Asthma, also known as bronchial asthma, is the most common chronic respiratory disease in the world. It is an airway inflammation and airway hyperresponsiveness (AHR) disease involving a variety of cells and cytokines. The main causes of asthma are air pollution, smoking and respiratory viral infections. In recent years, the prevalence and mortality of asthma have been rising. According to statistics, about 300 million people worldwide have asthma. In general, the incidence of asthma in developed countries is significantly higher than in developing countries. With advancement of airway inflammation and immunopathology, it is now recognized that chronic inflammation of the airways is a central issue in asthma attacks. The focus of asthma treatment has shifted from the treatment of acute attacks to the prevention and control of airway inflammation.
Glucocorticoid is the drug of choice for long-term control of asthma. Its advantage is that by inhaling, the drug acts directly on the airway mucosa, and the local anti-inflammatory effect is strong, while the systemic adverse reactions are less. However, it usually takes long-term, standardized inhalation to prevent it. In the acute exacerbation of asthma, the β2 receptor agonist should be inhaled first, followed by inhalation of glucocorticoids. Although anti-inflammatory treatment has become the basic method of asthma, it is still not effective in controlling symptoms in patients with severe asthma, and even systemic glucocorticoid therapy is needed. Therefore, finding new drugs for asthma treatment is critical to restoring the health of asthma patients. Clinical trials are a critical step in evaluating drug development, which is why you need an experienced professional team to help you with innovation in experimental design and management.
Case Study
In most clinical trials, recruitment of trial patients is often the primary difficulty of the trial. In order to obtain reliable and statistically significant experimental data, since the clinical manifestations of asthma are not specific to asthma, it is necessary to eliminate wheezing, chest tightness and cough caused by other diseases while establishing a diagnosis. Secondly, the judgment indicators of the experimental results should be formulated according to the purpose of the experiment. Previous studies have shown that although budesonide and formoterol have a certain effect on maintenance and relief therapy, the effect on eosinophilic airway inflammation remains uncertain. Another challenge in clinical trials is statistical analysis of data, which has many medical statistical methods, each applicable to different data. The statistical methods used in clinical trials must be carefully selected based on the data. In this report, the time of the first severe exacerbation was compared between the treatment groups, using a log-rank test, and was further described using a Cox proportional hazards model. The total numbers of severe exacerbations per patient were compared between treatment groups using a Poisson regression model with treatment as factor and time in the study as an offset variable.
Using the above strategy, we recruited appropriate patients to compare the efficacy, including anti-inflammatory effects, of as-needed budesonide/formoterol with salbutamol in Japanese patients with moderate-to-severe asthma.
Design:
This 1-year, randomized, parallel-group study was performed according to the Declaration of Helsinki and Good Clinical Practice guidelines. An independent ethics committee approved the research program. Informed consent was signed for all patients. Patients entered the clinic at the beginning and end of the enrollment and after 4, 8, 12, 24 and 48 weeks of treatment.
Participants:
Outpatients aged 16–80 years with a diagnosis of asthma (as defined by the American Thoracic Society) for at least 3 months treated with inhaled corticosteroid (ICS).
All Recruited Patients Had Performance as Follows:
- There are no patients with significant concomitant diseases, such as cardiovascular disease.
- The palliative was used 5 or more times per week when the study was enrolled.
- Smoking history is less than 10 years, and pregnant and lactating smokers are excluded from the study.
- Anticholinergics, jaundice and other anti-asthmatic drugs were not used during the study.
Interventions:
Patients were randomized to the same maintenance regimen, budesonide/formoterol 160/4.5μg, 2 inhalations twice a day, plus either as-needed budesonide/formoterol 160/4.5μg or as-needed salbutamol at 100μg. As-needed reliever use was permitted up to 4 inhalations/day.
Main Outcomes:
- The time to first asthma exacerbations.
- The cumulative number of both severe and mild exacerbations.
- Mean use of as-needed medication.
- Symptom scores (ACT).
- Airway inflammation.
Results:
We found that the reliever use of budesonide/formoterol significantly prolonged time to first exacerbations and reduced the rate of asthma exacerbations, and effects that were accompanied with the reduction of eosinophilic airway inflammation. A total of 63 patients (from 315 screened) underwent randomization. Judging from serum Ige levels, >80% of patients were considered as atopic and the percentage was not significantly different between the two groups. After a run-in period, the patients were randomized to study treatment: 32 patients to as-needed budesonide/formoterol and 31 patients to as-needed salbutamol. Characteristics of the treatment group were comparable at baseline (Table 1).
Table 1. Characteristics of the study patients
The time of first asthma exacerbation was significantly prolonged with as-needed budesonide/formoterol compared with as-needed salbutamol (log-rank test, p=0.0342; Figure 1).
Figure 1. Kaplan-Meier plot of time to first asthma exacerbation.
There was a 34% reduction in the hazard ratio for a first asthma exacerbation with budesonide/formoterol compared with salbutamol (hazard ratio, 0.34; 95% confidence interval, 0. 11-0.92 p=0.0334). The total number of both severe and mild asthma exacerbations was significantly reduced with budesonide/formoterol compared with salbutamol (mild, 15.6% versus 29.0%, P< 0.05; severe, versus 9.7%; p<0.05; Figure 2).
Figure 2. Cumulative rate of (A)mild asthma exacerbations (defined as unscheduled outpatient visits or reliever use more than four times a day) and (B)severe asthma exacerbations (defined as emergency department visits, systemic steroid use, or hospitalization).
The mean as-needed reliever use significantly decreased in both budesonide/formoterol (from 11.2 to 2.0 inhalations/wk) and salbutamol (from 10.6 to 3.6 inhalations/wk). The average number of inhalations of reliever use during the study was significantly lower with budesonide/formoterol than salbutamol(budesonide/ formoterol, 3.6±0.9 inhalations/wk; salbutamol, 5.6±0.8 inhalations/wk; p < 0.05; Figure 3).The mean daily additional dose of budesonide used in the budesonide/formoterol group was 76.8 ug. During the study, patients with as-needed budesonide/formoterol had never used systemic steroids.
Figure 3. Changes in frequency of reliever use during the study.
The ACT scores were significantly improved from run-in (15.3±2.2) to week 48(22.2±0.8) with as needed use of budesonide/formoterol(p <0.05),and were significantly higher than that of salbutamol at week 48(p<0.05; Figure 4).
Figure 4. Changes in asthma control test (ACT) score during the study.
Of the 63 subjects randomized into the study, 31 subjects (as-needed budesonide/formoterol, n= 15; as-needed salbutamol, n= 16) could produce sufficient sputum for analysis at weeks 0,8, 24, and 48. Mean eosinophil and mast cell counts, as well as mean volume of ECP and B12 tryptase, were similar between the two groups(budesonide /formoterol, eosinophil, 13±6% and mast cell, 0.7±0.2%; salbutamol, eosinophil 11 5% and mast cell, 0.6±0.6%). Mean eosinophil counts and ecp contents significantly decreased with budesonide /formoterol compared with salbutamol at weeks 8, 24, and 48(p<0.05 at week 8 and p <0.01 at weeks 24 and 48). In addition, mast cell count and B12 tryptase contents decreased only with budesonide formoterol at week 48(p <0.05; Table 2).
Table 2. Analysis of inflammatory markers in induced sputum
*p<0.05; **p<0.01 compared with salbutamol. ECP=eosinophil cationic protein.
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References:
1. Takeyama, K., et al. (2014) ‘Budesonide/formoterol maintenance and reliever therapy in moderate-to-severe asthma: effects on eosinophilic airway inflammation’, Allergy Asthma Proc, 35(2), 141-148.
2. Ohta, K. (2013) ‘The essence of "Asthma Prevention and Management Guideline 2012, Japan (JGL 2012)" for adults]’, Arerugi, 62(2), 139-143.
3. Jia, G, et al. (2012) ‘Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients’, J Allergy Clin Immunol, 130, 647–654.