were seen between the groups
(table 3). The daily means of PEFR before inhalation
were analysed for the detection of a trend with time.
The daily means differed only little between days, and
the mean value curves were very similar for the two
groups (fig. 1).
Asthma symptoms
The two treatment groups were compared using the
mean score during the treatment period minus mean
score during the run-in period. There were no
statistically significant differences in the between-group
analysis (figs 2 and 3).
Out of 258 patients, 177 were allocated to the
Turbuhaler group and 81 to the MDI group.
Additional medication, patient preference
Peak flow
Mean PEFR values in the morning in the Turbuhaler
group before inhalation were 321 lmin· 1 during run-in
(MDI) and 328 l·min· 1 with Turbuhaler. The
corresponding values in the MDI group were 339
lmin· 1 and 338 Z.min· 1 • The increase in the morning
values in the Turbuhaler group was statistically
significant (p=0.026).
The increases in PEFR after inhalation were 56
Z.min· 1 during run-in and 53 lmin·1 during the treatment
in the Turbuhaler group. In the MDI group the mean
Mean consumption of extra trial medication during
the daytime was analysed. There was a decrease of 0.30
inhalations from run-in to treatment period in the
Turbuhaler group (p<0.05). In the MDI group there was
no statistically significant difference from run-in to
treatment period. The inter-group analysis did not show
a significant difference between the two treatments.
During the night, there was an inter-group difference of
0.21 inhalations (p<0.05) in favour of Turbuhaler.
Fifty six percent of the patients in the Turbuhaler
group found both inhalers practical to carry around.
Thirty three percent of the patients found Turbuhaler
178
K. OSTERMAN, E. STAin., A. KALI.EN
MOl group
(n=81)
Turbuhaler roup
(n=177
% of patients
% of patients
100
100
80
80
Run-In
Run-In
Treatment
60
60
40
40
20
20
0
Treatment
0
0
1
2
3
0
2
0
3
1
2
Symptom score
0
3
2
3
Symptom score
Fig. 2. - Mean asthma symptom score during the day (O=none; l=mild; 2=moderate; 3=severe). CJ
(Turbuhaler); [=:J : treatment (MDI); MDI: pressurized metered dose inhaler.
Turbuhaler group
(n=177)
% of patients
1
~
: treatment
MOl group
(n=81)
%of patients
100
: run-in (MDI);
100
80
Run-In
Treatment
80
60
60
40
40
20
20
0
0
2
3
0
2 3
Symptom score
0
Run-In
0
1
2
Treatment
3
Discussion
The results of this study clearly show that Bricanyl
Turbuhaler is as effective as Bricanyl MDI, during the
whole Turbuhaler life-span i.e. the efficacy was not
2
3
Symptom score
Fig. 3. - Mean asthma symptom score during the night (O=none; l=mild; 2=moderate; 3=severe).
(Turbuhaler); r.::::;J : treatment (MDI); MDI: pressurized metered dose inhaler.
more practical, whilst 10% preferred MDI in that
respect. Only 2% found it difficult to inhale from any
of the inhalers.
Fifty percent of the patients in the Turbuhaler group
preferred to use Turbuhaler and 24% of the patients
were uncertain.
0
c::::J:
run-in (MDI);
~:
treatment
changed with time. Morning PEFR values before
inhalation increased slightly during Turbuhaler treatment
as compared with run-in. This was not seen in the MDI
group. In earlier studies the corresponding PEFR values
have been shown to be higher during Bricanyl
Turbuhaler treatment as compared with Ventolin
Rotahaler treatment [8, 9]. This could be due to a
difference in duration of action of the two drugs
[10, 11].
In this study, the higher morning PEFR values during
Turbuhaler treatment could, at least in part, be
attributable to a long duration of action of Bricanyl
Turbuhaler. A possible explanation may be that
A SIX WEEK TREATMENT WITH BRICANYL TURBUHALER
Turbuhaler is easier to use [12] and therefore more drug
can reach the airways.
The reduction in asthma symptoms score and need
for extra inhalations in the present study also indicate a
favourable duration of action of Bricanyl Turbuhaler.
However, since this was an open study it can not be
excluded that the improvement in lung function as well
as in asthma symptoms during Turbuhaler treatment in
the present study, could be due to patient expectation of
the new inhaler.
Turbuhaler was well accepted by the patients, which
is in agreement with a previous study [12]. Turbuhaler
was preferred by twice as many patients as MDI in the
present study. This is in accordance with the results
from previous studies [13, 14].
In conclusion, this study showed that Bricanyl
Turbuhaler is an effective and well accepted treatment
in the long-term therapy of asthma. The preferences,
asthma symptom scores and reduced need for extra
inhalations all show a tendency in favour of Bricanyl
Turbuhaler compared with Bricanyl MDI.
References
1. Crompton GK. - Problems patients have using pressurized aerosol inhalers. Eur J Respir Dis, 1982, 63 (Suppl. 119),
101-109.
2. Yarbrough J, Mansfield LE, Ting S. - Metered dose
inhaler induced bronchospasm in asthmatic patients. Ann
Allergy, 1985, 55, 25-27.
3. Wetterlin KIL. - Turbuhaler: a new powder inhaler for
administration of drugs to the airways. Pharm Res, 1988, 5,
(8), 506-508.
4. Johnsen CR, Weeke ER. - Turbuhaler: a new device for
dry powder terbutaline inhalation. Allergy, 1988, 43, 392-395.
5. Persson G, Gruvstad E, StAhl E.- A new multiple dose
powder inhaler, (Turbuhaler®), compared with a pressurized
inhaler in a study of Terbutaline in asthmatics. Eur Respir J,
1988, 1, 681-684.
6. Osterman K, Norborg A· M, StAhl E.- A multiple dose
powder inhaler (Turbuhaler®), compared with a conventional
aerosol. An acceptance study in asthmatics. Allergy, 1989, 44,
294-297.
7. Andersen EB. - Discrete statistical models with social
science application. North-Holland, 1980.
8. Anani A, Higgins AJ, Crompton GK.- Breath-actuated
inhalers: comparison of terbutaline Turbuhaler with salbutamol
Rotahaler. Eur Respir J, 1989, 2, 640-642.
179
9. Stallaert RALM. - The Bricanyl Turbuhaler, efficacy
and acceptability compared to the Ventolin Rotahaler. Abstract. ICACI XIII Congress, Montreux, October 1988.
10. Schwarz F, Engler R, Villiger B. Turbuhaler ®. -A new
concept in inhalation therapy. Abstract, Davos, April 1988.
11. Simonsson BG et al. - Double-blind trial with
increasing doses of salbutamol and terbutaline aerosols in
patients with reversible airway obstruction. Acta Med Scand,
1972, 192, 371-376.
12. Crompton GK. - New inhalation devices. (Editorial).
Eur Respir J, 1988, 1, 679-680.
13. Warner JO, Chetcuti P. - Efficacy and acceptability of
terbutaline sulphate Turbuhaler in children. In: A New
Concept in Inhalation Therapy. S.P. Newman et al. eds, 1987.
14. Ribeiro LB. -A comparison of Bricanyl Turbuhaler and
Berotec dry powder inhaler in asthmatic children. Eur Respir
J, 1989, 2 (Suppl. 8), Abstract No. 990.
Le Turbuhaler~ de Bricany~ dans le traitement de l'asthme.
Une etude multicentrique de six semaines conduite en Suede,
en Grande-Bretagne, au Danemark, en Norvege et en
Finlande. K. Osterman, E. Stdhl, A. Kiillen.
RESUME: Deux cent-cinquante-huit adultes atteints d'asthme
bronchique ont participe tt une etude ouverte, en groupe
parallele, d'une duree de huit semaines. L'etude a demarre
par une periode de mise en route de deux semaines pendant
laquelle la terbutaline (betal agoniste) a ete administree tt
raison de 5mg quatre fois par jour par un aerosol pressurise
au freon, le Bricanyl MDI. Pendant les six semaines suivantes,
un tiers des patients a continue a employer le MDI, et les
deux tiers ont re~u la meme dose de terbutaline sous forme
de poudre seche par le Turbuhaler. L'on n'a pas note de
difference statistiquement significative dans les augmentations
du DEP avant et apres inhalation entre les deux groupes de
traitement. Les scores des symptomes d'asthme ont diminue
dans le groupe Turbuhaler pendant I' etude, m ais sont res test
inchanges dans le groupe MDI. L'on n'a pas observe de
difference d'utilisation des medications hors essai pendant le
jour entre Ies deux groupes. Pendant la nuit la difference etait
statistiquement significative en faveur du Turbuhaler (p<0.05).
Le Turbuhaler a ete bien supporte et s'est avere facile a
utiliser. Compare au MD! utilise pendant la periode de mise
en route, 50% des patients du groupe Turbuhaler lui ont donne
la preference, 26% ont prefere le MD!, tandis que 24%
n'avaient pas de preference. En conclusion, cette etude montre
que le Turbuhaler est au moins aussi effectif que MD! pendant
toute la periode de vie du Turbuhaler (6 semaines).
Eur Respir J., 1991, 4, 175-179.