Efficacy of Regular ICS/LABA Sequential As-Needed Therapy in Newly Diagnosed Mild Asthma Patients: A Randomized, Parallel, Positive-Control Study
Phase: PHASE4
Conditions: Bronchial Asthma
Sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

1 
Version 3.0 (June 24, 2024) 
Shanghai General Hospital 
Clinical research projects initiated by 
researchers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Project 
Title 
Efficacy of Regular ICS/LABA 
Sequential As-Needed Therapy 
in Newly Diagnosed Mild 
Asthma Patients: A 
Randomized, Parallel, Positive-
Control Study 
Research Project 
Number 
20240512013241142
Research Project 
Version Number 
Version 3.0 (June 24, 2024)
Research Project 
Version Date 
2024-06-24
Principal 
Investigator 
Zhou Yan 

2 
Version 3.0 (June 24, 2024) 
Version History / Revision History 
Document 
Version Date 
Reason for Revision 
Research Proposal 
2024-01-01 
Format and content 
revision
2024-05-06
Partial content revision
 
2024-06-11
Partial content revision
 
2024-06-24 
Modified based on the 
second scientific review
 
 

3 
Version 3.0 (June 24, 2024) 
Clinical Study Protocol Abstract 
Study Title 
Efficacy of Regular ICS/LABA Sequential As-Needed Therapy in Newly 
Diagnosed Mild Asthma Patients: A Randomized, Parallel, Positive-Control 
Study 
Study 
Overview 
Bronchial asthma (referred to as asthma) is a chronic 
inflammatory disease of the airways and has become the second 
largest respiratory disease in China. Among different severity levels 
of asthma, mild asthma accounts for 50%-75%. Some patients with 
mild asthma have mild symptoms and atypical presentations, and their 
pulmonary function is relatively normal. However, airway 
inflammation still exists, and without sufficient treatment, there 
remains a risk of acute attacks or even death. 
 
The preferred treatment pathway for mild asthma is as-needed 
low-dose inhaled corticosteroids (ICS) combined with fast-acting 
long-acting β2 agonists (LABA). An alternative pathway involves 
maintenance treatment with low-dose ICS or other medications, 
supplemented by as-needed short-acting β2 agonists (SABA). 
Compared to daily maintenance ICS therapy, as-needed ICS-LABA 
therapy, such as ICS-formoterol, reduces the risk of emergency visits 
and hospitalizations. However, this dosing mode is symptom-driven 
and may not adequately control airway inflammation, particularly in 
newly diagnosed patients.  
 
Our early studies have shown that initiating maintenance therapy 
with low-dose ICS-formoterol as-needed can alleviate symptoms and 
improve lung function, establishing a habit of maintenance treatment. 
Therefore, initiating 4 weeks of combined maintenance and as-needed 
therapy aims to achieve better improvement in inflammation and lung 
function, helping patients identify their optimal health level for 
subsequent self-management of as-needed treatment. 
 

4 
Version 3.0 (June 24, 2024) 
Based on this premise, this study employs a randomized, parallel, 
positive-controlled design to enroll patients with newly diagnosed 
mild asthma. Participants will be randomized 1:1 to receive either as-
needed low-dose ICS-formoterol supplemented with initial 4-week 
maintenance therapy or as-needed low-dose ICS-formoterol alone 
until Week 24, comparing the efficacy in mild asthma patients. Study 
endpoints include the improvement rate of forced expiratory volume 
in one second (FEV1) after 4 weeks of maintenance treatment 
compared to baseline, and secondary endpoints include FEV1 
improvement rate at 24 weeks compared to baseline, asthma 
exacerbation-related indicators at 4 and 24 weeks, symptom 
improvement, and inflammation control. The study also explores 
biomarkers that can effectively predict the efficacy of initial 
maintenance therapy with low-dose ICS-formoterol in mild asthma 
patients, aiming to achieve more personalized initial treatment for 
mild asthma.  
Study 
Objective 
and 
Endpoints 
Study Objective 
Study endpoints 
 
Primary Objective 
Primary Endpoint 
 
 To assess the effectiveness of 
initiating 4 weeks of 
combined maintenance and 
as-needed low-dose ICS-
formoterol versus as-needed 
low-dose ICS-formoterol 
alone in newly diagnosed 
patients with mild asthma. 
Specifically, the study aims to 
determine the improvement in 
forced expiratory volume in 
one second (FEV1), a marker 
 The change in FEV1 from 
baseline at week 4. 

5 
Version 3.0 (June 24, 2024) 
of airflow limitation, after 4 
weeks of treatment compared 
to baseline. 
 
Secondary Objective 
Secondary Endpoints 
 
  Evaluate the improvement in 
symptoms, small airway 
function, and airway 
inflammation after 4 weeks of 
combined maintenance and 
as-needed low-dose ICS-
formoterol treatment, 
establishing the optimal 
patient population and 
treatment regimen for drug 
efficacy. 
 Compare the dynamic 
monitoring of clinical 
indicators between 4 weeks of 
combined maintenance and 
as-needed low-dose ICS-
formoterol treatment followed 
by as-needed therapy up to 
week 24 versus initial as-
needed therapy up to week 
24. Specifically, assess the 
impact on acute 
exacerbations, improvement 
in lung function compared to 
baseline, symptom relief, and 
airway inflammation from 1 
to 24 weeks. 
  Assessment of symptom 
improvement (ACT and ACQ 
scores), changes in small 
airway function, improvement 
in airway inflammation levels 
(eosinophils, Fractional 
Exhaled Nitric Oxide 
(FENO), induced sputum cell 
count, and inflammation 
markers), and incidence of 
acute exacerbations at Week 
4. 
  Evaluation from Weeks 1 to 
24 of improvement rates in 
FEV1 and small airway 
function compared to 
baseline, improvement in 
symptoms (ACT and ACQ 
scores), frequency of asthma 
exacerbations, time to first 
asthma exacerbation, 
instances of hospitalization 
(including intubation and ICU 
admission) or emergency 
room visits (not resulting in 
hospitalization), weeks of 
asthma symptom control, 
doses of ICS and oral 

6 
Version 3.0 (June 24, 2024) 
corticosteroids (OCS) used, 
and improvement in airway 
inflammation (FENO, 
eosinophils, induced sputum 
cell count, and inflammation 
markers). 
 
Exploratory Objective 
Exploratory Endpoints 
 
 Using comprehensive lung 
function parameters (FEV1, 
FEV1/FVC, PEF, FEF25%, 
FEF50%, FEF75%, MMEF) and 
levels of airway 
inflammation, explore 
population characteristics and 
biomarkers that effectively 
predict the efficacy of 
maintenance low-dose ICS-
formoterol treatment in 
patients with mild asthma. 
 Stratify the study based on the 
presence of baseline small 
airway dysfunction and 
conduct a layered 
investigation using 
comprehensive lung function 
parameters and levels of 
airway inflammation. This 
exploration aims to identify 
characteristics and biomarkers 
that determine the suitability 
of initial use of maintenance 
low-dose ICS/LABA therapy 
in patients with mild asthma. 
Study 
Design 
Randomized, Parallel, Positive-Control Study 
Study 
Cohort 
Chinese patients with newly diagnosed mild bronchial asthma 
Sample size
90 cases 
Inclusion 
criteria 
The eligible subjects for this study must meet all of the following 
criteria: 
 
1. Subjects must fully understand the purpose and procedures of the 
study, voluntarily agree to participate as a subject, and sign an 
informed consent form before any study procedures commence. 

7 
Version 3.0 (June 24, 2024) 
    
2. Adults (including males and non-pregnant, non-lactating females) 
aged 18 to 70 years (inclusive of borderline values), diagnosed for the 
first time with mild asthma according to the GINA and latest domestic 
guidelines for the prevention and treatment of bronchial asthma, and 
not in an acute exacerbation period. 
    
3. During screening, meet any of the following objective criteria for 
variable airflow limitation:  
   - Positive bronchodilator response (increase in FEV1 >12% 
and >200 mL absolute increase in FEV1 after inhalation of 
bronchodilator). 
   - Positive bronchial provocation test; FEV1 decrease ≥20% after 
inhalation of acetylcholine provocation agent. 
    
4. During screening and at the D-1 visit of the run-in period, have a 
predicted FEV1% of >80% in pulmonary function testing. 
    
5. Subjects or their guardians are capable of good communication 
with the researcher, understanding, and adhering to all study 
requirements. 
 
Exclusion 
criteria 
Subjects who meet any of the following criteria are not eligible 
for inclusion in this study: 
 
1. Allergy or intolerance to budesonide, formoterol, salbutamol, or 
any components of these medications. 
2. Respiratory tract infections, sinus infections, or otitis media 
requiring changes in asthma treatment within 2 months prior to 
randomization, or anticipated to change the subject's asthma status 
based on the investigator's judgment. 
3. History of chronic obstructive pulmonary disease, interstitial lung 
disease, restrictive lung disease, pulmonary tuberculosis, cystic 

8 
Version 3.0 (June 24, 2024) 
fibrosis, bronchiectasis, or alpha-1 antitrypsin deficiency during 
screening. 
4. Presence of major illnesses such as congestive heart failure, 
uncontrolled hypertension, severe coronary artery disease, myocardial 
infarction, severe arrhythmias, severe hematologic, liver, 
neurological, musculoskeletal, endocrine, metabolic, psychiatric, renal 
disease, or other significant medical history. Conditions that, if 
worsened during the study, could pose a risk to the patient by 
participating in the study or affect study results. 
5. During screening and the D-1 visit of the run-in period, having used 
short-acting beta-agonists (SABA) more than 8 times in one day. 
6. Use of beta-blockers (including eye drops) during the run-in period, 
oral corticosteroid treatment, systemic steroid treatment, treatment 
with study drugs, or use of leukotriene receptor antagonists (such as 
zafirlukast, pranlukast, montelukast, etc.). 
7. History of smoking with a smoking index >10 pack-years. 
8. Quitting smoking ≤6 months before screening visit (Visit 1) or 
current smoker. 
9. Known or suspected alcohol and/or drug abuse; alcohol abuse 
defined as consuming more than 2 units of alcohol daily (1 unit = 360 
mL of beer, 45 mL of 40% alcohol liquor, or 150 mL of wine). 
10. Abnormal clinically significant results in vital signs, physical 
examination, 12-lead electrocardiogram, chest CT, complete blood 
count, urinalysis, blood biochemistry, coagulation function, etc., 
during screening and the D-1 visit of the run-in period, except those 
judged by the investigator to be unrelated to the study disease and 
associated conditions and do not affect the enrollment of subjects. 
11. Positive pregnancy test or lactating female subjects. 
12. Use of medications within 1 month prior to screening that may 
interact with the study drug, such as CYP3A4 inhibitors 
(ketoconazole, itraconazole), cimetidine, disulfiram, metronidazole, or 
CYP3A4 enzyme strong inducers (rifampicin, carbamazepine, 
phenytoin, etc.). 

9 
Version 3.0 (June 24, 2024) 
13. Participation in other medical device clinical trials within 1 month 
prior to screening and/or participation in other drug clinical trials 
within 3 months prior to screening. 
14. Asthma total symptom score (daytime + nighttime) <2 points in 
the week prior to randomization. 
15. Inability to comply with study procedures or deemed unsuitable 
for study participation by the investigator. 
Treatment 
Groups 
 Treatment Plan for the First 4 Weeks: 
Study Group (Maintenance at initial treatment sequential as-
needed therapy group): Participants will inhale budesonide-
formoterol (Symbicort 160/4.5®) twice daily, morning and evening, 1 
inhalation each time, totaling 2 inhalations per day, continuously for 4 
weeks. If symptoms such as wheezing, shortness of breath, with or 
without chest tightness or cough persist during this maintenance 
phase, participants may additionally use budesonide-formoterol on an 
as-needed basis, up to a total daily dose not exceeding 8 inhalations. 
Control Group (As-needed therapy group): Participants will 
use budesonide-formoterol (Symbicort 160/4.5®) on an as-needed 
basis, up to a maximum of 8 inhalations per day, continuously for 4 
weeks. 
Participants should record the number of uses and times in their 
diary cards after each use. 
 
 Week 5 to Week 24: 
1. Study Group (Maintenance at initial treatment sequential as-
needed therapy group): Participants will continue to use 
budesonide-formoterol (Symbicort 160/4.5®) on an as-needed basis, 
up to a maximum of 8 inhalations per day, from Week 5 to Week 24, 
after receiving maintenance + as-needed low-dose ICS/LABA 
treatment for the initial 4 weeks. 
2. Control Group (As-needed therapy group): Participants will 
continue to use budesonide-formoterol (Symbicort 160/4.5®) on an 

10 
Version 3.0 (June 24, 2024) 
as-needed basis, up to a maximum of 8 inhalations per day, from 
Week 5 to Week 24. 
Participants should continue recording the number of uses and 
times in their diary cards after each use. 
Study 
Completion 
Criteria 
The study and control groups will follow the treatment plan for 4 
weeks, and complete pulmonary function tests, blood routine tests, 
FENO (Fractional Exhaled Nitric Oxide) measurement, and induced 
sputum examination at the end of 4 weeks. Follow-up visits according 
to the protocol will continue until week 24, when pulmonary function 
tests, blood routine tests, FENO measurement, and induced sputum 
examination will be completed again. 
Study 
Withdrawal 
Criteria 
The criteria and procedures for subject withdrawal from the 
study are as follows: 
Researcher-initiated early withdrawal: The researcher may 
decide to withdraw a subject from the study if it is deemed medically 
necessary from an ethics perspective, if there is a serious adverse 
event (SAE) that makes it inappropriate to continue participation, if a 
serious other concurrent illness arises that is judged by the researcher 
to be in the subject's best interest to withdraw, if additional clinical 
asthma medications (excluding those allowed by the protocol) are 
required during the study period, if there is poor compliance by the 
subject (e.g., non-adherence to medication and scheduled assessments, 
irregular diary card entries, use of other medications or foods 
affecting safety evaluations and study outcomes), if the subject 
becomes pregnant, if concomitant medications that may affect 
outcome assessments are used, or if the researcher determines other 
reasons unsuitable for continued participation in the study. 
Subject-initiated withdrawal: Subjects have the right to 
withdraw from the study at any time. Reasons for subject-initiated 
withdrawal include voluntary withdrawal by the subject or loss to 
follow-up. 
For subjects who withdraw from the study, the researcher should 
inquire about the reasons for withdrawal, document them, and attempt 

11 
Version 3.0 (June 24, 2024) 
to conduct exit safety assessments whenever possible. Reasons may 
include intolerance to adverse reactions, inability to continue 
participating in the clinical study due to other reasons, or loss to 
follow-up without explanation. And try to ensure that the subjects 
complete the exit safety inspection as much as possible. 
Study 
Termination 
Criteria 
Reasons for premature study termination may include but are not 
limited to the following: 
1.The study drugs are found to be ineffective or lack clinical value in 
the treatment regimen outlined by the study protocol. 
2.Significant errors or serious deviations are discovered in the clinical 
research protocol during implementation, making it difficult to 
evaluate the drug's effects. 
Dropout 
Criteria 
Setting a dropout rate of 20% according to the sample size. 
Data analysis 
and 
statistical 
methods 
Differences between groups were determined using differential 
test methods. For quantitative data, paired t-tests or Wilcoxon rank-
sum tests were used for analysis. For qualitative data, χ² tests or 
Fisher's exact probability tests were employed for analysis. Non-
parametric tests were used for inter-group or intra-group comparisons 
of ordinal data before and after treatment. 
Research 
units 
Shanghai General Hospital 
The duration 
of the study 
From March 31, 2024, to March 30, 2027. 
 
 
 
 
 

12 
Version 3.0 (June 24, 2024) 
1. Research Background 
Bronchial asthma (asthma) is a chronic inflammatory airway disease characterized by 
recurrent episodes of wheezing, shortness of breath, with or without chest tightness or 
coughing. It is associated with airway hyperresponsiveness and variable airflow 
limitation, and has become the second largest respiratory disease in China. 
Approximately 45.7 million adults in China suffer from asthma [1], with mild asthma 
accounting for 50%-75% of all asthma cases [2]. 
Mild asthma is defined differently at initial diagnosis and during follow-up. At initial 
diagnosis, it is based on non-acute symptoms and pulmonary function test results [3]: 
(1) symptoms < once daily; (2) may affect activity and sleep; (3) nocturnal asthma 
symptoms < once weekly; (4) forced expiratory volume in the first second (FEV1) ≥ 
80% predicted, or peak expiratory flow (PEF) ≥ 80% personal best, with PEF 
variability < 30%. For follow-up or treated patients, classification follows the Global 
Initiative for Asthma (GINA) guidelines [4], which assess if control is achieved with 
Step 1 or 2 treatment. 
Current issues in the treatment of mild bronchial asthma: Some patients with mild 
asthma have mild or atypical symptoms, relatively normal lung function, but still 
exhibit airway inflammation. Inadequate treatment may lead to acute exacerbations or 
even death. Nearly one-third of asthma deaths occur in patients with mild asthma [5], 
attributed to inadequate appreciation of the benefits of long-term anti-inflammatory 
therapy, treatment focus on symptom relief, and issues such as poor treatment 
adherence and lack of self-management. Due to these factors and the potential 
progression to moderate to severe asthma, GINA 2022 emphasizes the risk of severe 
exacerbations and the necessity of inhaled corticosteroid (ICS) therapy when using 
the term "mild asthma" [6]. 
Current strategies for initial treatment of mild bronchial asthma and recognition of 
acute exacerbations: Treatment strategies for mild asthma include preferred and 
alternative pathways. The preferred pathway involves as-needed low-dose ICS 
combined with a rapid-acting long-acting β2-agonist (LABA). The alternative 
pathway includes maintenance treatment with low-dose ICS or other medications, 
with as-needed short-acting β2-agonists (SABA) [7]. 

13 
Version 3.0 (June 24, 2024) 
Recognition of acute exacerbations in mild asthma: Even in cases of mild asthma, 
monitoring of symptoms to detect changes in disease status is essential. Signs 
indicating poor control or impending acute exacerbation include: daytime asthma 
symptoms, nocturnal awakening due to asthma, significantly limited activities due to 
asthma, increased use of reliever medications; asthma control test (ACT) scores < 19; 
PEF < 80% personal best; elevated fractional exhaled nitric oxide (FeNO), blood 
eosinophils, and total serum IgE compared to baseline [8]. These are critical indicators 
that should be closely monitored in clinical research. 
Why emphasize the early use of ICS-containing medications from diagnosis? 
Compared to using SABA alone, as-needed low-dose ICS-formoterol can reduce the 
risk of severe exacerbations and emergency visits or hospitalizations by 65% [9]. This 
anti-inflammatory relief strategy significantly reduces severe exacerbations, 
regardless of baseline symptom frequency, lung function, history of exacerbations, or 
inflammatory phenotype (T2-high or T2-low) [10, 11]. Early initiation of low-dose ICS 
treatment in asthma patients improves lung function to a greater extent compared to 
starting ICS 2-4 years later [12, 13]. Failure to start ICS early leads to higher required 
doses later and poorer lung function [14]. Patients not using ICS and experiencing 
severe exacerbations show more pronounced long-term decline in lung function 
compared to ICS users [15]. Early initiation of ICS treatment in occupational asthma 
significantly relieves symptoms, improves lung function, and reduces airway 
hyperresponsiveness [16]. Therefore, initial asthma treatment should commence with 
ICS-containing medications at the time of diagnosis (or shortly thereafter). 
Why is there still a need to optimize initial treatment strategies for mild bronchial 
asthma? 
 
In adults and adolescents with mild asthma, as-needed low-dose ICS-formoterol 
compared to SABA alone [10, 11] reduces the risk of severe exacerbations, 
emergency visits, or hospitalizations by approximately two-thirds. As-needed 
ICS-formoterol compared to daily ICS maintenance therapy reduces the risk of 
emergency visits and hospitalizations, with no clinically important difference in 
symptom control. However, this as-needed dosing model is based solely on 
symptom control, and the extent of airway inflammation control in newly 
diagnosed patients using as-needed medication warrants further exploration. 

14 
Version 3.0 (June 24, 2024) 
 
Maintenance therapy with low-dose ICS combined with as-needed SABA [17-20] 
effectively alleviates asthma symptoms and reduces the risk of exacerbations, 
hospitalizations, and mortality. However, poor adherence to ICS in clinical 
practice increases the risk of exacerbations when patients use SABA alone. As-
needed use of ICS-SABA may be an option for mild asthma, but data is limited to 
small-scale studies. 
 
Early initiation of maintenance therapy with low-dose ICS-formoterol at initial 
diagnosis improves symptom relief and enhances lung function more effectively 
[21]. 
FEV1, or forced expiratory volume in one second, is an objective indicator of the 
degree of airflow limitation. Improvements in FEV1 reduce the risk of future 
exacerbations and are positively correlated with symptom control. FEV1 serves as an 
objective assessment to evaluate the early effectiveness of medications [4]. 
Therefore, this clinical study hypothesizes whether starting daily maintenance therapy 
with low-dose ICS-formoterol at the onset of mild asthma treatment, followed by as-
needed therapy, can achieve better control of mild asthma by promoting sufficient 
anti-inflammatory treatment to attain a relative plateau in lung function. Hence, this 
study employs a randomized, parallel, positive-control design with a 1:1 random 
allocation. It focuses on newly diagnosed mild asthma patients, divided into: 1) initial 
treatment with 4 weeks of maintenance and as-needed low-dose ICS-formoterol 
therapy, followed by as-needed treatment with the same medication up to 24 weeks; 
2) as-needed low-dose ICS-formoterol therapy up to 24 weeks. The study aims to 
clarify FEV1 improvement after 4 weeks of maintenance therapy with low-dose ICS-
formoterol and to assess airway reversibility, symptom improvement, and 
inflammation control post bronchodilator testing. Based on comprehensive and 
precise evaluation of airway inflammation levels, the study aims to explore 
biomarkers that can effectively predict the efficacy of low-dose ICS-formoterol 
maintenance therapy in patients with mild asthma. Initial maintenance therapy with 
low-dose ICS-formoterol for 4 weeks, followed by as-needed therapy up to 24 weeks, 
while the control group receives only as-needed treatment, serves as the positive 
control. The study will evaluate FEV1 improvement rates from baseline, asthma 

15 
Version 3.0 (June 24, 2024) 
symptom control, acute exacerbations, and other outcomes during the 24-week 
follow-up to achieve more personalized treatment of mild asthma. 
References 
[1] Huang K, Yang T, Xu J, et al. Prevalence, risk factors, and management of asthma 
in China: a national cross-sectional study. Lancet, 2019, 394(10196): 407-418.  
[2] Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on 
epidemiology, clinical characteristics and treatment recommendations. Allergy, 2007, 
62(6): 591-604. 
[3] Cloutier MM, Dixon AE, Krishnan JA, et al. Managing asthma in adolescents and 
adults: 2020 asthma guideline update from the national asthma education and 
prevention program. JAMA, 2020,324 (22): 2301-2317.  
[4] Global Initiative for Asthma: Global Strategy for Asthma Management and 
Prevention. Updated 2021[EB/OL]. [2023-03-01]. http://www.ginasthma.org. 
[5] Bergström SE, Boman G, Eriksson L, et al. Asthma mortality among Swedish 
children and young adults, a 10-year study. Respir Med, 2008, 102(9): 1335-1341.  
[6] Global Initiative for Asthma. Global Strategy for Asthma Management and 
Prevention, 2023. Updated May 2023[EB/OL]. [2023-03-01]. 
http://www.ginasthma.org. 
[7] 中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南(2020 年版) [J]. 中华
结核和呼吸杂志, 2020; 43(12): 1023-1048.  
[8] Shen H, Hua W, Wang P, et al. A new phenotype of asthma: chest tightness as the 
sole presenting manifestation. Ann Allergy Asthma Immunol, 2013, 111(3): 226-227.  
[9] Crossingham I, Turner S, Ramakrishnan S, et al. Combination fixed-dose beta 
agonist and steroid inhaler as required for adults or children with mild asthma. 
Cochrane Database Syst Rev 2021; 5: CD013518. 
[10] Beasley R, Holliday M, Reddel HK, et al. Controlled trial of budesonide-
formoterol as needed for mild asthma. N Engl J Med 2019; 380: 2020-2030. 

16 
Version 3.0 (June 24, 2024) 
[11] Hardy J, Baggott C, Fingleton J, et al. Budesonide-formoterol reliever therapy 
versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to 
moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, 
randomised controlled trial. Lancet 2019; 394: 919-928. 
[12] Busse WW, Pedersen S, Pauwels RA, et al. The Inhaled Steroid Treatment As 
Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of 
early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol 
2008; 121: 1167-1174. 
[13] Selroos O, Pietinalho A, Lofroos AB, et al. Effect of early vs late intervention 
with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234. 
[14] Selroos O. Effect of disease duration on dose-response of inhaled budesonide in 
asthma. Respir Med 2008; 102: 1065-1072. 
[15] O'Byrne PM, Pedersen S, Lamm CJ, et al. Severe exacerbations and decline in 
lung function in asthma. Am J Respir Crit Care Med 2009; 179: 19-24. 
[16] Henneberger PK, Patel JR, de Groene GJ, et al. Workplace interventions for 
treatment of occupational asthma. Cochrane Database Syst Rev 2019; 10: CD006308. 
[17] Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and 
albuterol in a single inhaler for mild asthma. N Engl J Med 2007; 356: 2040-2052. 
[18] Martinez FD, Chinchilli VM, Morgan WJ, et al. Use of beclomethasone 
dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a 
randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 650-657. 
[19] Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, 
biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid 
therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012; 
308: 987-997. 
[20] Sumino K, Bacharier LB, Taylor J, et al. A pragmatic trial of symptom-based 
inhaled corticosteroid use in African- American children with mild asthma. J Allergy 
Clin Immunol Pract 2020; 8: 176-185.e172. 

17 
Version 3.0 (June 24, 2024) 
[21] Hao H, Bao W, Xue Y, et al. Spirometric Changes in Bronchodilation Tests as 
Predictors of Asthma Diagnosis and Treatment Response in Patients with 
FEV1 ≥ 80% Predicted. JACI in practice. 2021; 9(8): 3098-3108. 
2. Study Objectives and Endpoints  
2.1 Primary Study Objectives 
2.1.1 Evaluate the efficacy of initiating treatment with 4 weeks of maintenance 
combined with as-needed low-dose ICS-formoterol compared to as-needed low-dose 
ICS-formoterol alone in patients with mild asthma at initial diagnosis. Determine 
improvements in FEV1 compared to baseline after 4 weeks of treatment, and 
improvements in airway reversibility and inflammation levels, to establish the optimal 
patient population and treatment regimen. 
2.1.2 Explore biomarkers that effectively predict the efficacy of sequential 
maintenance as-needed low-dose ICS-formoterol treatment in patients with mild 
asthma based on comprehensive evaluation of lung function parameters (FEV1, 
FEV1/FVC, PEF, FEF25%, FEF50%, FEF75%, MMEF) and airway inflammation levels. 
2.1.3 Initiate treatment with 4 weeks of maintenance combined with as-needed low-
dose ICS-formoterol, followed by as-needed treatment with the same medication up to 
24 weeks, compared to as-needed treatment alone up to 24 weeks. Dynamically 
monitor clinical indicators to explore the impact of early maintenance low-dose ICS-
formoterol treatment on risk indicators for acute exacerbations, improvement rates in 
FEV1 from baseline, symptom improvement, and airway inflammation in mild 
asthma. 
2.2 Study Endpoints / Observational Indicators  
2.2.1 Primary Study Endpoints / Major Observational Indicators: Change in FEV1 
from baseline before bronchodilator use at week 4. 
2.2.2 Secondary Study Endpoints / Secondary Observational Indicators:  
(1) Observations after 4 weeks of treatment regarding symptom improvement, small 
airway function, airway inflammation, and acute exacerbations: 

18 
Version 3.0 (June 24, 2024) 
1）Change in ACT and ACQ questionnaire scores from baseline after 4 weeks of 
treatment; change in mean daytime and nighttime asthma symptom scores from 
baseline after 4 weeks of treatment; 
2）Change in lung function tests FVC, FEV1/FVC, and FEF25%-75% values from 
baseline after 4 weeks of treatment; changes in average morning and evening weekly 
PEF values from baseline after 4 weeks of treatment; weekly PEF variability during 
treatment; reversibility improvement after bronchodilator use; 
3）Airway inflammation: Improvement in FENO, eosinophil count, induced sputum 
cell classification counts, and inflammation markers after 4 weeks of treatment; 
4）Number of asthma exacerbations after 4 weeks of treatment, time to first 
exacerbation, number of exacerbations requiring hospitalization (including ICU 
admission) or emergency room visits (not resulting in hospitalization), weeks of 
asthma symptom control, doses of ICS and OCS used, and background medication 
use. 
(2) Observations after 24 weeks of treatment regarding large airway function FEV1, 
small airway function, symptom improvement, airway inflammation, and acute 
exacerbations: 
1） Change in FEV1 from baseline after 24 weeks of treatment; 
2）Change in lung function tests FVC, FEV1/FVC, and FEF25%-75% values from 
baseline after 24 weeks of treatment; changes in average morning and evening weekly 
PEF values from baseline after 24 weeks of treatment; weekly PEF variability during 
treatment; 
3）Change in ACT and ACQ questionnaire scores from baseline after 24 weeks of 
treatment; change in mean daytime and nighttime asthma symptom scores from 
baseline after 24 weeks of treatment; 
4）Peripheral blood eosinophils (absolute and relative values), IgE, FeNO, CaNO, 
cytokines (IL-4, IL-5, IL-13, etc.), and induced sputum inflammation levels after 24 
weeks of treatment; 

19 
Version 3.0 (June 24, 2024) 
5）Number of subjects experiencing asthma exacerbations; number of asthma 
exacerbations, weeks of asthma symptom control, use of rescue medication, doses of 
ICS and OCS used, and background medication use after 24 weeks of treatment. 
Exploratory Endpoints / Exploratory Observational Indicators:  
Stratification and correlation analysis based on the presence of baseline small airway 
dysfunction and comprehensive lung function parameters (FEV1, FEV1/FVC, PEF, 
FEF25%, FEF50%, FEF75%, MMEF), peripheral blood eosinophils (absolute and relative 
values), IgE, FeNO, and other parameters. Comparison of the predictive capabilities 
of these parameters for treatment outcomes. 
This exploratory analysis aims to: 
1) Evaluate whether baseline small airway dysfunction affects treatment response in 
patients with mild asthma. 
2) Assess the correlation between baseline lung function parameters, peripheral blood 
eosinophils, IgE levels, FeNO levels, and treatment efficacy. 
3) Investigate the predictive value of these parameters in determining the response to 
sequential maintenance and as-needed low-dose ICS-formoterol treatment in patients 
with mild asthma. 
The analysis will help identify potential biomarkers that could predict treatment 
response and guide personalized asthma management strategies. 
 
3. Research Methods  
3.1 Study Design  
This study employs a randomized, parallel-group, positive-control design.  
3.2 Sample Size  
For the primary efficacy endpoint, which is the change in FEV1 from baseline after 4 
weeks of treatment (positive increase), a superiority test will be conducted. The study 
will calculate a one-sided 97.5% confidence interval for the difference in means 

20 
Version 3.0 (June 24, 2024) 
between the study and control groups. If the lower limit of the confidence interval is 
greater than 0 mL, superiority will be established. Based on references from 
SYGMA1 and SYGMA2 studies, as well as preliminary studies, the study assumes a 
mean change of 290 mL in the study group and 105 mL in the control group, with a 
standard deviation of 279 mL (References: O'Byrne PM, et al. N Engl J Med. 
2018;378(20):1865-76; Beasley R, et al. N Engl J Med. 2019;380:2020-2030).  
The study employs a superiority analysis with a one-sided α of 0.025 and β of 0.2. 
Based on previous research and pilot study results using t-tests, each group requires 
37 subjects. Accounting for a 20% dropout rate, each group will enroll 45 subjects, 
totaling 90 subjects to be randomized into two groups, with 45 subjects each in the 
study and control groups.  
3.3 Randomization and Blinding  
Randomization is conducted using a central randomization system. During screening, 
subjects are identified using screening numbers, which are three-digit Arabic 
numerals (e.g., 001). A non-blinded statistician utilizes SAS 9.4 or higher statistical 
software to generate a randomization list in blocks of 1:1. The blinded allocation is 
then imported into the central randomization system. After screening qualification, 
researchers log into the system to input subject information and obtain a 
randomization number. The randomization number is visible to the randomization 
administrator and the patient but blinded to the evaluator (a professional independent 
from the clinical physician). 
3.4 Study Population 
The study includes adults (males and non-pregnant, non-lactating females) aged 18 to 
70 years, including the boundary values. Participants are newly diagnosed with mild 
asthma according to the "Guidelines for the Prevention and Treatment of Bronchial 
Asthma" (2020 edition) and GINA guidelines (2024 edition).3.4.1 Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for inclusion in the study: 
1) Informed Consent: Subjects must fully understand the purpose, nature, and 
methods of the study, voluntarily agree to participate as subjects, and sign an 
informed consent form before any study procedures begin.  

21 
Version 3.0 (June 24, 2024) 
2) Adults: Including males and non-pregnant, non-lactating females aged 18 to 70 
years, including boundary values. Patients must be newly diagnosed with mild asthma 
according to the latest domestic guidelines for the prevention and treatment of 
bronchial asthma and should not be in an acute exacerbation period.  
3) Objective Confirmation of Variable Airflow Limitation during Screening: Positive 
bronchodilator test (increase in FEV1 >12% and absolute increase >200 mL after 
inhalation of bronchodilator; or PEF ≥20%).  
Positive bronchial provocation test (FEV1 decrease ≥20% after inhalation of 
acetylcholine provocation agent).  
4) Lung Function Criteria: FEV1 % predicted >80% at screening and Day -1 visit.  
5) Communication and Compliance: Subjects or guardians must be able to 
communicate well with the investigator, understand, and comply with all study 
requirements. 
3.4.2 Exclusion Criteria 
Patients meeting any of the following criteria will not be included in the study:  
1) Allergy or Intolerance: Known allergy or intolerance to budesonide, formoterol, 
salbutamol, or any components of the study medications. 
2) Respiratory Infections: Occurrence of respiratory tract infection, sinusitis, or otitis 
media within 2 months prior to randomization, which led to changes in asthma 
treatment or is anticipated by the investigator to affect the subject's asthma status.  
3) Medical History: History of chronic obstructive pulmonary disease (COPD), 
interstitial lung disease, restrictive lung disease, pulmonary tuberculosis, cystic 
fibrosis, bronchiectasis, or alpha-1 antitrypsin deficiency at screening.  
4) Significant Diseases: Presence of significant diseases such as congestive heart 
failure, uncontrolled hypertension, severe coronary artery disease, myocardial 
infarction, severe arrhythmias, severe hematological, liver, neurological, 
musculoskeletal, endocrine, metabolic, psychiatric, renal diseases, or other conditions 

22 
Version 3.0 (June 24, 2024) 
deemed by the investigator to pose a risk to the patient's participation in the study or 
influence study results if worsened during the study. 
5) Excessive Short-Acting Beta-Agonist (SABA) Use: History of using SABA more 
than 8 times per day for one day during screening.  
6) Medication Use: Use of beta-blockers (including eye drops), oral glucocorticoids, 
systemic steroid treatment, study drug treatment, leukotriene receptor antagonists 
(such as zafirlukast, pranlukast, montelukast), within the induction period.  
7) Smoking: Past history of smoking with a smoking index >10 pack-years.  
8) Smoking Cessation: Smoking cessation ≤6 months before screening visit (Visit 1) 
or current smoker.  
9) Alcohol and Substance Abuse: Known or suspected alcohol and/or drug abuse, 
defined as daily average alcohol consumption exceeding 2 units (1 unit = 360 mL of 
beer, 45 mL of 40% alcohol, or 150 mL of wine).  
10) Clinical Laboratory Abnormalities: Clinically significant abnormalities in vital 
signs, physical examination, 12-lead electrocardiogram, chest CT, blood routine 
(elevated blood eosinophils), CRP, urine routine, blood biochemistry, coagulation 
function, etc., at screening and Day -1 visit, unless judged by the investigator to be 
unrelated to the study disease and associated conditions and not affecting subject 
enrollment.  
11) Pregnancy and Lactation: Positive pregnancy test or lactating female subjects.  
12) Medication Interactions: Use of medications within 1 month prior to screening 
that may interact with the study drugs, such as CYP3A4 inhibitors (ketoconazole, 
itraconazole), cimetidine, disulfiram, metronidazole, or CYP3A4 enzyme inducers 
(rifampicin, carbamazepine, phenytoin). 
13)  Participation in Other Trials: Participation in other medical device clinical trials 
within 1 month before screening or other drug clinical trials within 3 months before 
screening. 

23 
Version 3.0 (June 24, 2024) 
14) Asthma Symptoms: Total asthma symptom score (daytime + nighttime) <2 points 
in the week before randomization. 
15) Non-compliance or Unsuitability: Inability to comply with study procedures or 
deemed unsuitable for the study by the investigator.  
 
4. Treatment Regimen/Interventions 
4.1 Study Medication (ICS/LABA) 
Investigational Drug: Budesonide-Formoterol powder for inhalation (brand name: 
Symbicort Turbuhaler 160/4.5®). 
Positive Control Drug (ICS/LABA): Budesonide-Formoterol powder for inhalation 
(brand name: Symbicort Turbuhaler 160/4.5®). 
4.2 Dosage Regimen 
Week 1-4 Treatment Regimen: 
Study Group (Maintenance + As-Needed Sequential Treatment Group): 
Inhalation of Budesonide-Formoterol (Symbicort Turbuhaler 160/4.5®) twice daily 
(morning and evening), 1 inhalation each time, total of 2 inhalations per day for 4 
weeks. 
If symptoms such as wheezing, shortness of breath, with or without chest tightness or 
cough persist during this maintenance treatment phase, the study drug can be used as-
needed in addition to daily regular use, not exceeding a total of 8 inhalations per day. 
Control Group (As-Needed Treatment Group): 
Inhalation of Budesonide-Formoterol (Symbicort Turbuhaler 160/4.5®) as needed, 
not exceeding 8 inhalations per day for 4 weeks. 
The number of inhalations and times of use should be recorded in the subject's diary 
card. 
Week 5-24 Divided into: 

24 
Version 3.0 (June 24, 2024) 
Study Group: 
After initial maintenance + as-needed low-dose ICS/LABA treatment for 4 weeks, 
switch to as-needed treatment with the same medication until week 24. 
Control Group: 
Continuation of as-needed low-dose ICS/LABA treatment until week 24. 
Emergency Medications (Rescue Medications): 
Albuterol (Salbutamol) Inhaler: Inhalation of albuterol aerosol inhaler (brand name: 
Ventolin®) as needed during acute exacerbations, not exceeding 8 puffs per day, 100 
μg per puff. 
Usage details such as number of puffs, frequency, and time should be recorded in the 
subject's diary card. 
4.3 Permitted and Prohibited Concomitant Medications/Treatments 
Permitted Medications/Treatments: 
1) As-needed albuterol (salbutamol) inhaler (up to 8 puffs per day, 100 μg/puff). 
2) Intranasal corticosteroids: Subjects may receive intranasal corticosteroids to 
control symptoms of allergic diseases. 
3) Topical corticosteroids: Subjects may use topical corticosteroid preparations 
(≤1% hydrocortisone ointment) for skin diseases; use of creams containing 
corticosteroids is allowed. 
4) Antihistamines: Short-acting and long-acting antihistamines (such as loratadine, 
cetirizine, desloratadine, fexofenadine) for the treatment of allergic symptoms 
(excluding asthma). Additionally, the use of antihistamine eye drops is allowed 
during the study. 
5) Cold medications: Caution should be taken with antipyretic analgesics that may 
exacerbate asthma. 
6) Expectorants and cough suppressants without bronchodilators or anti-
inflammatory drugs. 

25 
Version 3.0 (June 24, 2024) 
7) Other medications as judged by the investigator not to affect the study.  
Prohibited Medications/Treatments: 
1) Other long-acting or short-acting β2-adrenergic receptor agonists except for 
rescue medication salbutamol. 
2) Sympathomimetic drugs. 
3) Promethazine, diphenhydramine, chlorpromazine, cimetidine, disulfiram, 
metronidazole. 
4) Inhibitors of cytochrome P450 subfamily CYP3A4 (ketoconazole, fluconazole, 
etc.). 
5) Inhaled corticosteroids, except for study medications. 
6) Leukotriene receptor antagonists. 
7) Theophylline or sustained-release theophylline preparations (e.g., aminophylline, 
theophylline, doxofylline, dyphylline). 
8) Anticholinergic drugs (e.g., ipratropium bromide, oxitropium bromide, 
tiotropium bromide). 
9) Mast cell stabilizers (e.g., ketotifen, nedocromil sodium, cromoglicic acid). 
10) CYP3A4 enzyme strong inducers such as rifampicin, carbamazepine, 
phenobarbital, dexamethasone, phenytoin. 
11) Anti-IgE antibody therapy. 
12) Traditional Chinese medicine or proprietary Chinese medicine for asthma and 
other allergic diseases (e.g., Su Huang Zhi Ke Capsule). 
13) Compound preparations containing theophylline or ephedrine alkaloids (e.g., 
compound methoxyphenamine capsules, pseudoephedrine solution). 
14) Other medications judged by the investigator to affect the study. 
All concomitant medication details must be recorded in detail. The investigator should 
record specific information regarding the subject's concomitant medications in the 

26 
Version 3.0 (June 24, 2024) 
original medical record, including the name of the medication, dosage, route of 
administration, frequency, dose, start date, and end date. 
5. Study Procedures 
5.1 Study Duration 
The study duration is approximately 24 weeks, including screening period, run-in 
period, treatment and efficacy observation period. 
5.2 Screening Period (D-8~D-4) - Visit 1 
Informed Consent: Obtain informed consent from subjects before screening. 
Information and Examination: 
1) Collect demographic information. 
2) Gather allergy history, medical history/treatment history, smoking and alcohol 
history, clinical research history. 
3) Confirm inclusion/exclusion criteria. 
4) Physical examination. 
5) Blood routine test. 
6) IgE levels. 
7) Chest CT scan. 
8) Pulmonary function tests. 
9) Bronchodilator or provocation tests. 
10) Induced sputum examination. 
11) Training on inhalation of study medications. 
12) Record concomitant medications. 
13) Record adverse events. 
Eligible subjects receive albuterol inhaler for run-in period use and diary card. 

27 
Version 3.0 (June 24, 2024) 
5.3 Run-in Period (D-3~D-1) 
Subjects use albuterol inhaler as needed, not exceeding 8 puffs per day, 100 μg per 
puff. 
Record the number of puffs used, frequency, and time in the diary card. 
5.4 Visit 2 (D-1) 
Eligible subjects return to the hospital for: 
1) Vital signs measurement. 
2) Daytime and nighttime symptom scoring. 
3) ACQ5 questionnaire. 
4) ACT questionnaire. 
Evaluate subjects for study group assignment based on assessments. 
Confirm inclusion/exclusion criteria. 
Manage symptomatic outpatient treatment for screen failures. 
Randomization into two groups: 
1) Study Group: Inhalation of Budesonide-Formoterol (Symbicort Turbuhaler 
160/4.5®) twice daily (morning and evening), 1 inhalation each time, not 
exceeding 8 inhalations per day, for 4 weeks. As-needed use allowed if 
necessary. 
2) Control Group: As-needed inhalation of Budesonide-Formoterol (Symbicort 
Turbuhaler 160/4.5®), not exceeding 8 inhalations per day, for 4 weeks. 
Dispense study medications (Budesonide-Formoterol powder inhaler, albuterol 
inhaler), diary cards, peak flow meter. 
Instruct daily morning and evening PEF (peak expiratory flow) measurements. 
Instruct recording of daytime and nighttime asthma symptom scores in the diary card. 
Enter into the initial 4-week treatment and efficacy observation period. 

28 
Version 3.0 (June 24, 2024) 
5.5 Week 1-4 Treatment and Efficacy Observation Period (D1~D28) 
 
Subjects inhale study medications daily at home. 
1) Study Group: Inhalation of Budesonide-Formoterol (Symbicort Turbuhaler 
160/4.5®) twice daily, not exceeding 8 inhalations per day if as-needed treatment 
is required. 
2) Control Group: As-needed inhalation of Budesonide-Formoterol (Symbicort 
Turbuhaler 160/4.5®), not exceeding 8 inhalations per day. 
 
Record medication usage frequency and times in the diary card. 
 
PEF measurements. 
 
Record daytime and nighttime asthma symptom scores. 
 
Record concomitant medications. 
 
Record adverse events. 
5.6 Visit 3 (D28±3d, i.e., 4 weeks ± 3 days) 
 
Vital signs measurement. 
 
Physical examination. 
 
Laboratory tests: Blood routine test, pulmonary function tests, induced sputum. 
 
ACQ assessment. 
 
ACT assessment. 
 
Collect diary cards, remaining medications and packaging for compliance 
assessment. 
 
Record concomitant medications. 
 
Record adverse events. 
 
Adjust subsequent medication administration: 

29 
Version 3.0 (June 24, 2024) 
1) Study Group: As-needed inhalation of Budesonide-Formoterol, not exceeding 8 
inhalations per day, for 4 weeks. 
2) Control Group: As-needed inhalation of Budesonide-Formoterol, not exceeding 8 
inhalations per day, for 4 weeks. 
Provide diary cards and schedule mobile pulmonary function and FeNO tests at 8, 12, 
16, 20 weeks. 
5.7 Week 5-24 Treatment and Efficacy Observation Period (D29~D168) 
1) Subjects inhale study medications daily at home. 
2) Both Study and Control Groups: As-needed inhalation of Budesonide-
Formoterol, not exceeding 8 inhalations per day. 
3) Record medication usage frequency and times in the diary card. 
4) PEF measurements. 
5) Record daytime and nighttime asthma symptom scores. 
6) Record concomitant medications. 
7) Record adverse events. 
5.8 Visit 4, 5, 6, 7 at Week 8 (DAY56), 12 (DAY84), 16 (DAY112), 20 (DAY140) 
1) Monitor full parameters of mobile pulmonary function and FeNO at each visit. 
2) Record concomitant medications. 
3) Record adverse events. 
4) Record acute exacerbations. 
5) Record weeks of asthma symptom control. 
6) ACT symptom score. 
7) Collect diary cards, remaining medications and packaging for compliance 
assessment. 

30 
Version 3.0 (June 24, 2024) 
5.9 Exit Visit at Week 24 (D168±3 days) 
1) Full pulmonary function test + bronchodilator test. 
2) FeNO. 
3) Blood routine test. 
4) Induced sputum examination. 
5) Markers of asthma exacerbation. 
6) Weeks of asthma symptom control. 
7) Record concomitant medications. 
8) Record adverse events. 
9) Record acute exacerbations. 
10) Record ICS and OCS usage doses and background medication usage. 
11) ACT symptom score. 
12) Collect diary cards, remaining medications and packaging for compliance 
assessment. 
5.10 Study Discontinuation/Early Withdrawal 
Follow-up procedures for subjects who discontinue or withdraw early: 
1) Vital signs measurement. 
2) Physical examination. 
3) Laboratory tests: Blood routine test, full pulmonary function test + 
bronchodilator test, FeNO, induced sputum. 
4) ACQ assessment. 
5) ACT assessment. 
6) Markers of asthma exacerbation. 

31 
Version 3.0 (June 24, 2024) 
7) Weeks of asthma symptom control. 
8) Record concomitant medications. 
9) Record adverse events. 
10) Record acute exacerbations. 
11) Record ICS and OCS usage doses and background medication usage. 
12) Collect diary cards, remaining medications and packaging for compliance 
assessment. 
5.11 Medication Compliance 
Use diary cards to record ACT and ACQ5 symptom scores. 
Use Langye APP for dynamic follow-up and monitoring of medication compliance. 
Real-time statistical analysis of medication usage frequency. 
This outline provides a comprehensive overview of the study procedures, ensuring 
adherence to protocol and thorough documentation of all relevant data throughout the 
24-week study duration. 
6. Study Evaluation 
Primary Efficacy Endpoints 
1) Change in FEV1 (Forced Expiratory Volume in 1 second) from baseline after 4 
weeks of treatment with bronchodilator therapy. 
Secondary Efficacy Endpoints 
1) Change in FEV1 from baseline after 24 weeks of treatment. 
2) Change in Asthma Control Test (ACT) questionnaire score from baseline after 
4-24 weeks of treatment. 
3) Change in pulmonary function tests (FVC, FEV1/FVC, FEF25%-75%) from 
baseline after 4-24 weeks of treatment. 
4) Improvement in FENO (Fractional exhaled Nitric Oxide), eosinophils, induced 
sputum cell counts, and inflammatory markers at 4 and 24 weeks of treatment. 
5) Number of asthma exacerbations from 1-24 weeks of treatment. 

32 
Version 3.0 (June 24, 2024) 
6) Amount of rescue medication use from 1-24 weeks. 
7) Number of weeks with asthma symptom control from 1-24 weeks. 
Exploratory Research 
 
Stratified study based on parameters such as large and small airway dysfunction, 
comprehensive lung function parameters (FEV1, FEV1/FVC, PEF, FEF25%, 
FEF50%, FEF75%, MMEF), peripheral blood eosinophils (absolute and relative 
values), FeNO, etc., to identify optimal treatment groups. 
Safety Evaluation Endpoints 
 
Summarize incidence, frequency, and occurrence rates of adverse events (AEs), 
treatment-emergent adverse events (TEAEs), and drug-related TEAEs by 
formulation group, severity, System Organ Class (SOC), and Preferred Term 
(PT). 
 
Calculate the incidence rate of adverse events statistically, considering each 
SOC and PT per subject up to once. 
7. Exiting or Terminating the Study 
Participant Withdrawal 
Researcher-Initiated Withdrawal: Participants may be withdrawn from the study by 
the researcher in the following circumstances: 
1) Ethical Considerations: The researcher determines it necessary to stop the trial 
from a medical ethics perspective. 
2) Serious Adverse Event (SAE): The participant experiences an SAE that makes 
continued participation inappropriate. 
3) Serious Other Concurrent Illness: The participant develops a severe concurrent 
illness that, in the researcher's judgment, makes withdrawal from the study in 
the participant's best interest. 
4) Acute Exacerbation: The participant experiences an acute exacerbation during 
the study period that warrants withdrawal from the trial. 
5) Need for Other Clinical Asthma Medication: During the study, the participant 
requires clinical asthma medication not allowed by the protocol. 

33 
Version 3.0 (June 24, 2024) 
6) Poor Compliance: Poor compliance with the study protocol (e.g., non-
compliance with medication or assessments, inadequate diary card records, 
use of other medications affecting safety evaluation or trial results). 
7) Pregnancy: The participant becomes pregnant during the study. 
8) Other Reasons Deemed Unsuitable: The researcher determines other reasons 
that make continued participation in the study unsuitable for the participant. 
Participant-Initiated Withdrawal: Participants have the right to withdraw from the 
study at any time for reasons including: 
1) Voluntary Withdrawal: The participant voluntarily decides to withdraw from 
the study. 
2) Lost to Follow-up: The participant becomes lost to follow-up for reasons such 
as inability to continue clinical research or unexplained absence. 
For participants who withdraw from the study, the researcher should inquire about the 
reasons for withdrawal, document and track these reasons (e.g., intolerable adverse 
reactions, inability to continue clinical research due to other reasons, or unexplained 
loss to follow-up), and attempt to complete safety assessments upon withdrawal if 
feasible. 
Study Termination Criteria 
The study may be terminated prematurely for reasons including but not limited to: 
1) Inadequate Treatment Effect: The study drug treatment shows poor or 
ineffective clinical outcomes, lacking clinical value. 
2) Major Protocol Deviations or Serious Bias: Significant errors or serious 
deviations occur in the clinical study protocol implementation, making it 
difficult to evaluate drug effects. 
8. Dropout Criteria: 20% Dropout Rate 
A dropout rate of up to 20% is anticipated in this study. Participants may discontinue 
their participation voluntarily or at the discretion of the researcher due to various 
reasons outlined in the protocol. 

34 
Version 3.0 (June 24, 2024) 
9. Adverse Events 
An adverse event (AE) refers to any untoward medical occurrence in a participant 
who has received study drug(s), including symptoms, signs, diseases, or laboratory 
findings, regardless of whether they are related to the investigational drug. 
10. Statistical Analysis 
Statistical analyses will be conducted with a significance level of 0.05 for two-sided 
tests, unless otherwise specified. Descriptive statistics for continuous variables will 
include counts, means, standard deviations, medians, quartiles, minimum, and 
maximum values. Categorical variables will be described using frequencies and 
percentages. 
11. Data Management 
The data collection and management system for this project is the Deppi Electronic 
Data Capture (EDC) System. 
 
eCRF Design: The eCRF is designed based on the protocol and includes all 
specified data points except for external data. 
 
Database Establishment: A database is constructed with logic check rules 
configured, system functionalities set up, and permissions managed by system 
administrators based on user roles. 
 
Database Testing: Testing involves data entry, export, logic checks, eCRF 
interface usability, and system functionality. 
 
Data Collection: Researchers access the data management system 
independently to collect study data. 
 
Data Verification: Medical and statistical personnel collaborate in data 
verification. 
12. Quality Control 

35 
Version 3.0 (June 24, 2024) 
 eCRF and Original Records: The eCRF is not the original document; all data 
entered in the Case Report Form (CRF) must trace back to original records in 
electronic or participant files. 
1) During the Study: Checks include completeness, consistency, and accuracy of 
eCRF entries; confirmation of original data; quality control of eCRF entries; 
progress of participant enrollment; compliance with the study protocol and 
Good Clinical Practice (GCP); and proper storage, distribution, and inventory 
of study drugs. 
2) Data Preservation: Researchers must retain original records for every 
participant, including demographics, medical information, laboratory data, 
ECG results, and any other assessments. Participant identity information in 
original records must remain confidential. 
3) eCRF Verification: Researchers enter data into the eCRF, while statisticians 
verify and address any data queries. 
 Quality Control (QC): Before initiating clinical research, researchers receive 
protocol training. Quality control personnel verify basic conditions to ensure 
compliance with study requirements. Throughout the study, researchers adhere 
to institutional Standard Operating Procedures (SOPs) and study protocols, 
maintaining accurate, timely, complete, and standardized records. At study 
completion, the research unit organizes and archives relevant project 
documents. 
 Quality Assurance (QA): Researchers establish their own quality assurance 
systems, fulfill their responsibilities, strictly follow the clinical research 
protocol, and implement appropriate Standard Operating Procedures (SOPs) to 
ensure the quality control and implementation of quality assurance systems in 
clinical research. 
Researchers and clinical research institutions have direct access to source data and 
source documents related to the clinical study. 
14. Ethics Protection and Informed Consent for Clinical Research 

36 
Version 3.0 (June 24, 2024) 
Ethical considerations relevant to this study are addressed, including the need for 
informed consent from participants. 
15. Appendix 
An appendix can include diagnostic criteria for important indicators relevant to the 
study. 
This comprehensive outline covers the essential aspects of data management, quality 
control, statistical analysis, adverse events, dropout criteria, and ethical considerations 
pertinent to conducting the clinical research study effectively and ethically.