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Assessment of Montelukast, Doxofylline, and Tiotropium With Budesonide for the Treatment of Asthma: Which Is the Best Among the Second-line Treatment? A Randomized Trial
Clinical Therapeutics/Volume ], Number ], 2015
Assessment of Montelukast, Doxofylline, and Tiotropium With Budesonide for the Treatment of Asthma: Which Is the Best Among the Second-Line Treatment? A Randomized Trial Muhasaparur Ganesan Rajanandh, MPharm, PhD1; Arcot D. Nageswari, MD, DTCD, FCCP, DTCE2; and Kaliappan Ilango, MPharm, PhD, FIC3 1
Department of Pharmacy Practice, Faculty of Pharmacy, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India; 2Department of Pulmonary Medicine, SRM Medical College Hospital and Research Centre, SRM University, Tamil Nadu, India; and 3Interdisciplinary School of Indian System of Medicine, SRM University, Tamil Nadu, India
ABSTRACT Purpose: Data comparing various second-line treatments for asthma with subjective and objective assessment are lacking. This study aimed to compare the efficacy and safety of montelukast, doxofylline, and tiotropium with a low-dose budesonide in patients with mild to moderate persistent asthma. Methods: Patients, all of whom were concurrently using inhaled budesonide (400 mg), were treated for 6 months with formoterol (12 mg), montelukast (10 mg), doxofylline (400 mg), or tiotropium (18 mg). Outcomes included forced expiratory volume in 1 second (FEV1), Saint George Respiratory Questionnaire (SGRQ) scores, asthma symptom scores (daytime and nighttime), and assessment of tolerability and rescue medication use. Findings: A total of 297 patients completed the study. In all 4 groups, significant improvements were observed in all the outcome measures, with formoterol treatment having greater and earlier improvements than the other 3 second-line controller medications with budesonide. Among the second-line treatments, monteradlukast improved the FEV1 from day 45 (P o 0.01), SGRQ scores from day 30 (P o 0.0001), daytime scores from day 30 (P o 0.05), nighttime scores from day 30 (P o 0.0001), and rescue medication use from day 15 (P o .0001) at a faster rate than doxofylline or tiotropium with budesonide. No patients discontinued the treatment because of adverse reactions. Implications: Among the tested second-line treatment regimens, the budesonide/montelukast combination was found to be superior to either the budesonide/doxofylline or budesonide/tiotropium
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combination in all the outcome measures without adversely affecting the tolerability of the patients. Further clinical studies with blinding techniques are likely to be useful. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: budesonide, doxofylline, formoterol, montelukast, tiotropium.
INTRODUCTION The brief background of this study was mentioned in the pilot study report.1 No clinical data are available on comparing montelukast (leukotriene modifier [LT-M]), doxofylline (sustained-release tablet [SR-T]), or tiotropium (long-acting muscarinic antagonist [LAMA]) with budesonide (inhaled corticosteroid [ICS]); therefore, the benefits of these drugs within an asthma management program are not yet very clear. For this reason, we designed a study to compare the efficacy and safety of 3 different controller medications and to find the best secondline controller medication of 3 different treatment protocols in patients with mild to moderate persistent asthma.
PATIENTS AND METHODS Study design, study criteria, treatment, pulmonary function, and rescue medication use procedures were same as those of the pilot study.1 In addition to that, Accepted for publication December 10, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.12.008 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics health-related quality of life (HRQoL) and asthma symptom scores were recorded. The HRQoL was assessed by the Saint George Respiratory Questionnaire (SGRQ). The SGRQ is a disease-specific instrument designed to measure effect on overall health, daily life, and perceived well-being. The SGRQ was scored according to the developer’s guidelines.2 Patients regularly recorded their daytime and nighttime asthma symptom scores and rescue medication use on diary cards daily.3 During the study period, patients were assessed for adverse events (nature, severity, and casual relationship), which were further classified according to their type, severity, and possible associations with the treatments. Patients’ adherence with the study medication was assessed with the help of medication adherence records. Patients not obeying the study protocol were withdrawn from the study. All the clinical assessments and adverse event monitoring were performed at baseline (day 0) and on days 15, 30, 45, 60, 90, 120, 150, and 180 (end visit). To calculate the sample size, we conducted a pilot study.1 From the pilot study report, a sample size of 242 was calculated using the standard formula to detect a significant difference in forced expiratory volume in 1 second (FEV1) measurements with 5% type I error (α) and 80% power of the study (β), and the dropouts considered were 20%. All the data are expressed as mean (SD). Descriptive analysis was performed on the baseline characteristics. One-way ANOVA was used for between-group comparisons across various periods. The Pearson correlation coefficient test was performed to find out the correlation between the FEV1 and SGRQ scores. Multiple linear regression (MLR) analysis was used to standardize the study model by keeping the efficacy variable of FEV1 baseline scores as the dependent variable and age, sex, duration of asthma, smoking history, and literacy levels as the independent variables. All hypothesis tests were 2-sided. P o .05 was considered statistically significant. All the analyses were performed with GraphPad Software, version 6.0 (GraphPad Software Inc, La Jolla, California) except for the MLR analysis, which was applied when testing determinants for the FEV1 scores. The MLR analysis using backward method was performed with SPSS statistical software, version 16.0 (SPSS Inc, Chicago, Illinois). Per protocol analysis was performed.
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RESULTS The study was conducted between December 2011 and May 2014. Each patient in the study was followed up for a period of 6 months at regular predetermined intervals in the duration of 2½ years.
Patient Characteristics A total of 559 patients attended the screening phase, and 362 patients met the study criteria. Finally, 297 patients completed the study, and 65 patients (21.8%) were lost to follow-up because of various reasons detailed in Figure 1. The demographic and baseline disease characteristics are similar between the groups (Table I).
Pulmonary Function In each of the 4 treatment groups, the FEV1 values were almost at the same level in the initial state, and no statistically significant difference was found among the groups (P 4 0.05). In the formoterol/budesonide (FB), montelukast/budesonide (MB), doxofylline/ budesonide (DB), and tiotropium/budesonide (TB) groups, statistically significant increases from baseline values were noted on days 30, 45, 60, and 90 (P o 0.01, P o 0.05, P o .01, and P o .05, respectively), and the increase in FEV1 values continued during subsequent days until the end visit. Statistically significant difference was observed when comparing second-line treatments (MB, DB, and TB) with the first-line treatment (FB), which revealed that none of the second-line treatments can replace the first-line treatment in improving FEV1 values. When data were analyzed for second-line treatments, no statistical difference was observed between the MB and DB groups (Figure 2).
Health-Related Quality of Life After 6 months, the mean differences in the SGRQ symptom, activity, and impact and total scores statistically and significantly exceeded the threshold for a clinically relevant change in all the groups. The mean difference in the total SGRQ score was significantly higher in the MB- group followed by the DB and TB groups among the second-line treatments (Figure 3A, 3B, 3C, and 3D). No significant correlation was observed for FEV1 values and SGRQ scores (Table II). Volume ] Number ]
M.G. Rajanandh et al.
Assessed for eligibility (n = 559)
Excluded (n = 197) Failed to meet study criteria (n = 142) Refused to participate (n = 31)
Randomization (n = 362)
Far off residents (n = 24)
Allocation
Formoterol + Budesonide (FB) (n = 84)
Montelukast + Budesonide (MB) (n = 99)
Doxofylline + Budesonide (DB) (n = 91)
Tiotropium + Budesonide (TB) (n = 88)
Lost to follow-up (n = 11)
Lost to follow-up (n = 13)
Lost to follow-up (n = 10)
Lost to follow-up (n = 11)
Stopped treatment (n = 2)
Relocation of family (n = 1)
Non adherence (n = 3)
Withdrew consent (n = 2)
No explanation (n = 3)
No explanation (n = 4)
Personal reasons (n = 2)
Non adherence (n = 3)
Completed (n = 68)
Completed (n = 81)
Completed (n = 76)
Completed (n = 72)
Figure 1. CONSORT flow diagram for patients in the study.
Asthma Symptom Scores No statistically significant difference was found among the initial daytime symptom scores of the patients (P 4 0.05). In each of the 4 groups, there was a decrease in daytime symptom scores compared with the initial values (P o 0.0001). When analyzed by treatment day, a significantly greater decrease in daytime symptom scores was noted in the FB and MB groups after 15 days of treatment (P o 0.01 for both), whereas for the DB and TB groups, it was from day 45 (P o 0.0001 and P o 0.001, respectively). No statistically significant difference was observed when comparing MB and DB with FB. Among the second-line treatments, no significant difference was found between MB and DB (P 4 0.05). In the same manner, the initial nighttime symptom scores of the patients were almost at the same level with no statistically significant difference among the groups (P 4 0.05). A significant decrease in nighttime symptom scores was observed after the treatment in each of the 4 groups (P 4 0.0001). However, a significantly greater decrease in the nighttime symptom score was observed from day 30 onward in the FB, MB, and DB groups and from day 45 onward in
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TB group. No statistically significant difference was observed when comparing the MB and DB groups with the FB group. Among the second-line treatments, no significant difference (P 4 0.05) was found between the MB and DB treatment groups (Figure 4).
Rescue Medication Use When analyzed by treatment day, FB and MB significantly reduced the number of rescue β2-agonist puffs from day 15 onward (P o 0.0001), whereas DB and TB reduced the number of rescue β2-agonist puffs from days 15 and 45 (P o 0.05 and P o .0001, respectively). No statistically significant difference in reducing the number of rescue medications was observed with any of the secondline treatments with the FB group. Among the second-line treatments, no statistically significant difference was found between the MB and DB groups (Figure 5).
MLR Analysis
To find the factors that predict the effect on FEV1, backward MLR analyses were performed. Analysis with baseline FEV1 as the dependent variable was performed on a model with sex, age, duration and
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Clinical Therapeutics Table I. Baseline characteristics of the study population.* Characteristic
FB (n ¼ 68)
MB (n ¼ 81)
DB (n ¼ 76)
Age, mean (SD), y Male, No. (%) Female, No. (%) Age at asthma onset, mean (SD), y Duration of asthma, mean (SD), y Smoking history, No. (%) Smoker Past smoker Passive smoker Nonsmoker Outcome measures, mean (SD) FEV1, % predicted SGRQ symptom score SGRQ activity score SGRQ impact score SGRQ total score Daytime symptom score Nighttime symptom score Rescue frequency Severity level, No. (%) Mild persistent Moderate persistent
38.37 37 31 31.42 6.64
(14.87) (55.41) (45.58) (8.96) (6.67)
36.33 36 45 30.00 5.86
38.34 41 35 32.40 6.24
13 (19.18) 6 (8.82) – 49 (72.05)
18 6 3 54
(22.2) (7.4) (3.7) (66.6)
67.24 72.15 80.83 74.03 76.82 3.1 2.7 4.48
(6.52) (6.69) (8.22) (8.74) (6.04) (0.6) (0.6) (1.16)
66.15 74.37 83.28 76.03 78.93 3.2 2.6 4.38
(8.32) (8.79) (8.70) (8.55) (7.45) (0.5) (0.4) (1.14)
17 (25.00) 51 (75.00)
(16.96) (44.44) (55.55) (9.58) (8.04)
23 (28.40) 58 (71.60)
TB (n ¼ 72)
(18.78) (53.94) (46.05) (11.84) (9.69)
37.38 38 34 32.54 5.84
(13.57) (52.77) (47.22) (9.58) (8.68)
16 (21.05) – 5 (6.57) 55 (72.36)
12 4 4 52
(16.66) (5.6) (5.6) (72.2)
66.29 74.63 83.86 75.23 78.65 3.1 2.7 4.54
(7.03) (8.17) (8.61) (8.70) (8.68) (0.6) (0.5) (1.13)
66.11 73.08 81.36 74.18 77.47 3.2 2.7 4.39
21 (27.64) 55 (72.36)
(6.38) (8.11) (6.98) (7.95) (7.96) (0.5) (0.7) (1.14)
19 (26.38) 53 (73.62)
DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; FEV1 ¼ forced expiratory volume in 1 second; MB ¼ montelukast/budesonide; SGRQ ¼ Saint George’s Respiratory Questionnaire; TB ¼ tiotropium/budesonide. * No statistically significant difference in baseline characteristics was found among the groups.
severity of asthma, smoking, daytime symptom score, nighttime symptom scores, and SGRQ total scores at baseline as independent variables. Table III lists the best predictors in each group. The best predictors were age, smoking, literacy level, and SGRQ total scores (R2 ¼ 0.838) for the FB group and sex, age, duration of asthma, daytime symptom score, and total score for the MB group (R2 ¼ 0.973). Sx, duration of asthma, age, and nighttime score were the best predictors (R2 ¼ 0.987) in the DB group. In the TB group, the best predictors were sex, age, literacy, SGRQ total scores, and smoking (R2 ¼ 0.787).
situations were faced by any of the study patients. A total of 13 different adverse events were reported by the study patients (Table IV). The reported adverse events were then assessed by a panel of 4 judges, which consisted of pulmonologists, pharmacologist, and clinical pharmacists. All the suspected adverse events were assessed for causality using the Naranjo algorithm, and most of the adverse events were confirmed to be possibly related to the study medications. No patients withdrew their consent from the study because of adverse events.
DISCUSSION Tolerability Asthma exacerbations that required hospitalization were considered serious adverse events. No such
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The goals of asthma therapy are to maintain a nearnormal lung function, absence of asthma symptoms, no activity limitations, and no episodes of asthma
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60 50
30
45
60 Day
90
120 150 180
Figure 2. Change in percentage predicted forced expiratory volume in 1 second (FEV1) from baseline by treatment day among the treatment groups. DB ¼ doxofylline/ budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
worsening. The objectives of the asthma treatment are not fulfilled completely with only and ICS. For this reason, without increasing the dose of the ICS, the
FB MB
100 80
DB TB
60 40 20
B
FB MB
100 80
40 20 0
Day
Day
80
DB TB
60 40 20 0
D SGRQ Total Score
FB MB
100
FB MB
100 80
DB TB
60 40 20
Day
30
0 15
90 12 0 15 0 18 0
60
45
0
0 15 30
SGRQ Impact Score
C
DB TB
60
90 12 0 15 0 18 0
60
45
0
0 15 30
SGRQ Symptom Score
A
90 12 0 15 0 18 0
15
45 60
0
90 12 0 15 0 18 0
70
45 60
80
0 15 30
FEV1, %
90
addition of a second drug with complementary mechanism is preferred.4,5 Patients whose asthma is not controlled ideally on a low-dose ICS alone can be defined as having moderate to persistent asthma. The combination of an ICS and long-acting β-agonist (LABA) is recommended by the Global Initiative for Asthma (GINA) guideline as the first-line preferred treatment in these patients. The other alternative treatment option recommended is an addition of a leukotriene antagonist or an SR-T to a low dose of an ICS. Despite the addition of agents such as LABAs, leukotriene antagonists, and SR-Ts to ICSs, many patients with asthma still remain symptomatic and obstructed. One intriguing option as an add-on therapy for patients not responding to ICSs is an LAMA. 6,7 Although clinical studies have supported the use of LAMAs in the treatment of asthma, we could not find many studies in this area. Therefore, the present study was performed for a head-to-head comparison of various second-line medications commonly used by physicians in their clinical setup. The chosen ICS, budesonide, was studied in combination with 4 different categories of drugs,
SGRQ Activity Score
FB MB DB TB
100
Day
Figure 3. Improvements in the Saint George’s Respiratory Questionnaire (SGRQ) scores at various intervals. DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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Clinical Therapeutics
Table II. Pearson correlation of percentage predicted FEV1 vs SGRQ score. Serial Number (S.No.) 1 2 3 4
Treatment
Pearson Correlation Coefficient (r)
(95% CI)
P Value
FB MB DB TB
0.019 0.037 0.067 0.179
(0.285 to 0.319) (0.332 to 0.265) (0.240 to 0.362) (0.123 to 0.451)
40.05 40.05 40.05 40.05
DB¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; FEV1 ¼ forced expiratory volume in 1 second; MB ¼ montelukast/budesonide; SGRQ ¼ Saint George’s Respiratory Questionnaire; TB ¼ tiotropium/budesonide.
namely, formoterol, montelukast, doxofylline, and tiotropium, to ensure specificity and uniformity in the efficacy assessment.
A
FB MB DB TB
4
Daytime Score
3 2 1 0
0
0
0
18
15
12
90
60
45
30
15
0
–1
The present study reveals that among the tested second-line controller medications, the MB combination resulted in improvements in lung function, HRQoL, and daytime and nighttime scores at a faster rate than DB or TB. Montelukast is a leukotriene receptor antagonist. The cysteinyl leukotrienes, especially leukotrienes C4, D4 and E4, induce many pathologic changes in the lungs, including airflow obstruction, mucous secretion, and inflammatory cell infiltration.8–10 Montelukast acts against these cysteinyl leukotrienes, thus having beneficial action in controlling asthma. In addition, it was observed that LT-M reduced eosinophils in the respiratory tract of patients with asthma. The effect of montelukast in controlling asthma was
B
4
FB MB DB TB
Nighttime Score
3 2 1 0
0
0
18
15
0 12
90
60
45
30
15
0
–1 Day
Figure 4. Change in asthma symptom scores from baseline to end visit. DB ¼ doxofylline/ budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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No. of Rescue Medications Used
Day FB MB DB TB
6 4 2 0 –2 0
15
30
45
60 Day
90
120 150 180
Figure 5. Patterns of rescue medication use among the MB and DB groups. DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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Table III. Multiple linear regression analysis. Predictor FB Constant Age Smoking Literacy Total score MB Constant Sex Age Duration of asthma Daytime score Total score DB Constant Sex Duration of asthma Age Nighttime score TB Constant Sex Age Literacy Total score Smoking
Standardized β Coefficient (SE) P Value 0.850 (0.124) 0.740 (0.123) 0.849 (0.121) 0.643 (0.117) 0.539 (0.116)
o0.05 o0.05 o0.05 o0.05 o0.05
0.918 (0.128) 0.817 (0.127) 0.915 (0.126) 0.802 (0.127) 0.796 (0.127) 0.987 (0.128)
o0.05 o0.05 o0.05 o0.05 o0.05 o0.05
0.981 (0.129) 0.871 (0.129) 0.981 (0.129) 0.874 (0.129) 0.981 (0.129)
o0.05 o0.05 o0.05 o0.05 o0.05
0.725 (0.136) 0.825 (0.134) 0.724 (0.132) 0.724 (0.131) 0.821 (0.131) 0.680 (0.121)
o0.05 o0.05 o0.05 o0.05 o0.05 o0.05
DB ¼ doxofylline/budesonide; FB ¼ formoterol/ budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide; SE ¼ Standard Error.
studied in the Randomised Androgen Deprivation and Radiotherapy and MONtelukast In Chronic Asthma trials by Keith et al11 and Virchow et al,12 respectively; however, these authors added montelukast to an ICS and a LABA combination. Joos et al13 conducted a systematic review of montelukast as an add-on therapy to an ICS in the treatment of mild to moderate asthma and concluded that montelukast has a better long-term safety profile and may be used as an alternative for patients with asthma. The DB combination stands next to the MB combination in all the clinical assessments except for
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nighttime symptom scores, for which DB is better than MB. However, no statistically significant difference was found between these groups in nighttime symptom scores. Doxofylline is a newer xanthine derivative drug used as an antitussive and a bronchodilator. It acts by inhibiting phosphodiesterase activity. Thus, it inhibits neutrophil migration and lymphocyte and inflammatory mediators. Doxofylline claims to have better gastrointestinal tolerability than theophylline.14,15 According to the initial state of the treatment, the TB combination exhibited less improvement in lung function and other clinical measures. Tiotropium is a potent anticholinergic agent with long-lasting bronchodilator action. Although the pharmacology of tiotropium is well studied, its role in asthma remains unproven.16 Studies on clinical benefit of tiotropium in asthma have been a focus of systematic clinical investigation.17 Bateman et al18 reported that tiotropium was noninferior to salmeterol in maintaining lung functions in patients with the B16-Arg/Arg genotype receiving regular ICSs. Improvement in FEV1 with tiotropium maintenance therapy in our study is of similar magnitude to previous investigations. Eosinophilic and noneosinophilic asthma
Table IV. Adverse drug events in various study groups. No. (%) of Adverse Events Adverse Event Nausea Vomiting Tachycardia Palpitation Constipation Insomnia Headache Stomachache Oral candidiasis Dry mouth Stomach upset Difficulty in urination Feeling tired
FB MB DB TB (n ¼ 68) (n ¼ 81) (n ¼ 76) (n ¼ 72) – 1 (1.5) – 1 (1.5) – – 1 (1.5) 1 (1.5) 2 (2.9) – – –
– – – – – – 4 (4.9) 1 (1.2) – – 1 (1.2) –
2 (2.6) – 1 (1.3) 2 (2.6) – 2 (2.6) – 1 (1.3) – – – –
–
1 (1.2)
–
3
5 1 1
– – – – (4.2) – – – – (6.9) (1.4) (1.4) –
DB ¼ doxofylline/budesonide; FB ¼ formoterol/ budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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Clinical Therapeutics phenotypes have been recognized.19 Iwamoto et al20 stated that a noneosinophilic phenotype is associated with a better response to tiotropium.20 In the present study, we chose asthmatic patients regardless of their specific genotype or phenotype, which could be the reason for the inferiority of tiotropium compared with other controller medications. Wang et al17 reported that tiotropium was slightly better than doxofylline, which was not statistically significant. Um et al21 compared tiotropium with the TB combination and found that the combination therapy was superior. However, the above mentioned studies were conducted in patients with chronic obstructive pulmonary disease, and no studies have compared tiotropium with other controller medications in asthmatic patients. Measurements of FEV1 only emphasize pulmonary function, whereas monitoring the patients’ quality of life will provide knowledge about their functional impairment (physical, mental, emotional, and social status), which is also important in a patient’s day-today life.22 In the present study, all the combinations of drugs significantly improved HRQoL. It was observed that the improvement in the SGRQ scores was fairly rapid until day 60, and in further followups the same was gradual. This finding is in line with the results of the study by Thomas et al23 in which a similar trend was observed for different classes of antiasthma drugs. This is the first study, to our knowledge, to assess various second-line treatment regimens using montelukast, doxofylline, and tiotropium with objective and subjective assessment. Our study design was contrived because the addition of an LAMA to an ICS is not included in the GINA guideline. Although we acknowledge this, data indicating the clinical benefit of tiotropium in asthma are scarce. The present study is an evidence-based report to concede this. A study with a placebo control arm is desirable in any clinical trial design. A true placebo arm with no therapy was not possible because of the severity of our patients’ asthma. Instead, ICS/LABA (first-line treatment) was used as a positive control to compare 3 other (second-line treatment) regimens. We believe this is a clinically meaningful comparison. The study had an open-labeled design, which may be another potential limitation.
CONCLUSIONS The data presented herein concluded that FB, MB, DB, and TB significantly improved pulmonary
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function, quality of life, and symptom scores (daytime and nighttime) without adversely affecting the patients. Among the 3 second-line treatments, the BM combination was better in patients with mild to moderate persistent asthma. Nonetheless, multicenter clinical studies with blinding techniques are needed to substantiate the results. The present study can be extended in the future to compare the relative efficacy and tolerability of different doses of ICS vs similar or lower doses of adjunctive therapies, such as an LT-M, SR-T, or LAMA in combination to find the best option for optimal control of asthma.
ACKNOWLEDGMENTS Dr. Rajanandh was responsible for the literature search, study design, data collection, interpretation and writing of this manuscript. Dr. Ilango and Dr. Nageswari were responsible for the study design, data interpretation and writing of the manuscript. Dr. Rajanandh thanks Dr. P.W. Jones, professor of respiratory medicine, St. George’s University of London, London, England, and Dr. Mathieu Molimard, professor of pharmacology, University of Bordeaux, Bordeaux, France, for giving their consent to use their questionnaire for this study. Dr. Rajanandh thanks Dr. M. Ramesh, Dr. S. Sriram, Dr. G.P. Mohanta, Dr. K.P. Arun, Dr. Siraj Sundaran, Dr. Arun Gandhi, and Dr. G. Prathiksha for their expert opinion.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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18.
Asthma (MONICA) study. Respir Med. 2010;104:644–651. Joos S, Miksch A, Szemcsenyi J, et al. Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review. Thorax. 2008;63:453–462. Rajanandh MG, Nageswari AD, Ilango K. Assessment of various second-line medications in addition to inhaled corticosteroid in asthma patients: a randomized controlled trial. Clin Exp Pharmacol Physiol. 2014;41:509–513. Akbari O, Faul JL, Hoyte EG, et al. CD4þ invariant T-cell-receptorþ natural killer T cells in bronchial asthma. N Engl J Med. 2006;354: 1117–1129. Befekadu E, Onofrei C, Colice GL. Tiotropium in asthma: a systematic review. J Asthma Allergy. 2014;7:11–21. Wang T, Luo G, Hu Y, et al. Comparative study on the efficacy of tiotropium bromide inhalation and oral doxofylline treatment of moderate to severe stable chronic obstructive pulmonary disease. J Huazhong Univ Sci Technol Med Sci. 2011;31:614–618. Bateman ED, Boushey HA, Bousquet J, et al, GOAL Investigators Group.
19.
20.
21.
22.
23.
Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170: 836–844. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–259. Iwamoto H, Yokoyama A, Shiota N, et al. Tiotropium bromide is effective for severe asthma with noneosinophilic phenotype. Eur Respir J. 2008;31:1379–1380. Um SW, Yoo CG, Kim YW, et al. The combination of tiotropium and budesonide in the treatment of chronic obstructive pulmonary disease. J Korean Med Sci. 2007;22:839–845. Moy ML, Israel E, Weiss ST, et al. Clinical predictors of health-related quality of life depend on asthma severity. Am J Respir Crit Care Med. 2001;163:924–929. Thomas S, Parthasarathi GS, Shilpa P, et al. Quality of life assessment in asthmatic patients receiving fluticosone compared with equipotent doses of beclomethasone or budesonide. Lung India. 2005;22:86–91.
Address correspondence to: Kaliappan Ilango, MPharm, PhD, FIC, SRM College of Pharmacy, SRM University, Kattankulathur - 603 203, Kanchipuram (DT), Tamil Nadu, India. E-mail: [email protected]; [email protected]
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Assessment of Montelukast, Doxofylline, and Tiotropium With Budesonide for the Treatment of Asthma: Which Is the Best Among the Second-Line Treatment? A Randomized Trial Muhasaparur Ganesan Rajanandh, MPharm, PhD1; Arcot D. Nageswari, MD, DTCD, FCCP, DTCE2; and Kaliappan Ilango, MPharm, PhD, FIC3 1
Department of Pharmacy Practice, Faculty of Pharmacy, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India; 2Department of Pulmonary Medicine, SRM Medical College Hospital and Research Centre, SRM University, Tamil Nadu, India; and 3Interdisciplinary School of Indian System of Medicine, SRM University, Tamil Nadu, India
ABSTRACT Purpose: Data comparing various second-line treatments for asthma with subjective and objective assessment are lacking. This study aimed to compare the efficacy and safety of montelukast, doxofylline, and tiotropium with a low-dose budesonide in patients with mild to moderate persistent asthma. Methods: Patients, all of whom were concurrently using inhaled budesonide (400 mg), were treated for 6 months with formoterol (12 mg), montelukast (10 mg), doxofylline (400 mg), or tiotropium (18 mg). Outcomes included forced expiratory volume in 1 second (FEV1), Saint George Respiratory Questionnaire (SGRQ) scores, asthma symptom scores (daytime and nighttime), and assessment of tolerability and rescue medication use. Findings: A total of 297 patients completed the study. In all 4 groups, significant improvements were observed in all the outcome measures, with formoterol treatment having greater and earlier improvements than the other 3 second-line controller medications with budesonide. Among the second-line treatments, monteradlukast improved the FEV1 from day 45 (P o 0.01), SGRQ scores from day 30 (P o 0.0001), daytime scores from day 30 (P o 0.05), nighttime scores from day 30 (P o 0.0001), and rescue medication use from day 15 (P o .0001) at a faster rate than doxofylline or tiotropium with budesonide. No patients discontinued the treatment because of adverse reactions. Implications: Among the tested second-line treatment regimens, the budesonide/montelukast combination was found to be superior to either the budesonide/doxofylline or budesonide/tiotropium
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combination in all the outcome measures without adversely affecting the tolerability of the patients. Further clinical studies with blinding techniques are likely to be useful. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: budesonide, doxofylline, formoterol, montelukast, tiotropium.
INTRODUCTION The brief background of this study was mentioned in the pilot study report.1 No clinical data are available on comparing montelukast (leukotriene modifier [LT-M]), doxofylline (sustained-release tablet [SR-T]), or tiotropium (long-acting muscarinic antagonist [LAMA]) with budesonide (inhaled corticosteroid [ICS]); therefore, the benefits of these drugs within an asthma management program are not yet very clear. For this reason, we designed a study to compare the efficacy and safety of 3 different controller medications and to find the best secondline controller medication of 3 different treatment protocols in patients with mild to moderate persistent asthma.
PATIENTS AND METHODS Study design, study criteria, treatment, pulmonary function, and rescue medication use procedures were same as those of the pilot study.1 In addition to that, Accepted for publication December 10, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.12.008 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics health-related quality of life (HRQoL) and asthma symptom scores were recorded. The HRQoL was assessed by the Saint George Respiratory Questionnaire (SGRQ). The SGRQ is a disease-specific instrument designed to measure effect on overall health, daily life, and perceived well-being. The SGRQ was scored according to the developer’s guidelines.2 Patients regularly recorded their daytime and nighttime asthma symptom scores and rescue medication use on diary cards daily.3 During the study period, patients were assessed for adverse events (nature, severity, and casual relationship), which were further classified according to their type, severity, and possible associations with the treatments. Patients’ adherence with the study medication was assessed with the help of medication adherence records. Patients not obeying the study protocol were withdrawn from the study. All the clinical assessments and adverse event monitoring were performed at baseline (day 0) and on days 15, 30, 45, 60, 90, 120, 150, and 180 (end visit). To calculate the sample size, we conducted a pilot study.1 From the pilot study report, a sample size of 242 was calculated using the standard formula to detect a significant difference in forced expiratory volume in 1 second (FEV1) measurements with 5% type I error (α) and 80% power of the study (β), and the dropouts considered were 20%. All the data are expressed as mean (SD). Descriptive analysis was performed on the baseline characteristics. One-way ANOVA was used for between-group comparisons across various periods. The Pearson correlation coefficient test was performed to find out the correlation between the FEV1 and SGRQ scores. Multiple linear regression (MLR) analysis was used to standardize the study model by keeping the efficacy variable of FEV1 baseline scores as the dependent variable and age, sex, duration of asthma, smoking history, and literacy levels as the independent variables. All hypothesis tests were 2-sided. P o .05 was considered statistically significant. All the analyses were performed with GraphPad Software, version 6.0 (GraphPad Software Inc, La Jolla, California) except for the MLR analysis, which was applied when testing determinants for the FEV1 scores. The MLR analysis using backward method was performed with SPSS statistical software, version 16.0 (SPSS Inc, Chicago, Illinois). Per protocol analysis was performed.
2
RESULTS The study was conducted between December 2011 and May 2014. Each patient in the study was followed up for a period of 6 months at regular predetermined intervals in the duration of 2½ years.
Patient Characteristics A total of 559 patients attended the screening phase, and 362 patients met the study criteria. Finally, 297 patients completed the study, and 65 patients (21.8%) were lost to follow-up because of various reasons detailed in Figure 1. The demographic and baseline disease characteristics are similar between the groups (Table I).
Pulmonary Function In each of the 4 treatment groups, the FEV1 values were almost at the same level in the initial state, and no statistically significant difference was found among the groups (P 4 0.05). In the formoterol/budesonide (FB), montelukast/budesonide (MB), doxofylline/ budesonide (DB), and tiotropium/budesonide (TB) groups, statistically significant increases from baseline values were noted on days 30, 45, 60, and 90 (P o 0.01, P o 0.05, P o .01, and P o .05, respectively), and the increase in FEV1 values continued during subsequent days until the end visit. Statistically significant difference was observed when comparing second-line treatments (MB, DB, and TB) with the first-line treatment (FB), which revealed that none of the second-line treatments can replace the first-line treatment in improving FEV1 values. When data were analyzed for second-line treatments, no statistical difference was observed between the MB and DB groups (Figure 2).
Health-Related Quality of Life After 6 months, the mean differences in the SGRQ symptom, activity, and impact and total scores statistically and significantly exceeded the threshold for a clinically relevant change in all the groups. The mean difference in the total SGRQ score was significantly higher in the MB- group followed by the DB and TB groups among the second-line treatments (Figure 3A, 3B, 3C, and 3D). No significant correlation was observed for FEV1 values and SGRQ scores (Table II). Volume ] Number ]
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Assessed for eligibility (n = 559)
Excluded (n = 197) Failed to meet study criteria (n = 142) Refused to participate (n = 31)
Randomization (n = 362)
Far off residents (n = 24)
Allocation
Formoterol + Budesonide (FB) (n = 84)
Montelukast + Budesonide (MB) (n = 99)
Doxofylline + Budesonide (DB) (n = 91)
Tiotropium + Budesonide (TB) (n = 88)
Lost to follow-up (n = 11)
Lost to follow-up (n = 13)
Lost to follow-up (n = 10)
Lost to follow-up (n = 11)
Stopped treatment (n = 2)
Relocation of family (n = 1)
Non adherence (n = 3)
Withdrew consent (n = 2)
No explanation (n = 3)
No explanation (n = 4)
Personal reasons (n = 2)
Non adherence (n = 3)
Completed (n = 68)
Completed (n = 81)
Completed (n = 76)
Completed (n = 72)
Figure 1. CONSORT flow diagram for patients in the study.
Asthma Symptom Scores No statistically significant difference was found among the initial daytime symptom scores of the patients (P 4 0.05). In each of the 4 groups, there was a decrease in daytime symptom scores compared with the initial values (P o 0.0001). When analyzed by treatment day, a significantly greater decrease in daytime symptom scores was noted in the FB and MB groups after 15 days of treatment (P o 0.01 for both), whereas for the DB and TB groups, it was from day 45 (P o 0.0001 and P o 0.001, respectively). No statistically significant difference was observed when comparing MB and DB with FB. Among the second-line treatments, no significant difference was found between MB and DB (P 4 0.05). In the same manner, the initial nighttime symptom scores of the patients were almost at the same level with no statistically significant difference among the groups (P 4 0.05). A significant decrease in nighttime symptom scores was observed after the treatment in each of the 4 groups (P 4 0.0001). However, a significantly greater decrease in the nighttime symptom score was observed from day 30 onward in the FB, MB, and DB groups and from day 45 onward in
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TB group. No statistically significant difference was observed when comparing the MB and DB groups with the FB group. Among the second-line treatments, no significant difference (P 4 0.05) was found between the MB and DB treatment groups (Figure 4).
Rescue Medication Use When analyzed by treatment day, FB and MB significantly reduced the number of rescue β2-agonist puffs from day 15 onward (P o 0.0001), whereas DB and TB reduced the number of rescue β2-agonist puffs from days 15 and 45 (P o 0.05 and P o .0001, respectively). No statistically significant difference in reducing the number of rescue medications was observed with any of the secondline treatments with the FB group. Among the second-line treatments, no statistically significant difference was found between the MB and DB groups (Figure 5).
MLR Analysis
To find the factors that predict the effect on FEV1, backward MLR analyses were performed. Analysis with baseline FEV1 as the dependent variable was performed on a model with sex, age, duration and
3
Clinical Therapeutics Table I. Baseline characteristics of the study population.* Characteristic
FB (n ¼ 68)
MB (n ¼ 81)
DB (n ¼ 76)
Age, mean (SD), y Male, No. (%) Female, No. (%) Age at asthma onset, mean (SD), y Duration of asthma, mean (SD), y Smoking history, No. (%) Smoker Past smoker Passive smoker Nonsmoker Outcome measures, mean (SD) FEV1, % predicted SGRQ symptom score SGRQ activity score SGRQ impact score SGRQ total score Daytime symptom score Nighttime symptom score Rescue frequency Severity level, No. (%) Mild persistent Moderate persistent
38.37 37 31 31.42 6.64
(14.87) (55.41) (45.58) (8.96) (6.67)
36.33 36 45 30.00 5.86
38.34 41 35 32.40 6.24
13 (19.18) 6 (8.82) – 49 (72.05)
18 6 3 54
(22.2) (7.4) (3.7) (66.6)
67.24 72.15 80.83 74.03 76.82 3.1 2.7 4.48
(6.52) (6.69) (8.22) (8.74) (6.04) (0.6) (0.6) (1.16)
66.15 74.37 83.28 76.03 78.93 3.2 2.6 4.38
(8.32) (8.79) (8.70) (8.55) (7.45) (0.5) (0.4) (1.14)
17 (25.00) 51 (75.00)
(16.96) (44.44) (55.55) (9.58) (8.04)
23 (28.40) 58 (71.60)
TB (n ¼ 72)
(18.78) (53.94) (46.05) (11.84) (9.69)
37.38 38 34 32.54 5.84
(13.57) (52.77) (47.22) (9.58) (8.68)
16 (21.05) – 5 (6.57) 55 (72.36)
12 4 4 52
(16.66) (5.6) (5.6) (72.2)
66.29 74.63 83.86 75.23 78.65 3.1 2.7 4.54
(7.03) (8.17) (8.61) (8.70) (8.68) (0.6) (0.5) (1.13)
66.11 73.08 81.36 74.18 77.47 3.2 2.7 4.39
21 (27.64) 55 (72.36)
(6.38) (8.11) (6.98) (7.95) (7.96) (0.5) (0.7) (1.14)
19 (26.38) 53 (73.62)
DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; FEV1 ¼ forced expiratory volume in 1 second; MB ¼ montelukast/budesonide; SGRQ ¼ Saint George’s Respiratory Questionnaire; TB ¼ tiotropium/budesonide. * No statistically significant difference in baseline characteristics was found among the groups.
severity of asthma, smoking, daytime symptom score, nighttime symptom scores, and SGRQ total scores at baseline as independent variables. Table III lists the best predictors in each group. The best predictors were age, smoking, literacy level, and SGRQ total scores (R2 ¼ 0.838) for the FB group and sex, age, duration of asthma, daytime symptom score, and total score for the MB group (R2 ¼ 0.973). Sx, duration of asthma, age, and nighttime score were the best predictors (R2 ¼ 0.987) in the DB group. In the TB group, the best predictors were sex, age, literacy, SGRQ total scores, and smoking (R2 ¼ 0.787).
situations were faced by any of the study patients. A total of 13 different adverse events were reported by the study patients (Table IV). The reported adverse events were then assessed by a panel of 4 judges, which consisted of pulmonologists, pharmacologist, and clinical pharmacists. All the suspected adverse events were assessed for causality using the Naranjo algorithm, and most of the adverse events were confirmed to be possibly related to the study medications. No patients withdrew their consent from the study because of adverse events.
DISCUSSION Tolerability Asthma exacerbations that required hospitalization were considered serious adverse events. No such
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The goals of asthma therapy are to maintain a nearnormal lung function, absence of asthma symptoms, no activity limitations, and no episodes of asthma
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60 50
30
45
60 Day
90
120 150 180
Figure 2. Change in percentage predicted forced expiratory volume in 1 second (FEV1) from baseline by treatment day among the treatment groups. DB ¼ doxofylline/ budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
worsening. The objectives of the asthma treatment are not fulfilled completely with only and ICS. For this reason, without increasing the dose of the ICS, the
FB MB
100 80
DB TB
60 40 20
B
FB MB
100 80
40 20 0
Day
Day
80
DB TB
60 40 20 0
D SGRQ Total Score
FB MB
100
FB MB
100 80
DB TB
60 40 20
Day
30
0 15
90 12 0 15 0 18 0
60
45
0
0 15 30
SGRQ Impact Score
C
DB TB
60
90 12 0 15 0 18 0
60
45
0
0 15 30
SGRQ Symptom Score
A
90 12 0 15 0 18 0
15
45 60
0
90 12 0 15 0 18 0
70
45 60
80
0 15 30
FEV1, %
90
addition of a second drug with complementary mechanism is preferred.4,5 Patients whose asthma is not controlled ideally on a low-dose ICS alone can be defined as having moderate to persistent asthma. The combination of an ICS and long-acting β-agonist (LABA) is recommended by the Global Initiative for Asthma (GINA) guideline as the first-line preferred treatment in these patients. The other alternative treatment option recommended is an addition of a leukotriene antagonist or an SR-T to a low dose of an ICS. Despite the addition of agents such as LABAs, leukotriene antagonists, and SR-Ts to ICSs, many patients with asthma still remain symptomatic and obstructed. One intriguing option as an add-on therapy for patients not responding to ICSs is an LAMA. 6,7 Although clinical studies have supported the use of LAMAs in the treatment of asthma, we could not find many studies in this area. Therefore, the present study was performed for a head-to-head comparison of various second-line medications commonly used by physicians in their clinical setup. The chosen ICS, budesonide, was studied in combination with 4 different categories of drugs,
SGRQ Activity Score
FB MB DB TB
100
Day
Figure 3. Improvements in the Saint George’s Respiratory Questionnaire (SGRQ) scores at various intervals. DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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5
Clinical Therapeutics
Table II. Pearson correlation of percentage predicted FEV1 vs SGRQ score. Serial Number (S.No.) 1 2 3 4
Treatment
Pearson Correlation Coefficient (r)
(95% CI)
P Value
FB MB DB TB
0.019 0.037 0.067 0.179
(0.285 to 0.319) (0.332 to 0.265) (0.240 to 0.362) (0.123 to 0.451)
40.05 40.05 40.05 40.05
DB¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; FEV1 ¼ forced expiratory volume in 1 second; MB ¼ montelukast/budesonide; SGRQ ¼ Saint George’s Respiratory Questionnaire; TB ¼ tiotropium/budesonide.
namely, formoterol, montelukast, doxofylline, and tiotropium, to ensure specificity and uniformity in the efficacy assessment.
A
FB MB DB TB
4
Daytime Score
3 2 1 0
0
0
0
18
15
12
90
60
45
30
15
0
–1
The present study reveals that among the tested second-line controller medications, the MB combination resulted in improvements in lung function, HRQoL, and daytime and nighttime scores at a faster rate than DB or TB. Montelukast is a leukotriene receptor antagonist. The cysteinyl leukotrienes, especially leukotrienes C4, D4 and E4, induce many pathologic changes in the lungs, including airflow obstruction, mucous secretion, and inflammatory cell infiltration.8–10 Montelukast acts against these cysteinyl leukotrienes, thus having beneficial action in controlling asthma. In addition, it was observed that LT-M reduced eosinophils in the respiratory tract of patients with asthma. The effect of montelukast in controlling asthma was
B
4
FB MB DB TB
Nighttime Score
3 2 1 0
0
0
18
15
0 12
90
60
45
30
15
0
–1 Day
Figure 4. Change in asthma symptom scores from baseline to end visit. DB ¼ doxofylline/ budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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No. of Rescue Medications Used
Day FB MB DB TB
6 4 2 0 –2 0
15
30
45
60 Day
90
120 150 180
Figure 5. Patterns of rescue medication use among the MB and DB groups. DB ¼ doxofylline/budesonide; FB ¼ formoterol/budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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Table III. Multiple linear regression analysis. Predictor FB Constant Age Smoking Literacy Total score MB Constant Sex Age Duration of asthma Daytime score Total score DB Constant Sex Duration of asthma Age Nighttime score TB Constant Sex Age Literacy Total score Smoking
Standardized β Coefficient (SE) P Value 0.850 (0.124) 0.740 (0.123) 0.849 (0.121) 0.643 (0.117) 0.539 (0.116)
o0.05 o0.05 o0.05 o0.05 o0.05
0.918 (0.128) 0.817 (0.127) 0.915 (0.126) 0.802 (0.127) 0.796 (0.127) 0.987 (0.128)
o0.05 o0.05 o0.05 o0.05 o0.05 o0.05
0.981 (0.129) 0.871 (0.129) 0.981 (0.129) 0.874 (0.129) 0.981 (0.129)
o0.05 o0.05 o0.05 o0.05 o0.05
0.725 (0.136) 0.825 (0.134) 0.724 (0.132) 0.724 (0.131) 0.821 (0.131) 0.680 (0.121)
o0.05 o0.05 o0.05 o0.05 o0.05 o0.05
DB ¼ doxofylline/budesonide; FB ¼ formoterol/ budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide; SE ¼ Standard Error.
studied in the Randomised Androgen Deprivation and Radiotherapy and MONtelukast In Chronic Asthma trials by Keith et al11 and Virchow et al,12 respectively; however, these authors added montelukast to an ICS and a LABA combination. Joos et al13 conducted a systematic review of montelukast as an add-on therapy to an ICS in the treatment of mild to moderate asthma and concluded that montelukast has a better long-term safety profile and may be used as an alternative for patients with asthma. The DB combination stands next to the MB combination in all the clinical assessments except for
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nighttime symptom scores, for which DB is better than MB. However, no statistically significant difference was found between these groups in nighttime symptom scores. Doxofylline is a newer xanthine derivative drug used as an antitussive and a bronchodilator. It acts by inhibiting phosphodiesterase activity. Thus, it inhibits neutrophil migration and lymphocyte and inflammatory mediators. Doxofylline claims to have better gastrointestinal tolerability than theophylline.14,15 According to the initial state of the treatment, the TB combination exhibited less improvement in lung function and other clinical measures. Tiotropium is a potent anticholinergic agent with long-lasting bronchodilator action. Although the pharmacology of tiotropium is well studied, its role in asthma remains unproven.16 Studies on clinical benefit of tiotropium in asthma have been a focus of systematic clinical investigation.17 Bateman et al18 reported that tiotropium was noninferior to salmeterol in maintaining lung functions in patients with the B16-Arg/Arg genotype receiving regular ICSs. Improvement in FEV1 with tiotropium maintenance therapy in our study is of similar magnitude to previous investigations. Eosinophilic and noneosinophilic asthma
Table IV. Adverse drug events in various study groups. No. (%) of Adverse Events Adverse Event Nausea Vomiting Tachycardia Palpitation Constipation Insomnia Headache Stomachache Oral candidiasis Dry mouth Stomach upset Difficulty in urination Feeling tired
FB MB DB TB (n ¼ 68) (n ¼ 81) (n ¼ 76) (n ¼ 72) – 1 (1.5) – 1 (1.5) – – 1 (1.5) 1 (1.5) 2 (2.9) – – –
– – – – – – 4 (4.9) 1 (1.2) – – 1 (1.2) –
2 (2.6) – 1 (1.3) 2 (2.6) – 2 (2.6) – 1 (1.3) – – – –
–
1 (1.2)
–
3
5 1 1
– – – – (4.2) – – – – (6.9) (1.4) (1.4) –
DB ¼ doxofylline/budesonide; FB ¼ formoterol/ budesonide; MB ¼ montelukast/budesonide; TB ¼ tiotropium/budesonide.
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Clinical Therapeutics phenotypes have been recognized.19 Iwamoto et al20 stated that a noneosinophilic phenotype is associated with a better response to tiotropium.20 In the present study, we chose asthmatic patients regardless of their specific genotype or phenotype, which could be the reason for the inferiority of tiotropium compared with other controller medications. Wang et al17 reported that tiotropium was slightly better than doxofylline, which was not statistically significant. Um et al21 compared tiotropium with the TB combination and found that the combination therapy was superior. However, the above mentioned studies were conducted in patients with chronic obstructive pulmonary disease, and no studies have compared tiotropium with other controller medications in asthmatic patients. Measurements of FEV1 only emphasize pulmonary function, whereas monitoring the patients’ quality of life will provide knowledge about their functional impairment (physical, mental, emotional, and social status), which is also important in a patient’s day-today life.22 In the present study, all the combinations of drugs significantly improved HRQoL. It was observed that the improvement in the SGRQ scores was fairly rapid until day 60, and in further followups the same was gradual. This finding is in line with the results of the study by Thomas et al23 in which a similar trend was observed for different classes of antiasthma drugs. This is the first study, to our knowledge, to assess various second-line treatment regimens using montelukast, doxofylline, and tiotropium with objective and subjective assessment. Our study design was contrived because the addition of an LAMA to an ICS is not included in the GINA guideline. Although we acknowledge this, data indicating the clinical benefit of tiotropium in asthma are scarce. The present study is an evidence-based report to concede this. A study with a placebo control arm is desirable in any clinical trial design. A true placebo arm with no therapy was not possible because of the severity of our patients’ asthma. Instead, ICS/LABA (first-line treatment) was used as a positive control to compare 3 other (second-line treatment) regimens. We believe this is a clinically meaningful comparison. The study had an open-labeled design, which may be another potential limitation.
CONCLUSIONS The data presented herein concluded that FB, MB, DB, and TB significantly improved pulmonary
8
function, quality of life, and symptom scores (daytime and nighttime) without adversely affecting the patients. Among the 3 second-line treatments, the BM combination was better in patients with mild to moderate persistent asthma. Nonetheless, multicenter clinical studies with blinding techniques are needed to substantiate the results. The present study can be extended in the future to compare the relative efficacy and tolerability of different doses of ICS vs similar or lower doses of adjunctive therapies, such as an LT-M, SR-T, or LAMA in combination to find the best option for optimal control of asthma.
ACKNOWLEDGMENTS Dr. Rajanandh was responsible for the literature search, study design, data collection, interpretation and writing of this manuscript. Dr. Ilango and Dr. Nageswari were responsible for the study design, data interpretation and writing of the manuscript. Dr. Rajanandh thanks Dr. P.W. Jones, professor of respiratory medicine, St. George’s University of London, London, England, and Dr. Mathieu Molimard, professor of pharmacology, University of Bordeaux, Bordeaux, France, for giving their consent to use their questionnaire for this study. Dr. Rajanandh thanks Dr. M. Ramesh, Dr. S. Sriram, Dr. G.P. Mohanta, Dr. K.P. Arun, Dr. Siraj Sundaran, Dr. Arun Gandhi, and Dr. G. Prathiksha for their expert opinion.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Address correspondence to: Kaliappan Ilango, MPharm, PhD, FIC, SRM College of Pharmacy, SRM University, Kattankulathur - 603 203, Kanchipuram (DT), Tamil Nadu, India. E-mail: [email protected]; [email protected]
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