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JPGM 2010 56 4 270 70937 PDF
JPGM 2010 56 4 270 70937 PDF
com
Department of ABSTRACT
Pharmacology,
Background: The goal of asthma therapy is to achieve clinical control and near normal lung functions. Many
Government Medical
College, 1Department
patients with persistent asthma fail to achieve this goal with a single controller medication add on to a inhaled
of Tuberculosis and corticosteroid. We have checked whether another controller medication add on to inhaled corticosteroid and
Respiratory diseases, long-acting β2 agonist helps in achieving the asthma goal or not. Objectives: To identify the effect of controller
Sir Takhtsinghji hospital medication add on to inhaled corticosteroid and the long-acting β2 agonist on the clinical symptom, lung function,
and Government and compliance in patients with asthma. Materials and Methods: We conducted a randomized, open-labeled,
Medical College, comparative trial in 50 participants with moderate-to-severe persistent asthma. The study duration was of 10
Bhavnagar-364001 weeks. During the first two weeks of the run-in period all the participants received a dry powder inhaler drug
Gujarat, India delivery of budesonide (400 mcg/day) and formoterol (12 mcg/day) combination. At the end of the run-in period
the participants were randomly allocated into three groups: group A (n = 16) received oral montelukast (10
Address for correspondence:
Dr. C. B. Tripathi mg/day); group B (n = 17) received oral doxophylline (400 mg/day), and group C (n = 17) received inhaled
E-mail: cbrtripathi@yahoo. budesonide (400 mcg) as add on to the above-mentioned drugs of the run-in period. The primary outcome
co.in was improvement in forced expiratory volume at 1 second (FEV1). Results: All the participants of the three
groups had significant improvement in FEV1 (P < 0.001) and asthma symptoms at the end of 10 weeks. The
mean increase in FEV1 (% of predicted) from the baseline, in groups A, B, and C was: 24.6; 21.33, and 19.86%,
Received : 03-03-10 respectively. Conclusions: All add on controller medications helped, with a significant improvement of lung
Review completed : 01-05-10 functions and asthma symptoms.
Accepted : 28-06-10
PubMed ID : ***
DOI: 10.4103/0022-3859.70937 KEY WORDS: Asthma, inhaled corticosteroid, long-acting beta2 agonist, montelukast sodium, doxophylline,
J Postgrad Med 2010;56:270-74 add on therapy
therapy with theophylline as an add on to inhaled corticosteroid and 17 participants in each group, respectively, with the help of
has shown more benefit in persistent asthma than inhaled random allocation software version 1.0.0.
corticosteroid alone, in previous studies.[11,12] Doxophylline,
a newer methylxantine claims to have better gastrointestinal After randomization, participants of groups A, B, and C were
tolerability than theophylline.[13] daily given an oral tablet of montelukast 10 mg/day (Romilast;
Ranbaxy Laboratories Ltd.) in the evening, an oral tablet of
From the above information we wanted to identify whether or doxophylline sustained release 400 mg/day (Doxolin-SR; German
not another controller medication in the form of montelukast, Remedies) in the morning, and inhaled budesonide 400 mcg/day
doxophylline or inhaled budesonide as add on to the (Budate dry powder inhaler drug delivery; Lupin Pharma) in two
combination of inhaled budesonide and formoterol would help divided doses, respectively, as add on to the above combination
in achieving better control of the symptoms and improving of budesonide (400 mcg/day) and formoterol (12 mcg/day) dry
the lung functions in the case of a moderate-to-severe type of powder inhaler drug delivery.
persistent asthma.
The participants were followed at two, four, and eight weeks
Materials and Methods post randomization. During each visit a detailed medical history,
physical examination, pulmonary function tests, asthma control
Protocol questionnaire score calculation, and inquiry about any adverse
The study was a randomized, open-labeled, and comparative drug reactions was conducted. During the study period all the
clinical trial. The protocol was approved by the institutional participants were allowed to use metered dose inhaler of a short
review board of the Government Medical College; Bhavnagar acting β2 agonist as a rescue medication.
(Gujarat).The study was conducted according to the ICH GCP
guidelines, 2008 amendment. The participants were recruited Outcomes
from the Department of Tuberculosis and Respiratory Diseases, The primary outcome was a percentage of improvement
Sir T. General Hospital, Bhavnagar, a tertiary care hospital. The in FEV1. The secondary outcomes included a percentage
participants included in the study were aged between 15 and of improvement in the peak expiratory flow rate (PEFR),
65 years, either gender; had clinically diagnosed asthma; poor improvement in the asthma control questionnaire scores, rates
asthma control, defined by an asthma control questionnaire of adverse drug reactions, and episodes of poor asthma control
score (ACQ) of 1.5 or greater; FEV1 value of 50% or more of the (EPACs) defined by any of the following events occurring any
predicted; and improvement in FEV1was greater than 15% after time during the follow-up period: a decrease in PEFR more
bronchodilator inhalation.[14,15] The participants were excluded if than 30% over baseline; increased use of metered dose inhaler
they were smokers; pregnant and lactating woman; had a major of the short acting β2 agonist by more than four metered doses
illness other than of the respiratory system; had a major illness of a day; use of oral corticosteroid; or any unscheduled asthma
the respiratory system other than asthma; had taken long-acting healthcare visit.
antihistamines within the preceding week of enrollment, or had a
history of hypersensitivity to any of the above-mentioned drugs. Statistical analysis
The statistical analysis was done using Sigma Stat version 3.5.
No formal sample size calculation was performed, as this was Wilcoxon signed ranked test was used to compare the 10-week
a pilot study to compare the effectiveness of three different values of FEV1 and PEFR with the baseline and the two-week
treatment strategies with controller medications, in the values, and to compare the 10-week values of the asthma control
management of moderate-to-severe asthma. The total study questionnaire score with the baseline value. Kruskal-Wallis One
period was of 10 weeks, which included a run-in period of two Way Analysis of Variance on Ranks was used to compare the 10-
weeks. The aim of the run-in period (based on previous studies week values of FEV1 and PEFR among the three groups, when
[16,25]
) was to make all the groups comparable, with regard to adjusted for the baseline, age, and sex; to compare the episodes
the treatment strategy at the point of randomization.[16,25] At of poor asthma control rates (EPACs) among the three groups;
the time of recruitment: informed consent; a detailed medical and the group difference of asthma control questionnaire score
history and physical examination; baseline pulmonary function at 10 weeks. A P value of < 0.05 was considered significant. Per
tests; and asthma control questionnaire score calculation was protocol analysis has performed.
conducted.[14,15] Also the laboratory test including routine
blood counts, liver function tests, and kidney function tests Results
were conducted at the time of recruitment and at the end of 10
weeks. During the run-in period, all the participants were given FEV1 and PEFR
dry powder inhaler drug delivery of budesonide (400 mcg/day) A total of 50 participants were randomized. Forty-five
and formoterol (12 mcg/day) combination, with the help of a participants had completed all the follow-up visits, with 15
dry powder inhaler (Rotahaler; Cipla Ltd.), in two divided doses. participants in each group. Five participants were excluded
(Budamate dry powder inhaler drug delivery; Lupin Pharma) The from the final analysis because they were lost to follow up (n =
next follow-up was conducted at the end of two weeks. On this 4) before the first follow-up visit, and withdrawal of consent (n
visit, pulmonary function tests, history of medical illness, and = 1), at the first follow-up visit, 15 days after randomization.
physical examination were carried out. The participants were Baseline characteristics of the participants were matched and
randomly allocated to three groups: A, B, and C with 16, 17, are shown in Table 1. The daily treatment history of participants
of all groups, during the past six months is shown in Table 1. weeks (P < 0.001) [Table 2], but the difference in the extent of
After adjusting for age, sex, and baseline characteristics all improvement among the three groups was not significant (P =
the groups had shown significant improvement in FEV1 at 10 0.807). Similarly in the case of PEFR all the groups had shown
significant improvement at 10 weeks (P = 0.004 for Group A; P
< 0.001 for Groups B and C), but the difference in the extent
Table 1: Baseline characteristics at the time of recruitment of improvement among the three groups was not significant
Group A (ICS Group B (ICS Group C (Table 2; P = 0.341). When adjusted for the two-week results
+LABA+ +LABA + (double ICS (addition of controller medication) improvement in FEV1 and
montelukast) doxophylline) +LABA)
PEFR at 10 weeks was significant in every group (group A — P
Age 39.33±8.78 41.33±12.15 37.13±12.92 = 0.002 for FEV1 and 0.027 for PEFR; group B — P < 0.001
Male 09 06 10 for FEV1 and P = 0.001 for PEFR; group C — P < 0.001 for
Female 07 11 07 FEV1 and PEFR; Table 2). The difference in the median values
Age at asthma onset (yr) 31.40±9.59 32.33±11.80 30.00±11.11 of the episodes of poor asthma control rates (EPACs) among the
Daily treatment history three treatment groups was not significant (P = 0.889; Table 3).
of past six months When adjusted for baseline there was significant improvement
(number of participants) in the asthma control questionnaire score in all three groups
Inhaled long acting β2 05 06 05 (P < 0.001), but among the three groups, the difference in
agonist the improvement was not significant (P = 0.652; Table 4).
Leukotrine receptor 02 03 01 No major adverse drug reaction was noted in any of the three
antagonist
groups [Table 5]. Furthermore, there was no major alteration
Oral steroid 00 00 00 in blood counts, liver function tests or kidney function tests in
Inhaled anticholinergic 04 05 07 any of the participants at the end of 10 weeks.
Inhaled short acting β2 10 08 10
agonist
Combination drugs 07 07 08 Table 3:EPACs in each group during the study period
Oral methylxanyhine 11 07 08 (n=15 in each group)
Age (in years) is expressed as Mean ± SD, Male and female are Group A (ICS +LABA Group B (ICS +LABA Group C (ICS +LABA)
absolute number in each groups (n=16, 17 and 17 in group A, B and C + montelukast) + doxophylline)
respectively)
0.00 0.00 1.00
0.00, 1.75 0.00, 2.75 0.00, 1.00
Table 2: Change in pulmonary function tests from baseline Kruskal-Wallis one way analysis of variance on ranks. (P=0.889), Data
by treatment (n=15 in each group) expressed as median and Interquartile range
Acknowledgement J 1999;14:902-7.
15. Juniper EF, Bousquet J, Abetz L, Bateman ED. The GOAL
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