The Outcomes of Different Dexamethasone Regimens for the Prevention of Bronchopulmonary Dysplasia in Preterm Infants: A Multicenter Randomized Controlled Trial
Phase: PHASE3
Conditions: Infant, Premature, Bronchopulmonary Dysplasia (BPD)
Sponsor: The Children's Hospital of Zhejiang University School of Medicine

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Study Protocol 
 
Official 
Title 
of 
the 
Study: 
The 
Outcomes 
of 
Different 
Dexamethasone Regimens for the Prevention of Bronchopulmonary 
Dysplasia in Preterm Infants: A Multicenter Randomized Controlled 
Trial 
 
NCT Number: NCT07052201 
 
Date of the Document: September 26, 2025 
 
 
 
 
 
 
 
 
 
 
 
 

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I. Research Background 
Bronchopulmonary dysplasia (BPD) is a serious chronic pulmonary disease primarily 
affecting preterm infants, especially those with very low birth weight (VLBW) and extremely 
low birth weight (ELBW). The pathological features of BPD mainly include simplified alveolar 
structures and abnormal pulmonary vascular development, which can lead to long-term 
respiratory disorders, neurodevelopmental impairments, and even death [1,2]. The 
pathogenesis of BPD is complex and involves multiple factors such as prematurity, mechanical 
ventilation, oxygen toxicity, infection, and inflammatory responses [3]. 
As early as the late 1970s to early 1980s, researchers began exploring the use of 
corticosteroids, particularly dexamethasone (DEX), for the prevention and treatment of 
neonatal respiratory distress syndrome (RDS) and BPD [4]. Initial studies employed relatively 
high doses of DEX (0.5–1.0 mg/kg/day) over prolonged treatment courses, showing significant 
improvements in lung function, reduced duration of mechanical ventilation, and lower 
incidence of BPD. As a result, DEX became widely used in neonatal intensive care units (NICUs) 
during the 1990s, entering what was referred to as a “honeymoon period.” However, with the 
accumulation of long-term follow-up studies, concerns about the safety of DEX began to 
emerge. In 1998, Yeh et al. reported that early use of DEX in preterm infants significantly 
increased the incidence of severe neurodevelopmental impairments at 18 months (41% vs. 
31%) [5], and was associated with a higher rate of short-term adverse effects, such as 
gastrointestinal perforation (13% in the DEX group vs. 4% in controls, P = 0.02) [6]. Other 
studies also linked DEX to cerebral palsy, cognitive dysfunction, and reduced brain volume 
[7,8]. These findings prompted the American Academy of Pediatrics (AAP) to issue a warning 
statement in 2002, explicitly opposing the routine use of DEX for the prevention or treatment 
of BPD. Consequently, clinical practice shifted from aggressive use toward more cautious 
evaluation. 
In this context, researchers began exploring safer alternatives or optimized strategies for 
DEX use. Hydrocortisone (HC), which acts on mineralocorticoid receptors, was considered 
potentially less neurotoxic. Some studies suggest HC has a milder impact on 
neurodevelopmental outcomes, but its efficacy in preventing BPD remains controversial [9]. 

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For instance, early administration of HC (within 7–14 days after birth) showed no significant 
differences compared to placebo in terms of BPD incidence, oxygen use duration, or brain 
volume [9]. Although prophylactic use of HC (cumulative dose 18–72.5 mg/kg) did not 
increase the risk of cerebral palsy or neurodevelopmental delay, its overall effectiveness still 
requires further validation. 
Meanwhile, low-dose DEX strategies (e.g., <0.5 mg/kg/day) have been proposed to 
achieve a balance between efficacy and safety. Some studies have demonstrated that even 
with low doses of DEX, when initiated between postnatal day 7 and 14, it can effectively 
reduce the incidence of BPD without increasing adverse neurological outcomes [10,11]. A 
meta-analysis including 669 participants showed that starting DEX between days 7 and 14 
after birth reduced the incidence of BPD or death at both day 28 and 36 weeks postmenstrual 
age, facilitated earlier extubation, and did not increase the occurrence of severe complications 
such as hypertension, severe retinopathy of prematurity (ROP), or infections [8]. A Cochrane 
review (2003) also noted that DEX initiated after three weeks of age could reduce oxygen 
dependence and extubation failure, without significantly affecting mortality or increasing the 
risk of infection, necrotizing enterocolitis (NEC), or gastrointestinal bleeding [12]. 
In recent years, researchers have re-evaluated the role of DEX in BPD prevention and 
treatment. A large retrospective study (n=1136) found that DEX use between days 7 and 14 
after birth was associated with a 6.2% reduction in cerebral palsy and a 6.6% reduction in 
cognitive impairment. Moreover, DEX administration after 3 weeks of age did not increase the 
risk of neurodevelopmental delay [10]. In a 2019 study, infants in the high-dose, long-course 
DEX group demonstrated significantly better functional survival at age 7 compared to those in 
the moderate-dose, short-course group [13]. A 2021 network meta-analysis further suggested 
that a moderate cumulative dose of DEX (2–4 mg/kg) may represent the optimal regimen for 
BPD prevention, achieving a better balance between efficacy and safety, although high-dose 
strategies are less acceptable in clinical practice [13]. 
The timing of the first dose is also a key factor in corticosteroid intervention strategies for 
BPD. In a 1997 RCT conducted in Taiwan involving 262 preterm infants, initiating DEX within 
24 hours of birth significantly reduced the incidence of BPD by 50%, but also increased the 

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rate of severe neurodevelopmental impairment at 18 months [4]. At Brigham and Women’s 
Hospital, initiating DEX within 24 hours after birth was associated with an increased incidence 
of intestinal perforation by day 14 [4,6]. These findings indicate that although very early 
administration of DEX may have strong lung-protective effects, the associated adverse events 
are significant. In contrast, initiating DEX after 7 days of life is considered to have a more 
favorable risk-benefit profile, particularly for high-risk infants. Recent reviews have pointed 
out that early systemic use of DEX or HC is not recommended due to adverse effects, while 
late systemic use of DEX (≥7 days postnatal age) effectively reduces BPD risk without 
increasing neurodevelopmental impairment in high-risk infants [14,15]. 
In summary, there remain numerous unresolved issues regarding the optimal use of DEX 
in BPD prevention. Early administration shows strong efficacy but carries high neurotoxicity 
risks; late administration is safer but may miss the optimal intervention window. High-dose 
regimens offer pronounced benefits but are associated with more side effects, while low-dose 
regimens are relatively safer but may be less effective. Short-course treatments yield rapid 
effects, but the sustainability of benefits is unclear, whereas long-course treatments may offer 
prolonged benefits at the cost of cumulative side effects. Moreover, preterm infants of 
different gestational ages, birth weights, and disease severities may respond differently to 
corticosteroid therapy. Despite decades of clinical experience with DEX in BPD prevention and 
treatment, the AAP still emphasizes the lack of sufficient evidence in its current guidelines and 
refrains from providing a definitive recommendation [16]. Therefore, there is an urgent need 
for a well-designed, large-scale, multicenter randomized controlled trial to systematically 
evaluate the short- and long-term efficacy and safety of different DEX regimens—including 
dosage, timing, and duration—in preterm infants with high BPD risk. 
This research holds significant scientific and clinical value. Currently, there is a severe lack 
of high-quality evidence regarding the optimal DEX regimen for BPD prevention. This study 
will help fill that gap and provide clearer guidance for clinical practice. By comparing different 
DEX strategies, the study aims to identify the optimal balance between efficacy and safety, 
thereby optimizing preventive strategies for BPD. By assessing the impact of various DEX 
regimens on long-term neurodevelopmental outcomes, the research will contribute to 

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reducing BPD-associated neurodevelopmental impairments and improving the long-term 
quality of life for preterm infants. Ultimately, this study will offer evidence-based 
recommendations to guide clinicians in the rational use of DEX for BPD prevention, minimizing 
unnecessary risks, and maximizing potential benefits. 
In conclusion, this study will comprehensively explore the complex issues surrounding 
DEX use in the prevention of BPD in preterm infants. It aims to provide critical evidence to 
resolve longstanding controversies, with the ultimate goal of improving health outcomes for 
preterm infants and reducing the long-term burden of BPD on patients and their families. 
 
II. Study Objectives 
Primary Objective: 
To compare the incidence of BPD and/or BPD-related mortality at a postmenstrual age of 36 
weeks in preterm infants meeting the inclusion criteria, treated with two different 
dexamethasone regimens (the DART regimen versus a medium-dose tapering regimen). 
Secondary Objectives: 
• To compare the duration of weaning ventilation, total days of ventilator use, and length of 
hospital stay between the two groups. 
• To assess the changes in the Oxygenation Index (OI) on days 0, 3, 7, 10, 14, and 28 of 
treatment in both groups. 
• To compare the incidence of complications at discharge, such as Retinopathy of Prematurity 
(ROP), Intraventricular Hemorrhage (IVH), Necrotizing Enterocolitis (NEC), infection, and 
Pulmonary Hypertension, between the two groups. 
• To compare the incidence of adverse effects associated with steroid therapy between the 
two groups. 
• To evaluate neurodevelopmental outcomes at a corrected age of 18-24 months using the 
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) Mental 
Development Index (MDI)/Psychomotor Development Index (PDI) or the Griffith Mental 
Development Scales. 

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III. Study Methods 
This study is a multicenter, prospective, randomized, parallel-controlled clinical trial.   
Study Sites: Multiple hospitals across China with high-level Neonatal Intensive Care Units 
(NICUs) will participate. 
 
Randomization:   
A block randomization method will be used to assign participants to one of two study groups 
in a 1:1 ratio. Subjects will receive a unique randomization number in the order of enrollment 
and will be assigned to one of the following treatment groups: 
- DART regimen   
- Moderate-dose tapering regimen 
 
Blinding:   
Blinding will be applied for the assessment of secondary outcomes (e.g., neurodevelopmental 
outcomes). Evaluators will be from an independent team and will not be involved in the 
routine clinical care of the infants. 
 
 1. DART Regimen Group   
Cumulative dose: 0.89 mg/kg over 10 days Intravenous dexamethasone [17], administered as 
follows: 
- 0.075 mg/kg/dose, every 12 hours for 3 days   
- 0.05 mg/kg/dose, every 12 hours for 3 days   
- 0.025 mg/kg/dose, every 12 hours for 2 days   
- 0.01 mg/kg/dose, every 12 hours for 2 days, then discontinue 
 
If extubation is not successful more than or equal to two weeks after completing the 
treatment (FiO2 > 40% and MAP > 8 cmH2O), the DART regimen may be repeated. The number 
of repeated courses, reasons, and specific timing must be documented. 
 

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(Note: According to reference [13], if the infant meets respiratory criteria again at least 72 
hours after completing the initial 9-day course, a second 9-day course may be administered. 
If the infant meets the criteria again during the 42-day observation period, a third course may 
be considered.) 
 
Rationale for design:   
Due to the rapid physiological changes in preterm infants, early responses to interventions are 
often evident within short timeframes. The shorter assessment intervals aim to capture early 
treatment effects more sensitively and dynamically.   
Previous exploratory observations indicated that two-week intervals are feasible and safe for 
evaluating parameters such as weight gain and lab changes, with no significant adverse effects 
observed. 
 
2. Moderate-Dose Tapering Regimen Group   
Cumulative dose: 2.35 mg/kg over 7 days Intravenous dexamethasone [19], administered as 
follows: 
- 0.5 mg/kg/d for 3 days   
- 0.25 mg/kg/d for 3 days   
- 0.1 mg/kg/d for 1 day   
 
If extubation is not successful more than or equal to two weeks after completing the 
treatment (FiO2 > 40% and MAP > 8 cmH2O), the same regimen may be repeated. The number 
of repeated courses, reasons, and specific timing must be documented. 
 
Definition of BPD Severity (based on 2019 consensus criteria):   
Clinically, BPD is defined as oxygen and/or respiratory support dependency for at least 28 days 
or continuing until 36 weeks corrected gestational age in preterm infants born at <32 weeks 
gestation. 
 

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2019 severity classification (Jensen definition)[20]        
• 
Severity is determined by the mode of respiratory support required at 36 
weeks PMA, regardless of FiO2:Mild BPD (grade I): Requires low flow nasal 
cannula (<2 L/min) 
• 
Moderate BPD (grade II): Requires CPAP, NIPPV, or nasal cannula flow of ≥2 
L/min (including HFNC) 
• 
Severe BPD (grade III): Requires invasive mechanical ventilation 
 
Standardized Supportive Care (applied to all groups): 
Respiratory Support:   
- Target SpO₂: 90–95%, PaCO₂: 45–65 mmHg 
 
Monitoring for Hemodynamically Significant PDA (HsPDA):   
- Evaluations on days 3, 7, 14, and 28 using the Iowa PDA score 
 
Nutritional Support:   
- Early enteral nutrition + parenteral nutrition   
- Caloric goal: 110–130 kcal/kg/day 
 
Infection Monitoring:   

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- Ureaplasma (airway): DNA tested within 72 hours and again by day 21, with treatment 
documented   
- CMV (urine): CMV DNA tested twice within 21 days, with treatment documented 
 
Fluid Management and Other Supportive Care:   
- Includes transfusions, vasoactive medications, etc. 
 
 Standardized Ventilator Management Protocol: 
Ventilator Mode Selection:   
- SIMV, AC, PSV, VG, etc. 
 
Ventilator Parameter Adjustments:   
- FiO₂, MAP, PEEP, respiratory rate, tidal volume, etc. 
 
Extubation Criteria:   
- Mandatory extubation attempt within 72 hours of starting dexamethasone and again within 
24 hours of meeting all of the following conditions:   
  - FiO₂ < 0.40 to maintain SpO₂ ≥ 88%   
  - Mean airway pressure (MAP) < 8 cm H₂O   
  - Hemodynamically stable as assessed by the clinical care team   
- Daily review of ventilator settings by study personnel to ensure protocol adherence   
Pre-Extubation Considerations:   
- Caffeine use is allowed   
- No frequent/severe apnea episodes   
- Stable spontaneous breathing 
 
Extubation Method:   
- Gradual weaning from ventilator support   
- Transition to NIPPV/CPAP or high-flow nasal cannula 

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Sample Size 
In this study, the primary outcome measure is the comparison of the incidence of BPD and/or 
BPD-related mortality at a postmenstrual age of 36 weeks in preterm infants meeting the 
inclusion criteria, treated with two different dexamethasone regimens (the DART regimen 
versus a medium-dose tapering regimen). This is a categorical variable, and intergroup 
analysis will be performed using the chi-square test. Based on previous literature, it is 
anticipated that the intervention could reduce this incidence by an absolute difference of 10% 
in the study population. With a two-sided alpha of 0.05 and a statistical power (1–β) of 0.80, 
the calculated required sample size is approximately 388 participants per group, totaling 776 
participants. Accounting for an estimated dropout and loss-to-follow-up rate of approximately 
20%, the final planned enrollment is approximately 970 infants (485 per group) to ensure 
adequate study power. 
 
IV. Study Population 
This study aims to enroll preterm infants with a gestational age of 24 weeks to 29 weeks 
+ 6 days who have required invasive mechanical ventilation for at least 14 days after birth and 
are receiving their first dose of study medication between 14 and 28 days of life. Prior to 
enrollment, infants must have required an inspired oxygen concentration (FiO₂) > 40% and a 
mean airway pressure (MAP) > 8 cmH₂O for at least 24 consecutive hours to ensure an 
adequate level of illness severity. In addition, informed consent must be obtained from the 
parents or legal guardians, and infants must not have received any other corticosteroid 
treatment prior to enrollment to avoid potential confounding factors. The goal is to enroll a 
well-defined population of preterm infants based on strict eligibility criteria. 
 
1. Inclusion Criteria   
(All of the following must be met) 
1) Gestational age between 24 weeks and 29 weeks + 6 days; Invasive mechanical ventilation 
for ≥14 days after birth; First dose of study drug administered between 14 and 28 days of life.   

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2) FiO₂ > 40% and MAP > 8 cmH₂O maintained for at least 24 hours prior to enrollment.   
3) Informed consent signed by parent(s) or legal guardian.   
4) No use of other corticosteroids prior to enrollment as specified in the inclusion criteria. 
 
2. Exclusion Criteria   
(Any of the following will exclude the infant from participation) 
1) Presence of ventilator-associated pneumonia (VAP) at the time of enrollment, diagnosed 
based on clinical signs, imaging, and microbiological findings.   
   According to the U.S. Centers for Disease Control and Prevention (CDC) and the National 
Nosocomial Infections Surveillance System (NNIS), VAP is defined as pneumonia occurring at 
least 48 hours after the initiation of mechanical ventilation [22].   
   Although the CDC/NNIS definition lacks specific criteria for neonates and preterm infants 
under 1 year of age, most NICU-based studies on VAP still adopt these criteria [23]. Infants 
with cytomegalovirus (CMV) pneumonia treated for less than 2 weeks are also excluded.   
2) Severe congenital malformations (e.g., complex congenital heart disease, diaphragmatic 
hernia), or known immunodeficiency.   
3) Other severe illnesses with a poor prognosis or short expected survival.   
4) Refusal of participation by parents or legal guardians. 
 
3. Withdrawal Criteria 
Subjects may voluntarily withdraw from the study at any time and for any reason. In addition, 
subjects will be withdrawn from the study under any of the following circumstances: 
1) The subject experiences a serious adverse event (SAE), and the study physician determines 
that continued participation poses an unacceptable risk.   
2) The subject receives medications or interventions prohibited by the study protocol that 
may impact the accuracy or safety of the trial results.   
3) The subject’s condition deteriorates and requires emergency treatment not aligned with 
the study protocol.   
4) The subject is later found to not meet inclusion criteria or to meet exclusion criteria but 

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was mistakenly enrolled.   
5) The trial monitor or ethics committee recommends the termination of the subject’s 
participation.   
6) The parent or legal guardian withdraws informed consent or explicitly requests to 
discontinue participation. 
 
 4. Study Termination Criteria 
Study termination refers to the complete discontinuation of the clinical trial before its planned 
conclusion. 
1) A major safety concern arises during the study, necessitating immediate termination.   
2) A significant error in protocol design or major deviation in implementation is discovered, 
making it impossible to evaluate the drug’s effect.   
3) The sponsor requests termination of the study. 
 
V. Study Procedure 
1. Pre-enrollment Screening   
Eligible infants will begin screening on day 14 of life. Once eligibility is confirmed, informed 
consent will be obtained from the parents or legal guardians, and randomization will be 
performed. 
 
2. Intervention   
Participants will be randomly assigned in a 1:1 ratio to receive one of the dexamethasone 
regimens. Standardized supportive care and ventilator management will be administered 
concurrently. Monitoring of intervention adherence will be implemented to ensure all 
treatments are delivered according to protocol. 
 
3. Follow-up and Assessments   
- Short-term follow-up: Record extubation outcomes at 72 hours and 7 days; monitor for 
complications such as intestinal perforation, gastrointestinal bleeding, hyperglycemia, 

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hypertension, and myocardial hypertrophy.   
- Mid-term follow-up: Document the number of steroid treatment courses and related 
complications.   
- Long-term follow-up: At 18–24 months corrected age, conduct neurodevelopmental 
assessments using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-
III), or the Griffiths Mental Development Scales (GMDS), along with evaluations of hearing, 
vision, and other developmental outcomes. 
 
VI. Outcome Measures 
Primary Outcome Measure:   
- Efficacy Indicator:   
  The incidence of BPD and/or BPD-related mortality at a corrected age of 36 weeks in 
preterm infants meeting the inclusion criteria, treated with two different dexamethasone 
regimens (the DART regimen and the medium-dose tapering regimen). 
- Incidence and severity of BPD at 36 weeks corrected gestational age, classified according to 
Jensen criteria:   
    - Grade I (mild): Nasal cannula < 2 L/min   
    - Grade II (moderate): CPAP, NIPPV, or nasal cannula ≥ 2 L/min   
    - Grade III (severe): Ongoing need for invasive mechanical ventilation 
Secondary Outcome Measures:   
Short-term Indicators:   
- Efficacy Indicator:   
Extubation success rate following the first course of treatment, defined as no reintubation 
within 72 hours and 7 days after initial extubation.  
  Oxygenation Index (OI) on days 0, 3, 7, 10, 14, and 28 of treatment   
  (OI = MAP × FiO₂ × 100 / PaO₂)   
- Safety Indicators:   
  Incidence of adverse events, including hyperglycemia, hypertension, infection, 
gastrointestinal bleeding, etc. 

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Indicators During Total Hospitalization:   
- Efficacy Indicators:   
   - Incidence of complications at discharge, including:   
    Retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), necrotizing 
enterocolitis (NEC), infections, pulmonary hypertension, and growth retardation   
  - Total days on mechanical ventilation   
  - Total length of hospital stay 
Long-term Indicators:   
- Safety Indicator:   
  Neurodevelopmental outcomes at 18–24 months corrected age, assessed using the Bayley 
Scales of Infant and Toddler Development, Third Edition (Bayley-III MDI/PDI), or the Griffiths 
Mental Development Scales (GMDS). 
 
VII. Risk Prevention and Management 
This study involves preterm infants, a population with inherent risks related to medication 
use and clinical interventions. To ensure the highest level of participant safety, the research 
team has established comprehensive risk prevention and response strategies. These include 
strict inclusion and exclusion criteria, standardized treatment protocols, an adverse event 
monitoring system, and oversight by an independent Data and Safety Monitoring Board 
(DSMB). These measures aim to minimize risks and safeguard the well-being of all participants. 
Strict Inclusion and Exclusion Criteria to Ensure Safety: The inclusion criteria require that 
participants be in stable condition, while those with severe infections, major congenital 
anomalies, or other high-risk conditions are excluded. The use of other corticosteroids prior 
to enrollment is strictly prohibited to eliminate confounding factors. 
Standardized Medication and Treatment Protocols: All medications and interventions will 
be administered strictly in accordance with the study protocol by experienced neonatologists. 
Each administration will be preceded by an evaluation to assess contraindications or high-risk 
factors. Medication may be withheld or discontinued if safety concerns arise. 
An adverse event monitoring system will be implemented, including daily assessments of 

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blood glucose, blood pressure, weight changes, and other relevant parameters. A Data and 
Safety Monitoring Board (DSMB) will conduct regular reviews of safety data. In the event of a 
serious adverse event (SAE), the incident will be immediately reported to the Ethics 
Committee and relevant authorities, and an evaluation will be conducted to determine 
whether the study should be suspended. 
Clear Withdrawal and Termination Mechanisms: Explicit criteria for withdrawal are in 
place (e.g., clinical deterioration, use of prohibited medications, withdrawal of parental 
consent). If any withdrawal or termination criteria are met, the intervention will be stopped 
immediately, and the infant will receive optimal clinical care. 
Protection of Participant Privacy: All data collection and management will be handled 
using coded identifiers. Data storage and transmission will be encrypted to prevent any breach 
of personal information. 
Enhanced Informed Consent Process: Trained research staff will communicate thoroughly 
with parents or legal guardians, using clear and accessible language to explain the study 
procedures and associated risks. Written materials will be provided, and families will have 
ample time to make an informed decision. During the study, parents may consult with the 
research team at any time, provide feedback, or withdraw from the study without penalty. 
 
VIII. Adverse Event Recording and Reporting 
During the study, investigators must closely monitor for the occurrence of adverse events 
(AEs). Upon the occurrence of any AE, including significant adverse events, the investigator is 
responsible for analyzing its cause, making a clinical judgment, and documenting the following: 
time of occurrence, symptoms, severity, duration, treatment measures, and outcome, as well 
as assessing the event’s relevance to the study intervention. All relevant medical 
documentation, including laboratory reports, must be recorded in the source documents. 
In the event of a serious adverse event (SAE), immediate protective measures must be 
taken to safeguard the participant. Investigators must promptly complete a Serious Adverse 
Event Report Form and notify the Ethics Committee within 24 hours. The affected participant 
must be followed closely, and the event must be documented continuously until resolution, 

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stabilization, or death. 
 
IX. Data Management 
- Completion of Case Report Forms (CRFs):   
  CRFs will be completed by clinical investigators. 
 
- Data Entry and Modification:   
  Dr. Chen Zheng is responsible for data entry and management. Data will be entered and 
managed using the Rien Electronic Data Capture (EDC) System for clinical trials. To ensure data 
accuracy, dual data entry will be performed independently by two data managers, followed 
by cross-verification. 
 
- Database Locking:   
  Once the accuracy and completeness of the database are confirmed, the Principal 
Investigator and the statistical analysis team will jointly lock the database. 
 
X. Statistical Analysis Methods 
Data analysis will be conducted using SPSS, R, or other statistical software. 
Baseline Data Analysis: 
Descriptive statistical analysis will be conducted on the baseline characteristics of each group 
(e.g., gestational age, birth weight, sex, antenatal steroid use, etc.). Continuous variables will 
be compared using analysis of variance (ANOVA) or the Kruskal-Wallis test, while categorical 
variables will be compared using the chi-square test or Fisher’s exact test to assess the balance 
between groups. 
 
Primary Outcome Analysis: 
The 72-hour and 7-day extubation success rates will be compared among groups using the 
chi-square test or logistic regression analysis. 
 

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Secondary Outcome Analysis: 
For continuous variables (e.g., time to extubation, oxygenation index [OI]), ANOVA or the 
Kruskal-Wallis test will be used. For categorical variables (e.g., incidence of bronchopulmonary 
dysplasia [BPD], incidence of complications), the chi-square test or Fisher’s exact test will be 
applied. Repeated measures ANOVA will be used to assess changes in OI at different time 
points (days 0, 3, 7, 10, 14, and 28). Linear regression analysis will be employed to assess the 
relationship between dexamethasone dosage and neurodevelopmental outcomes (MDI/PDI). 
 
Multivariate Analysis: 
Multivariate logistic regression or Cox regression analysis will be conducted to control for 
potential confounding factors (e.g., gestational age, birth weight, antenatal steroid use) and 
to evaluate the independent effect of dexamethasone regimens on outcomes such as 
extubation success rate and incidence of BPD. 
 
XI. Dissemination of Research Findings 
Upon completion of the study, the research team will prepare manuscripts based on the 
data and submit them to high-quality national and international journals for publication. The 
manuscripts will include primary findings, subgroup analyses, monitoring of adverse events, 
and long-term follow-up outcomes. 
Additionally, the results will be presented at national and international conferences in the 
fields of pediatrics and neonatology to enhance the academic impact of the study. If funding 
is obtained, a final report will be submitted in accordance with the funding agency’s 
requirements. 
The findings from this study will serve as an important reference for optimizing hormonal 
interventions during extubation in neonates and may contribute to the development of 
relevant clinical guidelines or expert consensus. Research data, subject to ethical approval, 
may be shared and used for subsequent analyses in future studies. 
 
XII. Ethical Considerations 

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1. Risks and Benefits 
Participants in this study may face drug-related risks. Dexamethasone is a glucocorticoid that 
may lead to a range of side effects during short-term use, including but not limited to 
hyperglycemia, hypertension, gastrointestinal bleeding, increased risk of infection, intestinal 
perforation, and myocardial hypertrophy. Although the study uses tapering regimens at 
different doses to mitigate these risks, adverse effects cannot be completely ruled out. 
Participants may not directly benefit from this study. However, the information obtained 
from this research could provide valuable insights into the risk factors associated with 
prematurity and may benefit future patients facing similar conditions. 
 
2. Protection of Participant Privacy 
Only research personnel involved in this study will have access to participants’ medical records, 
and they are bound by confidentiality agreements or researcher declarations. Ethics 
committees and regulatory authorities have the right to review clinical trial records. Data will 
be anonymized during processing, omitting any identifying personal information. Publication 
of results will not disclose individual participant identities. Medical records will be securely 
stored in the archives of the Children's Hospital, Zhejiang University School of Medicine, under 
strict confidentiality measures. 
 
3. Informed Consent and Consent Form Signing 
Before the clinical study begins, investigators must provide the participant's legal guardians 
with detailed information about the study, including its nature, purpose, potential benefits, 
and risks, ensuring that they fully understand the research. The study can only commence 
once the informed consent form has been signed. 
 
Each participant’s contact details (address and phone number) will be collected, and the 
attending physician will provide their own contact information to ensure participants can 
reach the research team at any time. 
 

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11. 
Yoder, B.A., M. Harrison, and R.H. Clark, Time-related changes in steroid use and 
bronchopulmonary dysplasia in preterm infants. Pediatrics, 2009. 124(2): p. 673-9. 

20 
 
12. 
Halliday, H.L., R.A. Ehrenkranz, and L.W. Doyle, Delayed (>3 weeks) postnatal corticosteroids 
for chronic lung disease in preterm infants. Cochrane Database Syst Rev, 2003(1): p. CD001145. 
13. 
Marr, B.L., et al., Randomized Trial of 42-Day Compared with 9-Day Courses of Dexamethasone 
for the Treatment of Evolving Bronchopulmonary Dysplasia in Extremely Preterm Infants. J 
Pediatr, 2019. 211: p. 20-26 e1. 
14. 
Jensen, E.A., et al., Assessment of Corticosteroid Therapy and Death or Disability According to 
Pretreatment Risk of Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants. 
JAMA Netw Open, 2023. 6(5): p. e2312277. 
15. 
van de Loo, M., et al., Corticosteroids for the prevention and treatment of bronchopulmonary 
dysplasia: an overview of systematic reviews. Cochrane Database Syst Rev, 2024. 4(4): p. 
CD013271. 
16. 
Cummings, J.J., et al., Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease 
Following Preterm Birth. Pediatrics, 2022. 149(6). 
17. 
Doyle, L.W., et al., Low-dose dexamethasone facilitates extubation among chronically 
ventilator-dependent infants: a multicenter, international, randomized, controlled trial. 
Pediatrics, 2006. 117(1): p. 75-83. 
18. 
Cloherty, John P., Eichenwald, Eric C., Stark, Ann R. Manual of Neonatal Care, Lippincott 
Williams & Wilkins, 2007, Chapter 24J 379. 
 
19. 
Ramaswamy, V.V., et al., Assessment of Postnatal Corticosteroids for the Prevention of 
Bronchopulmonary Dysplasia in Preterm Neonates: A Systematic Review and Network Meta-
analysis. JAMA Pediatr, 2021. 175(6): p. e206826. 
20. 
Jensen, E.A., et al., The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An 
Evidence-based Approach. Am J Respir Crit Care Med, 2019. 200(6): p. 751-759. 
21. 
Watterberg, K.L., et al., Hydrocortisone to Improve Survival without Bronchopulmonary 
Dysplasia. N Engl J Med, 2022. 386(12): p. 1121-1131. 
22. 
National Healthcare Safety Network, Pneumonia (Ventilator-Associated [VAP] and Non-
Ventilator-Associated Pneumonia [PNEU]) Event. January 2023. [(accessed on 1 November 
2023)]; Available online: https://www.cdc.gov/nhsn/pdfs/pscmanual/6pscvapcurrent.pdf 

21 
 
23. 
Baltimore, R.S., The difficulty of diagnosing ventilator-associated pneumonia. Pediatrics, 2003. 
112(6 Pt 1): p. 1420-1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
 
 
Statistical Analysis Plan 
 
Official 
Title 
of 
the 
Study: 
The 
Outcomes 
of 
Different 
Dexamethasone Regimens for the Prevention of Bronchopulmonary 
Dysplasia in Preterm Infants: A Multicenter Randomized Controlled 
Trial 
 
NCT Number: NCT07052201 
 
Date of the Document: September 26, 2025 
 
 
 
 
 
 
 
 
 
 
 

23 
 
Sample Size 
In this study, the primary outcome measure is the comparison of the incidence of BPD 
and/or BPD-related mortality at a postmenstrual age of 36 weeks in preterm infants meeting 
the inclusion criteria, treated with two different dexamethasone regimens (the DART regimen 
versus a medium-dose tapering regimen). This is a categorical variable, and intergroup 
analysis will be performed using the chi-square test. Based on previous literature, it is 
anticipated that the intervention could reduce this incidence by an absolute difference of 10% 
in the study population. With a two-sided alpha of 0.05 and a statistical power (1–β) of 0.80, 
the calculated required sample size is approximately 388 participants per group, totaling 776 
participants. Accounting for an estimated dropout and loss-to-follow-up rate of approximately 
20%, the final planned enrollment is approximately 970 infants (485 per group) to ensure 
adequate study power. 
Statistical Analysis Methods 
Data analysis will be conducted using SPSS, R, or other statistical software. 
Baseline Data Analysis: 
Descriptive statistical analysis will be conducted on the baseline characteristics of each group 
(e.g., gestational age, birth weight, sex, antenatal steroid use, etc.). Continuous variables will 
be compared using analysis of variance (ANOVA) or the Kruskal-Wallis test, while categorical 
variables will be compared using the chi-square test or Fisher’s exact test to assess the balance 
between groups. 
Primary Outcome Analysis: 
To compare the incidence of BPD and/or BPD-related mortality at a postmenstrual age of 36 
weeks in preterm infants meeting the inclusion criteria, treated with two different 
dexamethasone regimens (the DART regimen versus a medium-dose tapering regimen). 
Secondary Outcome Analysis: 
For continuous variables (e.g., time to extubation, oxygenation index [OI]), ANOVA or the 
Kruskal-Wallis test will be used. For categorical variables (e.g., incidence of complications), the 
chi-square test or Fisher’s exact test will be applied. Repeated measures ANOVA will be used 
to assess changes in OI at different time points (days 0, 3, 7, 10, 14, and 28). Linear regression 

24 
 
analysis will be employed to assess the relationship between dexamethasone dosage and 
neurodevelopmental outcomes (MDI/PDI). 
Multivariate Analysis: 
Multivariate logistic regression or Cox regression analysis will be conducted to control for 
potential confounding factors (e.g., gestational age, birth weight, antenatal steroid use) and 
to evaluate the independent effect of dexamethasone regimens on outcomes such as 
extubation success rate and incidence of BPD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

25 
 
 
 
 
Informed Consent Form 
 
Official 
Title 
of 
the 
Study: 
The 
Outcomes 
of 
Different 
Dexamethasone Regimens for the Prevention of Bronchopulmonary 
Dysplasia in Preterm Infants: A Multicenter Randomized Controlled 
Trial 
NCT Number: NCT07052201 
 
Date of the Document: September 26, 2025 
 
 
 
 
 
 
 
 
 
 

26 
 
Dear Parent or Legal Guardian, 
Your child is invited to participate in a research study titled: “The Outcomes of Different 
Dexamethasone Regimens for the Prevention of Bronchopulmonary Dysplasia in Preterm 
Infants: A Multicenter Randomized Controlled Trial.” Participation in this study is entirely 
voluntary. This informed consent form is intended to provide you with important information 
about the study. Please read it carefully before deciding whether to allow your child to 
participate. If you have any questions or do not understand any part of the form, please ask 
the study doctor. The research team will answer all your questions. 
  
This study is being conducted by Dr. Chen Zheng and his team from the Neonatal Intensive 
Care Unit (NICU) of the Children's Hospital, Zhejiang University School of Medicine. The study 
has been reviewed and approved by the Medical Ethics Committee of the Children's Hospital, 
Zhejiang University School of Medicine. 
 
1. Why is this study being conducted? 
Background: With advances in perinatal medicine and neonatal intensive care, the survival 
rate of extremely and very preterm infants has significantly increased. However, both short- 
and 
long-term 
prognoses 
remain 
challenging. 
The 
presence 
and 
severity 
of 
bronchopulmonary dysplasia (BPD) can greatly affect the long-term outcomes of preterm 
infants. Glucocorticoids, such as dexamethasone, are commonly used to prevent and treat 
BPD. On one hand, dexamethasone can improve respiratory outcomes by reducing 
inflammation, decreasing pulmonary edema, and promoting alveolar development. On the 
other hand, there are concerns about its potential negative effects on the nervous system, 
growth, and metabolism of preterm infants. Currently, there is no consensus on the optimal 
timing, dosage, and duration of dexamethasone therapy. This study aims to evaluate the 
impact of dexamethasone regimens on the incidence of BPD and/or BPD-related mortality in 
preterm infants meeting the inclusion criteria at a postmenstrual age of 36 weeks. The goal is 
to provide an evidence-based foundation for optimizing dexamethasone therapy in preterm 
infants and to improve their long-term outcomes. 

27 
 
The primary objective is to compare the effects of two dexamethasone regimens (the DART 
regimen versus the medium-dose tapering regimen) on the incidence of BPD at 36 weeks' 
postmenstrual age in eligible preterm infants. 
2. What needs to be done before participating in the study? 
If you and your child decide to participate, we will ask you to sign this informed consent form 
before conducting any study-related procedures. If a new version of the consent form is issued 
during the study, we will ask you to sign the updated version as well. 
 
3. How will the study be conducted? 
This study will be conducted at 24 hospitals and will involve 970 patients in total. Enrollment 
is competitive across centers, and our hospital aims to recruit at least 100 patients. 
 
After signing this consent form, your child will undergo a screening process.   
Inclusion criteria:   
- Gestational age between 24 weeks and 29 weeks + 6 days   
- Requires invasive mechanical ventilation for at least 14 days after birth   
- First dose of dexamethasone administered between 14 and 28 days of life   
- Before enrollment, your child must have required more than 40% oxygen (FiO2 > 40%) and 
a mean airway pressure (MAP) > 8 cmH2O for at least 24 hours   
- Parents must sign the informed consent form   
- No prior use of other corticosteroids 
 
Exclusion criteria:   
- Ventilator-associated pneumonia (VAP) at the time of enrollment (based on clinical 
symptoms, imaging, and microbiological tests)   
- Severe congenital malformations (e.g., major cardiac defects, diaphragmatic hernia)   
- Known immunodeficiency   
- Other severe illnesses with poor prognosis or limited life expectancy 
 

28 
 
The purpose of the screening is to determine whether your child meets the inclusion criteria. 
After the screening, the study physician will inform you whether your child is eligible to 
continue in the study. If your child is not eligible, the physician will explain the reason and 
discuss alternative treatment options with you. 
The total duration of participation in the study is approximately 24 months. 
 
If enrolled, your child will undergo the following procedures: 
1. Randomization:   
Your child will be randomly assigned to one of two groups (1:1 ratio):   
- DART regimen group   
- Medium-dose tapering regimen group   
Dexamethasone will be administered before the first planned extubation attempt. 
 
2. Short-term follow-up:   
We will monitor for outcomes such as extubation success at 72 hours and 7 days, intestinal 
perforation, gastrointestinal bleeding, hyperglycemia, hypertension, and myocardial 
hypertrophy. 
 
3. Mid-term follow-up:   
We will track the number of steroid treatment courses, BPD incidence, and related 
complications. 
 
4. Long-term follow-up:   
At 18–24 months corrected age, we will evaluate your child’s neurodevelopment using the 
Bayley III or Griffiths Developmental Scales, as well as assess hearing and vision. 
 
4. What are the risks or discomforts of participating in this study? Are there any protective 
measures? 
Dexamethasone used in this study may cause side effects such as infections, peptic ulcers or 

29 
 
gastrointestinal perforation, electrolyte imbalance, and high blood pressure. We will closely 
monitor for these complications during treatment. 
This study only involves the collection of clinical data and does not alter the standard care or 
treatment procedures your child would otherwise receive. Therefore, participation will not 
result in additional risks related to examinations or treatments. 
 
5. What are the benefits of participating in this study? 
Participation in this study may improve your child’s respiratory outcome, but it is also possible 
that there will be no benefit. However, the valuable data provided by your child will contribute 
to future research on bronchopulmonary dysplasia (BPD) in preterm infants. 
 
6. Are there other treatment options besides participating in this study? 
Yes. If you choose not to participate, your child may still receive dexamethasone treatment 
before extubation during hospitalization, depending on their clinical condition. It is also 
possible that your child will not receive dexamethasone at all or may be extubated directly 
without steroid use once extubation criteria are met. 
 
7. What if my child is injured as a result of participating in the study? 
If your child experiences any injury or adverse event related to participation in this study or 
during the course of treatment, please contact your study doctor immediately. Your child will 
receive timely medical treatment.   
If the injury is determined to be related to the study, the Neonatal Intensive Care Unit (NICU) 
of the Children's Hospital, Zhejiang University School of Medicine, will cover the medical 
expenses and provide appropriate compensation in accordance with national laws and 
regulations.   
Even after signing this informed consent form, you still retain all your legal rights. 
 
8. Are there any costs for participating in this study? 
There are no additional costs for participating in this study. You will only be responsible for 

30 
 
the regular hospitalization and medical treatment expenses. 
 
9. Will I be compensated for participating in this study? 
No. You will not receive any financial compensation for participating in this study. 
 
10. Is participation mandatory? Can I withdraw after joining? 
No, participation in this study is entirely voluntary. You may choose not to allow your child to 
participate. You may also withdraw your child from the study at any time, for any reason. 
Choosing to withdraw will not result in any penalty, discrimination, or retaliation and will not 
affect your child’s future medical care or rights. If you decide to withdraw your child from the 
study, please inform us. We will ensure your child exits the study in the safest manner possible. 
 
11. Under what circumstances might my child be withdrawn from the study? 
Your child may be withdrawn from the study by the research doctor under the following 
conditions:   
- You or your child do not follow the instructions of the study team or show poor compliance;   
- The study doctor determines that continuing participation may pose unnecessary risks to 
your child;   
- The study is terminated by the Ethics Committee or a regulatory authority. 
 
12. What happens if new information becomes available during the study? 
If any new information arises during the study that could affect your decision to continue 
participation, the study doctor will inform you promptly. You will be given ample time to 
consider whether to continue participation.   
 
After the study ends, relevant results will be communicated to you and your child. 
 
13. Will my child’s information be kept confidential? 
Yes. All documents related to your child will be coded to protect identity. Any published 

31 
 
reports or presentations from this study will not include any personal information about you 
or your child. All data and related codes will be securely stored by the research institution. 
Study data will be retained for at least 10 years. Your child's medical records may be reviewed 
by the researchers, the Ethics Committee of the Children's Hospital, Zhejiang University School 
of Medicine, and relevant government regulatory authorities. 
 
14. Who can I contact if I have questions about the study? 
If you have any questions or concerns about any part of this study, the research team will be 
available to answer them. If you feel your questions are not fully answered or you do not 
understand the responses, please continue to ask until you are satisfied. 
 
Principal Investigator: Dr. Chen Zheng; Dr. Yanping  
Phone Number: +86 13857151000 
If you have concerns about your child’s rights as a research participant, or if you have any 
complaints or concerns about the research process, you may contact the Ethics Committee: 
Name: Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine   
Address: No. 3333 Binsheng Road, Binjiang District, Hangzhou, Zhejiang Province, China   
Phone Number: +86 571-86670076 
 
 
 
 
 
 
 
 
 
 
 

32 
 
Informed Consent Signature Page 
 
I have read and understood the information in this informed consent form. I have asked 
questions and am satisfied with the answers provided by the study physician. I have been 
given sufficient time and opportunity to inquire about the details of the study and to consider 
whether to allow my child to participate. 
 
I voluntarily agree to allow my child to participate in this study. 
 
Signing this informed consent form does not mean I give up any of my legal rights. 
 
I have been informed that I will receive a signed copy of this document. 
 
I authorize study personnel, the ethics committee, and government regulatory authorities to 
review my child's medical records. 
 
I  Agree /  Disagree that my child's data from this study may be used in other research. 
 
Participant’s Name (Print): ______________________   
Guardian’s Name (Print): _______________________         
Relationship to Participant: __________________   
Guardian’s Signature: __________________________   
Date and Time of Signature: _____________________         
Contact Phone Number: __________________   
 
(Only one guardian's signature is required for this study) 
 
 

33 
 
 
Statement of Person Obtaining Informed Consent: 
 
I confirm that I have explained the details of this study to the participant’s guardian, including 
their rights and the possible benefits and risks. I have answered the guardian’s questions and 
provided them with a signed copy of the informed consent form. 
 
Name of Person Obtaining Consent (Print): __________________   
Signature of Person Obtaining Consent: _____________________   
Date and Time of Signature: _____________________________      
Contact Phone Number: __________________   
 
Impartial Witness Statement (if applicable): 
 
I confirm that the study doctor accurately explained the contents of the informed consent 
form to the participant’s guardian, and that a discussion was held with the guardian. The 
guardian was given the opportunity to ask questions and voluntarily agreed to allow their child 
to participate in the study. 
 
Impartial Witness Name (Print): __________________________   
Impartial Witness Signature: _____________________________   
Date and Time of Signature: _____________________________      
Contact Phone Number: __________________   
 
(An impartial witness signature is required if the participant or their guardian is illiterate.)