Thromboxane A2 receptor inhibitor, a better controller of asthma as compared to leukotriene inhibitor: a multi-centric, double blind, double dummy, randomized,

comparative study to evaluate the efficacy and safety of seratrodast versus montelukast.
Dr.Bhupesh Dewan, Dr. Sanjaykumar Navale, Dr. Sandeep Singh, Chandrashekhar Borkar, Deepashri Shah ABSTRACT: Background: Thromboxane A2 (TXA2) has been shown to play an important role in the pathogenesis of asthma. Guidelines recommend controller therapy for mild to moderate persistent asthma. Seratrodast, a specific TXA2 receptor antagonist, given orally, has demonstrated consistent benefit in controlling symptoms of asthma. Therefore, we designed a randomized, double blind, double dummy, multicentric, parallel group study to assess the efficacy, safety and tolerability of seratrodast versus montelukast in controlling mild to moderate asthma in adult patients. Methods: Patients aged >18 years (n=205) with mild to moderate asthma continuing on the lowest dose of inhaled corticosteroid were recruited from 4 different centers across India. Patients were randomly assigned to receive either seratrodast 80mg (n=103) or montelukast 10mg (n=102) once daily for 28 days. The objective was to compare the treatments in terms of improvement from the baseline values, based on the change in asthma symptom score (wheezing, shortness of breath, expectoration, cough and chest tightness), lung function parameters (PEF, FVC and FEV1), and sputum and mucociliary clearance score (Fucose test, Eosinophil Cationic Protein and Albumin). Results: The two treatments showed improvement in the clinical parameters of asthma as well as in the lung function tests and sputum & mucociliary clearance score from baseline. Both, seratrodast and montelukast significantly increased mean values of PEF, FVC and FEV1 from the baseline after a 4 week treatment but seratrodast produced a significantly higher improvement in PEF (0.614 vs. 0.199 L/s), which is equivalent to 24.9L/min higher PEF with seratrodast (P<0.05). Moreover, significantly higher reduction in expectoration score, sputum concentrations of eosinophil cationic protein and albumin in seratrodast group (P<0.05), signifying improvement in asthma condition. The two treatment groups had similar tolerability profiles. Mild increase in hepatic enzymes was seen in both the groups with equal incidence; no serious adverse events were reported during the study. Conclusions: Seratrodast, a TXA2 receptor antagonist, was found to be better in the improvement of PEF, expectoration score, ECP and albumin level as compared to montelukast justifying preference of seratrodast as a controller medication in mild to moderate asthma patients.

Trial registration: Clinical Trial Registry of India (Reg. No: REF/2011/07/002531). Keywords: Thromboxane A2 receptor antagonist, asthma, seratrodast, montelukast, peak expiratory flow (PEF), eosinophil cationic protein (ECP), albumin.

INTRODUCTION: Asthma is one of the most common chronic diseases, characterized by infiltration of various inflammatory cells including eosinophils, T lymphocytes and mast cells in airway smooth muscle [1]. Activation of these cells release number of inflammatory mediators which give rise to bronchial hyperresponsiveness, bronchoconstriction, mucus secretion, increased vascular permeability and smooth muscle hypertrophy [2]. Recently, thromboxane A2 (TXA2) has been considered to be an important mediator in the pathophysiology of asthma. It is demonstrated to have potent bronchoconstrictive activity, and is thought to be involved both in airway hyperresponsiveness as well as in late asthmatic responses [3]. In support of this there is an increasing evidence of inhibition of bronchoconstrictor responses and airway hyperresponsiveness with TXA2 receptor antagonists and TXA2 synthase inhibitors in asthmatic patients [4-6]. Inhaled corticosteroids (ICS) are the most effective anti-inflammatory medication and are recommended as the initial controller treatment for asthma. However, for many patients with persistent asthma, ICS may fail to achieve the adequate control. Increasing the ICS dose may be useful in some cases but is associated with local and systemic side effects [7]. Thus addition of an alternative controller medications like prostanoid and leukotriene modifiers to ICS would be an appropriate option [8,9]. Previous reports show that, seratrodast, a selective TXA2 receptor antagonist, improves airway inflammation and bronchial responsiveness along with improvement in mucociliary clearance in mild to moderate asthmatic patients [3, 10]. It also significantly improves the asthma symptoms, peak expiratory flow (PEF), and diurnal variation in PEF along with a significant reduction in the number of activated eosinophils in the bronchial mucosa [3]. GINA guideline 2011 placed leukotriene receptor antagonists and TXA2 receptor antagonists (seratrodast) as an alternative treatment in mild to moderate asthma and as an add on therapy in mild to moderate persistent asthma [9]. Several placebo-controlled clinical studies have shown the effectiveness of seratrodast and montelukast in the treatment of asthma [3, 6, 11, and 12]. However there is no direct comparison demonstrating the efficacy and safety of seratrodast and montelukast in Indian asthmatic patients. Therefore, we planned a randomized, double blind, double dummy, multicentric, comparative clinical

trial to evaluate the efficacy and safety of seratrodast 80mg as compared to montelukast 10mg in the treatment of mild to moderate asthma. MATERIALS AND METHODS: Study design, setting and objectives This was a prospective, randomized, double blind, double dummy, multicentric, comparative, parallel group study conducted at 4 centres across India. The study was performed in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and Indian regulatory guidelines for conducting clinical trials (schedule Y). Study was approved by institutional and independent ethics committees and written informed consent was obtained from each participant before the study. The study was initiated in February 2012 and was completed (last patient, last visit) in June 2012. This trial has been registered with the Clinical Trial Registry of India (Reg. No: REF/2011/07/002531). The primary objective of the study was to demonstrate efficacy of seratrodast compared with montelukast in the improvement of clinical, pulmonary function and mucociliary parameters of asthma in adult patients. Secondary objectives of the study were to compare the two treatments with regards to safety and patient compliance to investigational drugs. Outcomes were measured as the proportion of patients showing an improvement in the severity of asthma clinical symptoms at week 4, mean change from baseline in the various lung function parameters ( peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)); mean change from baseline in the sputum parameters (visco-elasticity, sputum fucose, albumin and eosinophil cationic protein level); mean change from baseline in the mucociliary clearance and proportion of patients with adverse events associated with the drug. Inclusion and exclusion criteria Two hundred and five non-smoking male or female patients (age range, 18 to 65 years) with active bronchial asthma of mild to moderate severity, as defined by National Asthma Education and Prevention Program, were recruited from the outpatient department. Patients were required to demonstrate FEV1 >60% of predicted value, morning PEF >60% of predicted value or these values achieved with the lowest dose of an inhaled corticosteroids as monotherapy. Patient expectorating

sputum of >20 g/d for at least 2 weeks prior to the study were eligible for inclusion. Among the exclusion criteria were: history of hypersensitivity to study medication; those treated with a course of systemic or inhaled high dose corticosteroids or any other anti-inflammatory drugs, such as sodium cromoglycate or nedocromil sodium, during the previous 4 weeks; patients receiving either a short acting or long acting beta-2 agonists either as monotherapy or in combination with a corticosteroid as inhaler puffs; patients receiving a course of antibiotics or mucolytic agents during the previous 4 weeks; patients showing evidences of pulmonary infection on chest radiograph and sputum bacteriology (bacteria > 107/ml); pregnant and breastfeeding women, reproductive age group women not using birth control measure; those with uncontrolled heart disease, thyroid disorders, coagulation disorders and hematologic problems, etc. Interventions and randomization Patients were randomized 1:1 to receive either montelukast 10mg or seratrodast 80mg treatment for a period of 28 days. Computer generated simple block randomization chart was used to randomize the eligible patients. Each patient was administered two tablets for 28 days; one tablet of either seratrodast 80 mg (Emcure Pharmaceuticals Ltd, India) or montelukast 10 mg (MSN Laboratories, India) and second tablet of masking placebo similar in appearance to the other arm. Patients were allowed to continue with their pre-randomization lowest dose inhaled corticosteroids therapy (budesonide 200 g; fluticasone 250 g) as per the dosage established under the supervision of the principal investigator. As per the randomization chart, the medication packets to be given to each patient were prepared and then supplied to the investigator. Randomization was concealed from patients, investigator, and study personnel. It was disclosed to investigator at the end of the study or in case of any serious adverse events. As there was a difference in size, shape and colour of the investigational drugs, we adopted double dummy design. Placebos of seratrodast 80 mg and montelukast 10 mg were provided to patients based on their respective randomization. Adherence to assigned regimen was assessed by recording the amount of returned investigational drug at the end of study. Treatment compliance was considered adequate, if patients have used at least 75% of scheduled doses. Use of analgesics, antibiotics, mucolytics and drugs acting on central nervous system was restricted during study period. Drugs like warfarin, theophylline, phenytion, bisphosphonates,

itraconazole, diazepam, aminopyrine, corticosteroids and monoamine oxidase inhibitors were not permitted at any time during the study. Any other concomitant medications given to patients were recorded in the case report form. Efficacy assessments The efficacy of both the treatments was assessed based on the change in asthma symptom score, lung function parameters and sputum and mucociliary clearance score from the baseline. Asthma symptoms score comprised of wheezing score, shortness of breath score, expectoration score, cough score and chest tightness score on scale of 0-3 (0= No symptom; 1= mild (symptoms occurred > 2 days/week but not daily); 2= moderate (symptoms occurred daily, with minor limitation in normal activity); and 3= severe (symptoms occurred throughout the day, with extreme limitations in normal activity)). Total asthma symptom score was ranging from 0 to 15. Pulmonary function test were evaluated under three major components e.g. PEF, FEV1, FVC. Spirometry was performed at the baseline and at each follow up visit (week 2 and week 4). Each of these parameters was measured three times to ensure reproducibility. Best reading of these was considered for evaluating the improvement in pulmonary function parameters. To analyze sputum, at the baseline and each follow up visit, the samples of sputum were collected and weighted. Its appearance was noted as 1= serous; 2= mucous; 3= mucopurulent; and 4= purulent and density as 1= fluid; 2= semi-fluid; 3= dense; and 4= very dense. The sputum was analyzed for biochemical parameters (eosinophil cationic protein, fucose, and albumin). At each visit the nasal clearance time was determined in each patient using saccharin method. The time required to perceive a sweet taste after placing a 1 mm diameter particle of saccharin approx. 1 cm behind the anterior end of the inferior turbinate was recorded. Same test was carried in other nostril at an interval of half an hour. Average of two readings was taken as nasal mucous clearance time. Safety and tolerability assessments Adverse events were documented based on spontaneous reporting and investigators assessment at each visit. Safety assessments included clinical or laboratory adverse events reported during the study period. Adverse events were coded using the medical dictionary for regulatory activities (MedDRA) version 13.1. If hospitalization was required, it was

considered as serious adverse event and patient was withdrawn from the study. The patient was treated with standard medical therapy by investigator. The tolerability of the study medication was assessed based on the physicians and patients opinion using 4 point rating scale (1=excellent; 2=satisfactory; 3=good and 4=poor). Sample size From published data it was found that, asthma control rates for seratrodast 80mg and zafirlukast 20mg as add-on with inhaled corticosteroids treatment were 71.68 % and 62.62% respectively. Similarly, assuming the acceptable response rate difference of 10% and confidence level of 95%, a sample size of 194 patients was calculated for the present study to provide 80% power with 50% assumed proportion. We planned to randomize 200 completed patients with 100 in each arm for evaluation of clinical improvement in asthma symptoms. Statistical analysis: The demographic data was analyzed descriptively by using frequency distribution table. All values are expressed as mean standard deviation (SD), unless stated otherwise. All outcome indicators were

normally distributed and analyzed with respect to change from the baseline value by using paired students t test. Comparisons between treatment groups were made by using unpaired Students t test. The degree of statistical significance was expressed as a P value, which was considered significant if < 0.05. Tolerability was assessed by evaluating the total number of patients reporting adverse effects. All efficacy analyses (improvement in clinical, pulmonary and mucociliary parameters) were performed on the intent-to-treat (ITT) population, which included all patients who were randomized to receive at least 14 days of treatment with either of the study medication and had post baseline efficacy data. All safety analyses were performed on the safety population, which included patients who have completed the study.

RESULTS
The study was conducted between February 2012 and June 2012. Of 205 patients, 103 were assigned to seratrodast treatment group and 102 to montelukast. During the treatment period, two patients were withdrawn; one from each group. These patients were considered as intent to treat (ITT) population for efficacy analysis and were excluded from safety analysis. The mean age of the patients enrolled in the study was 44.71 12.89 and 42.47 12.2 years in montelukast and seratrodast treatment groups, respectively. All the patients demonstrated FEV1 > 60% and PEF > 60% of predicted values, as described in the inclusion criteria.

Baseline demographics and characteristics The demographics and lung function characteristics of patients in both the groups were similar (Table 1).

Table 1: Baseline characteristics and lung function tests of study patients Characteristics No. of patients Male, n (%) Female, n (%) Age, years (Mean SD) Body weight, Kg (Mean SD) BMI, kg/m2 (mean SD) Lung function FVC (L) FEV1 (L) PEF (L/sec) Montelukast 10mg (n=102) 64 (62.7) 38 (37.3) 44.71 12.89 61.52 14.60 24.40 8.54 2.580 0.552 1.994 0.365 4.358 1.281 Seratrodast 80mg (n=103) 56 (54.4) 47 (45.6) 42.47 12.2 60.10 14.33 23.87 5.59 2.463 0.608 2.008 0.494 4.124 1.333 P-value

NS* NS# NS# NS# NS# NS# NS#

* - Chi-square test; # - unpaired students t test; NS - P>0.05; BMI: Body mass index; FVC= Forced vital capacity; FEV1 = forced expiratory volume in 1 second; PEF= Peak expiratory flow rate

Efficacy Assessment
During the 4 weeks study period, patients were assessed for improvement in the clinical symptom of asthma, lung function tests, and sputum & mucociliary clearance on day 0, day 14 and day 28. Patients demonstrating improvement in asthma Both, seratrodast and montelukast showed similar improvement in asthma symptoms after 4 weeks of

therapy (Table 2). When evaluated on the basis of at least one parameter showing improvement, seratrodast demonstrated an efficacy of 99.03% as compared to 98.04% of montelukast, a net difference of 0.99% (P>0.05). Moreover, the percentage of patients with decreased asthma score, was higher in seratrodast group as compared to montelukast (72.82% vs. 66.66%), but the difference was not statistically significant.

Table 2: Proportion of patients in seratrodast and Montelukast treatment groups demonstrating improvement in asthma at week 4.
Montelukast 10mg (n=102) Seratrodast 80mg (n=103) Parameter (at 4 week) 66.66 (68) 72.82 (75) Patients with Decreased asthma score, % (n) 82.35 (84 79.61 (82) Patients with Increased FVC, % (n) 82.35 (84) 82.52 (85) Patients with Increased FEV1, % (n) 74.51 (76) 80.58 (83) Patients with increased PEF, % (n) 38.235 (39) 39.80 (41) Patients with Decreased nasociliary clearance score, % (n) 19.61 (20) 22.33 (23) Patients with Improvement in all asthma parameters, % (n) 98.04 (100) 99.03 (102) Patients with Improvement in at least one asthma parameter, % (n) FVC= Forced vital capacity; FEV1 = forced expiratory volume in 1 second; PEF= Peak expiratory flow rate

Clinical Symptoms Assessment: Although, both the treatments significantly improved the symptom score for all five major symptoms (wheezing, shortness of breath, expectoration, cough and chest tightness) from the baseline after a 4 week treatment period (P< 0.05), the reduction in expectoration score was found to be significant in seratrodast group as compared to the montelukast treated patients (P<0.05). The reduction in total asthma score between both the treatments was not differing significantly, thus demonstrating a similar efficacy in asthma symptom resolution (p>0.05). The change in mean the symptom scores at baseline, day 14 and day 28 in both the groups is represented in the Table 3.

Lung function tests: The effect of seratrodast and montelukast on lung function tests is shown in Table 4. Both the treatments significantly increased the mean values of FVC, FEV1 and PEF from the baseline after a 4 week treatment period (P<0.05).

Table 3: Change in mean symptom scores from baseline, at day 14 and day 28 in both study groups. Treatment Montelukast 10mg (n=102) Seratrodast 80mg (n=103) p value for

Groups Baseline Wheezing 1.4 0.7 Day 14 1.1 0.7 Day 28 0.9 0.6 1.1 0.7 1.0 0.7 1.1 0.6 0.9 0.7 5.0 2.6

Mean Change from baseline (028; 95% CI) -0.5 (-0.7 to -0.4)

Baseli ne 1.4 0.8

Day 14 1.0 0.7 1.2 0.7 1.2 0.6 1.2 0.6 1.0 0.7 5.6 2.7

Day 28 0.9 0.7

Mean Change from baseline (0-28; 95% CI) -0.5 (-0.6 to -0.4)

difference in mean changes

NS

Shortness of breath Expectoration Cough

1.5 0.8

1.3 0.8 1.2 0.7 1.2 0.7 1.1 0.8

-0.4 (-0.5 to -0.2) -0.5 (-0.8 to -0.4) -0.6 (-0.7 to -0.4) -0.5 (-0.6 to -0.3) 2.5 (-3.1 to -1.9)

1.5 0.7 1.5 0.6 1.6 0.6 1.3 0.8 7.3 2.8

1.1 0.7 0.9 0.5 1.0 0.6 0.9 0.7 4.6 2.6

-0.4 (-0.5 to -0.2) -0.7 (-0.8 to -0.5) -0.6 (-0.7 to -0.5) -0.4 (-0.5 to -0.2) -2.8 (-3.4 to -2.2)

NS

1.5 0.6 1.6 0.6 1.4 0.7

NS

Chest Tightness

NS

7.5 5.9 Total 2.5 3.0 Asthma Score NS- P > 0.05; S- P < 0.05

NS

The difference in mean changes of FVC and FEV1 Seratrodast treatment significantly improved PEF as was -0.004 (95% CI:-0.065 to 0.073) and -0.029 compared to montelukast, where the mean difference (95% CI: -0.106 to -0.048) respectively, which was between the two groups was 0.416 (95% CI: 0.015 to not significantly different between the two groups 0.682; P<0.05). (P>0.05) at the end of the study. However, Table 4: Lung function tests after 28 days of montelukast and seratrodast treatment.

Parameters

Montelukast 10mg (n=102) Mean Change from baseline (day 0-28, 95% CI)

Seratrodast 80mg (n=103) Mean Change from baseline (day 0-28, 95% CI)
0.181 (0.128 to 0.235)

Difference in Mean Changes

p value of mean changes

FVC (L)

0.177 (0.134 to 0.221)

-0.004 (-0.065 to 0.073) -0.029 (-0.106 to -0.048) 0.416 (0.15 to 0.682)

NS

FEV1 (L) PEF (L/sec)

0.217 (0.168 to 0.308)

0.188 (0.138 to 0.239) 0.614 (0.397 to 0.832)

NS S

0.199 (0.135 to 0.606)

NS- P>0.05; S- P<0.05; FVC= Forced vital capacity; FEV1 = forced expiratory volume in 1 second; PEF= Peak expiratory flow

Sputum analysis and mucocilliary clearance: After 28 days of treatment, the mean change in nasal clearance time (NCT) from baseline was found to be

-2.506 (95% CI: -3.31 to -1.70) and -2.12 (95% CI: -2.920 to -1.32) in montelukast and seratrodast group, respectively. Both the groups showed similar

improvement in the NCT and sputum characteristics on the 28th day of the study and there was no statistical difference observed between them (P>0.05). Interestingly, in sputum laboratory tests, there was a significant difference observed between the groups with respect to change from the baseline values of ECP and albumin, favoring seratrodast (P<0.05; table 5). Global assessment for efficacy by investigator towards the therapy showed that 98.04% and 99.03% patients observed satisfactory-toexcellent efficacy in montelukast and seratrodast group, respectively (Fig. 1). No difference was observed in the overall drug compliance (99.02% vs 98.06%) calculated as average of compliance from visit 2 to 3 in both the groups. Safety and tolerability

Safety assessments were made at weeks 2 and 4 after the start of treatment in safety population (n=203). We observed that, the two treatment groups had similar safety and tolerability profiles (P>0.05). The most frequently reported AEs were increase in the level of hepatic enzymes (AST- 24, ALT- 44), changes in WBC count and differential WBC count and platelets count abnormalities (Table 6). All these adverse events were clinically irrelevant and were established by laboratory examination. All patients were followed up regularly until adverse events were completely resolved. No serious adverse events were reported during the study.

Table 5: Summary of sputum analysis and mucocilliary clearance

P value for difference in Mean Changes

-0.025 (-0.03 to -0.01) -0.022 (-0.026 to -0.019) -0.003 (-0.0046 to NS Fucose -0.0091) (mg/ml) -23.55 (-24.64 to -22.47) -27.20 (-28.38 to -26.01) 3.64 (5.24 to 2.04) S ECP (ng/ml) -32.82 (-34.09 to -31.55) -37.51 (-39.20 to -35.81) 4.68 (6.79 to 2.57) S Albumin (mg/dl) NS- P>0.05; S-P<0.05; NCT- nasal clearance time; NSC- nasocilliary clearance score; ECP- eosinophil cationic protein

Table 6: Adverse events reported during the study period. Body Systems GIT Respiratory system CVS Skin Elevated Hepatic Enzymes TLC increased Eosinophillia Other abnormal lab parameters (leucocytes, serum creatinine) Montelukast (n=60) 1 0 0 1 31 9 7 11 Seratrodast (n=63) 3 1 1 0 37 11 4 6 NS P-Value

NS- P>0.05; GIT: gastrointestinal tract; CVS: cardiovascular system; TLC: total leucocytes count

50 40 Number of patients 30 20 10 0 19 20 34 36

47 46 Montel Seratro

airway hyperresponsiveness by reducing airway inflammation [3,4,6,13]. It is well known that eosinophilic airway inflammation is a hallmark characteristic of bronchial asthma. These infiltrated eosinophil releases various chemical mediators and cytotoxic proteins like ECP which are found to be responsible for bronchoconstriction, mucus hypersecretion, bronchial edema, and epithelial damage, and airway hyperreactivity. Airway inflammation can be directly assessed by measurement of ECP level in sputum [16]. TXA2 was found to increase the eosinophil degranulation resulting in greater ECP release [17]. Moreover, activation of prostanoid TP (Thromboxane) receptors exacerbates the inflammation of the airways by synthesis and release of eosinophilic chemokines [18]. This suggests TXA2 is an important mediator in the regulation of eosinophil degranulation, and might prove beneficial target in the treatment of bronchial asthma. As already established, ECP levels in sputum are significantly increased in asthmatic patients and directly correlated to severity of asthma. Studies also report, a high sputum ECP levels are associated with deterioration of previously well controlled asthma [19]. In addition, ECP levels were significantly correlated with the parameters of airway obstruction such as PEF, FVC, FEV1, airway responsiveness, number of inhaler puffs needed and patient symptom scores [17]. Fukuoka et al. demonstrated a significant reduction in ECP concentrations with seratrodast treatment and its withdrawal resulted in increased ECP levels [20]. Consistent with these results, in our study, seratrodast significantly reduces the sputum ECP concentration compared to montelukast (P<0.05) suggesting better control of asthma condition with seratrodast compared to montelukast. We also observed a significant increase in the PEF in seratrodast group after 28 days compared to montelukast. This improvement in lung function test is in line with previous studies [26]. PEF is one of the important parameter used for diagnosis and monitoring of asthma control [13, 21]. This improvement may due to inhibition of bronchial inflammation induced by both prostanoid pathway and leukotriene pathway. In addition better sputum ECP and albumin control by seratrodast may have contributed to the improvement in PEF compared to montelukast. Thus blockade of TXA2 receptors should be considered for better asthma control over leukotriene antagonists. It has been shown that mucociliary transport function is generally disturbed in asthmatic patient. This

2 1 Excellent Good Satisfactory Poor

Fig 1: Number of patients showing symptom resolution by Investigators perspective DISCUSSION This was a multi-centric, double blind, double dummy, randomized, comparative study, the first of its kind to evaluate the efficacy and safety of seratrodast with montelukast in Indian asthmatic patients. We demonstrated that addition of both treatment agents showed a significant improvement in all major clinical parameters of asthma, lung function tests, and sputum & mucocilliary clearance from baseline. However, seratrodast was associated with significantly greater improvement in PEF compared to montelukast after 28 days of study. In addition, seratrodast group showed a significant reduction in expectoration score, and ECP & albumin levels in sputum as compared to montelukast. A wealth of data proposed the importance of TXA2 in the pathophysiology of airway diseases. It is a biologically potent arachidonic acid metabolite derived from the cyclo-oxygenase pathway [13]. It is a strong bronchial smooth muscle spasmogen and implicated in airway inflammation, impairment of mucociliary clearance, increased microvascular leakage, smooth muscle proliferation and in the genesis of bronchial hyperresponsivenes [6]. Seratrodast is a novel competitive, long acting TXA2 receptor antagonist developed and marketed as an effective anti-asthmatic agent in Japan since 1997 [9]. Japanese Guideline for Adult Asthma recommends the use of seratrodast as a controller medication [15]. It was noted that, seratrodast not only blocks bronchoconstriction induced by prostanoid pathway (TXA2, PGD2 and PGF2) which is mediated through a TXA2 receptor, but also that induced by leukotriene pathway (LTC4, LTD4) and antigen, which is mediated through TXA2 synthesis [14]. Several randomized clinical trials in adult asthma patients demonstrated a reliable efficacy of seratrodast in improving clinical symptoms and

mucociliary dysfunction increases accumulation of bronchial secretions and mucus plugging leads airway obstruction and exacerbation of asthma. Albumin is regarded as marker of sputum viscosity which agglutinates individual cilia and destroys coordinated ciliary motion leading to impairment of mucociliary clearance [14]. Plasma protein leakage (sputum albumin) in the airways is correlated with airway inflammation, severity of asthma and PEF value [17,20]. We found that, sputum albumin concentration measured in the seratrodast treated patients was significantly lower than that of the montelukast indicating pronounced attenuation of microvascular permeability and reduction of albumin leakage into the mucosa associated with airway inflammation. These results are in accordance with previous studies [22], confirming the role of seratrodast in improving mucociliary clearance and bronchial inflammation. We also found that seratrodast treatment significantly decreased the expectoration score as compared to montelukast at the end of the study. This superior efficacy might be attributed to the inhibitory action of seratrodast on TXA2 mediated increase in sputum production. Previous comparative trials against leukotriene receptor antagonist have also highlighted the superiority of seratrodast. The asthma control rate of seratrodast (71.68%) was significantly higher than that of zafirlukast (62.62%, P<0.05) [23]. Seratrodast significantly increased the cough threshold in chronic bronchitis compared to pranlukast [24]. Xin Li et al. concluded that seratrodast is as effective as montelukast in treating patient with asthma [25]. Seratrodast was also found to be more effective in perennial allergic rhinitis than terfenadine. [26]. In the present study both the drugs showed excellent patient compliance and were comparable in safety.
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The major adverse events reported were gastrointestinal disorders (1.9%) like nausea, vomiting, and diarrhea, and elevated liver enzymes (AST and ALT) along with increase in WBC count and platelet count. The number of cases reported with elevated liver enzymes were not-significantly differing between two groups (P>0.05), inferring that both montelukast and seratrodast have effect on elevation of liver enzymes. These results are in accordance with the previous safety data wherein the elevated liver enzyme with seratrodast treatment along with overall side effect reported were 6% to 12% [27]. All these adverse events were subclinical and were established at the end of the study. CONCLUSIONS In summary, this study has demonstrated that seratrodast, a TXA2 receptor antagonist, has comparable efficacy to montelukast for patients with mild-to-moderate asthma with regards to clinical parameters of asthma, lung function tests, and sputum & mucocilliary clearance from baseline. Superiority of seratrodast over montelukast was shown for the improvement of PEF, reduction in expectoration score, reduction in ECP and albumin level after 4 weeks treatment. Both therapies showed a similar safety and tolerability profiles. Therefore, these data suggest that the addition of seratrodast as a controller medication should be considered in management of mild to moderate asthma patients.

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