INITIAL – An observational study of disease severity in newly diagnosed asthma patients and initial response following 12 weeks’ treatment

In China, there are an estimated 30 million people with asthma, a condition that remains poorly controlled in many patients. The INITIAL study (NCT02143739) was a 12-week, multicentre, prospective, observational study comprising 45 centres across Northern and Southern China that aimed to assess asthma severity among newly diagnosed patients as well as their prescribed medications and response to treatment. The primary objective was to evaluate asthma severity using Global Initiative for Asthma (GINA) 2006 research criteria. Secondary objectives included the distribution of asthma medication by GINA severity category and evaluation of GINA 2012-defined control levels. Medications were prescribed as per usual clinical practice. At baseline, among 4491 patients, 3.9%, 12.0%, 22.6% and 61.6% had intermittent, mild persistent, moderate persistent and severe persistent asthma, respectively. Inhaled corticosteroid/long-acting β2 agonist was the most common initial therapy in 90.2% of patients. GINA 2012-defined controlled asthma levels increased in all groups, rising from 6.1% at baseline to 43.0%, 53.8% and 67.8% at Weeks 4, 8 and 12, respectively. Most patients presented with severe persistent asthma. Newly diagnosed patients with asthma could benefit from at least 3 months of regular treatment followed by long-term pharmacological management.

Scientific RepoRts | (2019) 9:1254 | https://doi.org/10.1038/s41598-018-36611-w the 402 Chinese patients with asthma surveyed during a wider Asia-Pacific study using the GINA definition of symptom control, 56% had partly controlled asthma and only 2% were judged to have controlled asthma 7 . According to GINA, the long-term goal of asthma management is to achieve good symptom control and maintain normal activity levels while minimising the future risk of exacerbations, fixed airflow limitation and side effects of treatment 8 . Treatment with regular low-dose inhaled corticosteroids (ICS) is highly effective in reducing asthma symptoms and reducing the risk of asthma-related exacerbations, hospitalisation and death 8 . For patients at GINA Step 2 or above, ICS (with or without long-acting β 2 agonists [LABA] depending on Step) is the recommended initial controller treatment 8 . GINA recommends that asthma severity be assessed retrospectively after a patient has been on controller treatment, with adjustment as necessary, over several months 8 . However, classification of asthma by severity may be useful for management decisions during initial assessments and to characterise patients not receiving ICS when initiating a study 6 . Furthermore, assessment of disease severity (intermittent, mild persistent, moderate persistent and severe persistent asthma) is recommended by the Chinese Guideline for Prevention and Management of Bronchial Asthma when selecting initial treatment 9,10 .
To date, few studies in China have addressed disease severity in newly diagnosed patients and their initial response to treatment. Therefore, this non-interventional study aimed to assess asthma severity among newly diagnosed Chinese patients who had not received ICS (the recommended initial controller treatment of choice in all but those with the mildest symptoms), their prescribed medications and response to treatment. In the context of this study, a new diagnosis of asthma was defined as one occurring no more than 3 months prior to enrolment. The primary objective was to evaluate asthma severity using GINA 2006 research criteria 6 and the Chinese Thoracic Society Guidelines 2008 9 . The main secondary objectives were to assess the distribution of asthma medication by GINA severity category and evaluate GINA 2012-defined control levels during 12 weeks of treatment 11 .

Patients.
Of the 4907 patients screened, 4817 were subsequently enrolled and 4492 were included in the full analysis set (FAS). Overall, 79.9% (3587) of the FAS completed the study (see Fig. 1 for patient flow). The majority of patients (92.8% [4168]) had no history of asthma. Of the 6.5% (293) patients with a history of asthma, the mean duration of illness was 10 days (range 1-83 days). Patient characteristics are given in Table 1.

Asthma control.
Over the course of the study, the proportion of patients with GINA 2012-defined controlled asthma increased in all groups (Fig. 2), rising from 6.1% at baseline to 43.0%, 53.8% and 67.8% at Weeks 4, 8 and 12, respectively. The proportion of patients with GINA 2012-defined partly controlled and uncontrolled asthma decreased over the course of the study, with an overall change from baseline to Week 12 of 50.4% to 29.3% and 43.5% to 2.9%, respectively (Fig. 2). When asthma control was analysed by baseline severity, 61.6% of patients with severe persistent asthma were uncontrolled at baseline, falling to 4.2% at Week 12. At Week 12, among patients receiving budesonide/formoterol, the most common ICS/LABA combination, asthma was controlled in 67.2%, partly controlled in 29.7% and uncontrolled in 3.2%. The figures are similar to those observed in the FAS population at Week 12 irrespective of medicine type (67.8% controlled; 29.3% partly controlled; 2.9% uncontrolled).
Asthma Control Questionnaire. Patient-reported asthma control was assessed using the Asthma Control Questionnaire (5-item version; ACQ-5) 12 . The ACQ-5 consists of five questions on symptom control scored on a scale of 0-6, in which mean scores of ≤0.75 indicate adequately controlled asthma and ≥1.5 indicate inadequately controlled asthma. An ACQ-5 score change of ±0.5 was deemed clinically important 13 . ACQ-5 scores indicated that asthma control improved over the course of the study (    persistent and three intermittent at baseline, respectively. The majority of patients requiring hospitalisation (12) were classified as severe persistent, and the remaining patients were moderate and mild persistent (one patient each). Patients requiring systemic corticosteroids for ≥3 days were distributed between severe persistent (eight) and moderate persistent (six) asthma. Of the severe persistent patients initially prescribed ICS/LABA, 2.5% experienced an exacerbation compared with 3.1% of those who were not.

Discussion
In this non-interventional study of 4492 newly diagnosed patients with asthma who had not received prior therapy with ICS (the GINA-recommended initial controller therapy of choice at Step 2 or above), 61.6% presented with severe persistent asthma; 3.9%, 12.0% and 22.6% presented with intermittent, mild and moderate persistent asthma at baseline, respectively. A retrospective study of asthma trajectory over 10 years demonstrated that most patients classified as severe in the first year transitioned to less severe states in subsequent years 14 . While the severity measure used in that study was derived from medication use and markers of exacerbations 15 rather than GINA criteria, it indicates that the course of severe asthma is potentially modifiable in line with the results presented here, albeit over a much shorter timescale. At baseline, all but the intermittent group had low levels of asthma control. The proportion of patients with GINA 2012-defined controlled asthma increased in all severity groups, rising from 6.1% at baseline to 67.8% at Week 12. There was a corresponding decrease in the proportion of patients with partly controlled and uncontrolled asthma from baseline to Week 12 of 50.4% to 29.3% and 43.5% to 2.9%, respectively. Taken together, 97.1% of patients achieved GINA 2012-defined control or partial control at Week 12. These figures represent a marked improvement over those seen in the studies of Su et al. and Thompson et al., in which 73.8% and 58% of patients overall achieved GINA-defined control (28.7% and 2%) and partial control (45.2% and 56%), respectively 4,7 . Possible explanations for this discrepancy include differences in study design (post hoc survey vs. non-interventional study), patient population (asthma diagnosis ≥1 month vs. newly diagnosed) and treatment. Despite being the most commonly used regimen, less than half (45.6%) of patients surveyed by Su et al. were using ICS/LABA regularly (see below) 4 . A clinically significant improvement in ACQ-5 test score from baseline was seen in 72.8% patients at Week 4, rising to 82.9% patients at Week 12. This suggests that even 4 weeks of regular treatment can improve patient-reported asthma control. This improvement in patient-reported asthma control follows the trajectory of the observed increase in the proportion of patients with GINA-defined controlled and partly controlled asthma.
Overall, 90.2% of patients were initially prescribed ICS/LABA. This figure is considerably higher than the proportion of daily ICS/LABA use (45.6%) reported by Su et al. 4 . Possible explanations for this discrepancy include the fact that patients in that study were not newly diagnosed, having a mean duration of disease of 153 months 4 . Furthermore, it is unclear if they were visiting healthcare professionals (HCPs) as regularly as the patients in the     3 . Results from the present study also showed no discernible difference in GINA 2012-derived control level at Week 12, irrespective of whether an LTRA was prescribed with an ICS/ LABA at baseline. In the present study, the level of GINA 2012-defined asthma control increased at each visit and was greater at Week 12 than Week 8, which may be related to treatment compliance. Multivariate analysis provided further evidence that treatment non-compliance is a risk factor for suboptimal asthma control, in line with the findings of the study by Zhong et al. 2 . Baseline severity, sex, occupation, education level and standard of care (ICS or ICS combination) at Week 12 were associated with good asthma control and should be subject to further investigation in the future.
As lung function testing is not mandatory as per the Chinese Thoracic Society Guidelines 2008 9 , the collection of lung function data after the initial visit was at the investigator's discretion. This is a limitation of our study, as GINA 2012 control level could not be determined in 2942, 2947 and 964 patients at Weeks 4, 8 and 12, respectively. The GINA 2014 major revision altered the determination of symptom control by removing lung function testing from the assessment criteria 16 . Since all other criteria were unchanged in the revision and were collected during this study, a post hoc analysis of this data set using the latest GINA criteria (2018) 8 is planned to assess how the level of asthma control compares with GINA 2012 11 . Control levels improved during the study, and the involvement in the trial itself combined with regular visits and contact with HCPs may have positively influenced the outcome. However, monthly visits do represent the standard of care in China.
In conclusion, over 60% of newly diagnosed patients in this large, observational study presented with severe persistent asthma and only 0.5% of these patients had controlled asthma at baseline. ICS/LABA was the most commonly prescribed initial therapy type, with most patients receiving budesonide/formoterol. Asthma control levels improved considerably following the introduction of therapy, and after 12 weeks of regular treatment  two-thirds of patients achieved GINA 2012-defined controlled asthma. Greater baseline severity, medication non-compliance, male sex, educational level, occupation and non-standard care at Week 12 were identified as risk factors for poor asthma control. Asthma is a chronic disease; these results suggest that newly diagnosed patients with asthma could benefit from at least 3 months of regular treatment followed by long-term maintenance therapy. Further work is required, but this study provides evidence that special attention should be paid to those presenting with severe persistent asthma at baseline. Furthermore, patient education may be required to encourage patients to contact HCPs sooner and to maintain long-term therapy once symptoms improve. Patients. In this study, a new diagnosis of asthma was defined as one occurring no more than 3 months prior to enrolment. Patients newly diagnosed with asthma aged ≥18 years were eligible for study enrolment providing they were stable (i.e. no asthma exacerbation in the previous 2 weeks) and had not used ICS in the 3 months prior to enrolment. An exacerbation was defined as an asthma deterioration that required the use of systemic corticosteroids for ≥3 days, an ER visit or hospitalisation. Exacerbations that occurred within 14 days of each other were defined as one event. Patients who had participated in other clinical studies in the 3 months prior to enrolment or who had a diagnosis of/suspected chronic obstructive pulmonary disease were ineligible for enrolment.

Methods
Assessments. At baseline, informed consent and medical history were obtained. Patients were screened and GINA-defined asthma severity 6 and control were assessed 11 as is standard clinical practice in China when initiating therapy 9,10 . Patient-reported outcomes were assessed using the ACQ-5 12  Statistical analysis. The statistical analysis was primarily descriptive in nature. Quantitative variables were described by frequency, mean, standard deviation, median, minimum and maximum, and number of missing data. Qualitative variables were described using the absolute and relative (%) frequencies of each modality and number of missing data. Statistical tests were two-tailed and performed at the 0.05 significance level; 95% confidence intervals were calculated if applicable. Changes in ACQ-5 test scores from baseline were analysed by paired t-test. Factors influencing asthma control status at Week 12 were investigated using regression analysis. Variables with a p-value ≤ 0.15 in univariate analysis were subsequently included in multivariate analysis. Study size. According to unpublished market research conducted in 2010, among 800 newly diagnosed asthma patients in China, the proportion of patients with moderate and severe asthma was approximately 89%. Based on this assumption, with a ~30% drop-out rate, a sample size of approximately 5000 patients will provide a 95% confidence level with a 0.9% margin of error.

Data Availability
The datasets generated and/or analysed during the current study are available via the AstraZeneca Group of Companies -Data Request Portal at: https://astrazenecagroup-dt.pharmacm.com/DT/Home. More information on AstraZeneca's clinical trials disclosure policy is available at: http://astrazenecagrouptrials.pharmacm.com// ST/Submission/Disclosure.