1. What data in particular will be shared?
   Response - All of the individual participant data collected during the trial, after de-identification.
   


2. What additional supporting information will be shared?
   Response -  Study Protocol
   
   
3. Who will be able to view these files?
   Response - Researchers who provide a methodologically sound proposal.
   


4. For what types of analyses will this data be available?
   Response - For individual participant data meta-analysis.
   


5. By what mechanism will data be made available?
   Response - Proposals should be directed to [arnabmck999@gmail.com].
   


6. For how long will this data be available start date provided 19-05-2027 and end date provided 19-05-2032?
   Response - Beginning 3 months and ending 5 years following article publication.
   


7. Any URL or additional information regarding plan/policy for sharing IPD? 
   Additional Information - NIL

1.     Title of the dissertation:

Efficacy of Caffeine on Duration of  Respiratory Support in Preterm Neonates Weighing 1250–2000 gram: A Randomized Controlled Trial

2.     Introduction:  

a)     According to the National Neonatal Perinatal Database of India (NNPD), respiratory distress in neonates is defined by the presence of any two of the following features: Respiratory rate exceeding 60 breaths per minute, Subcostal or intercostal retractions, Expiratory grunting or groaning (1).

In addition to these primary indicators, other signs such as nasal flaring, suprasternal retractions, and decreased air entry upon auscultation of the chest further support the diagnosis of respiratory distress. Life-threatening signs that require immediate attention include gasping, apnea, poor respiratory effort, bradycardia, poor perfusion, and cyanosis (2).

Respiratory distress affects around 4-7% of all neonates and accounts for 30-40% of all admissions to neonatal intensive care units (NICUs). The incidence is significantly higher among preterm infants, approximately 30%, compared to 21% of post-term infants and only 4.2% of term neonates (3).

Among preterm neonates, respiratory distress syndrome (RDS) is the most prevalent cause of respiratory distress, accounting for 36% of cases. Following RDS, pneumonia contributes to 28% of cases, while transient tachypnea of the newborn (TTN) is responsible for 27% (4). RDS primarily results from a deficiency of surfactant in the lungs of preterm infants, which is critical for maintaining alveolar stability and preventing collapse. On the other hand, TTN occurs due to a defect in the amiloride-sensitive epithelial sodium channel, leading to delayed clearance of fetal lung fluid after birth (5). Pneumonia can arise from either congenital infections or postnatally acquired infections that cause inflammation in the lung parenchyma.

Effective management of respiratory distress involves a thorough evaluation to determine both the severity and underlying cause of the condition. This assessment is crucial for initiating timely respiratory support, which may include supplemental oxygen, continuous positive airway pressure (CPAP), or mechanical ventilation. In recent years, there has been a shift towards non-invasive ventilation strategies in NICUs to minimize lung injury associated with invasive procedures (6).

Caffeine is frequently prescribed for preterm infants to prevent and treat apnea of prematurity (AoP) due to its proven efficacy and well-established safety profile. It acts by inhibiting adenosine receptors in the central nervous system, which allows it to act as a stimulant, enhancing respiratory drive and improving ventilation.

Research has demonstrated that caffeine therapy not only decreases the incidence of apnea but also facilitates earlier extubation, thereby reducing the duration of mechanical ventilation and associated complications such as bronchopulmonary dysplasia (BPD). The CAP trial, a landmark study involving over 2,000 preterm infants, found that caffeine administration significantly improved outcomes related to respiratory support. Infants treated with caffeine were extubated earlier and required less oxygen therapy compared to those receiving placebo. These findings underscore the critical role of caffeine in managing respiratory distress syndrome (RDS) and preventing long-term complications associated with prolonged mechanical ventilation (7).

Caffeine’s role as an adjunct to respiratory support in neonates can be attributed to several potential mechanisms. Firstly, caffeine exhibits a diuretic effect, which may assist in the removal of excess fluid from the lungs, thereby facilitating easier breathing. This diuretic action is thought to occur through the inhibition of phosphordiesterases in the kidneys, leading to increased urine output and improved fluid balance. Secondly, caffeine induces the transcription of surfactant protein B via a cAMP-dependent pathway, which is essential for maintaining alveolar stability and enhancing gas exchange in the lungs. This effect is particularly advantageous for preterm infants who often experience surfactant deficiency. Additionally, studies indicate that caffeine improves diaphragmatic contractility and function within 30 minutes after administration in extremely low birth weight (ELBW) infants. This rapid enhancement in diaphragmatic activity contributes to more effective ventilation and overall respiratory function. Furthermore, caffeine appears to inhibit pulmonary inflammation induced by hyperoxia by decreasing the expression of pro-inflammatory cytokines, as shown in animal models. Collectively, these mechanisms lead to several beneficial effects: a reduction in ventilatory requirements, improved minute ventilation and tidal volumes, and a decrease in extubation failure rates (8). 

The use of caffeine is particularly recommended for very low birth weight infants (those weighing less than 1250 grams), where its prophylactic use has become standard practice. However, there remains a gap in routine caffeine administration for preterm infants weighing between 1250 and 2000 grams who also require respiratory support. This population is at risk for similar complications as their extremely low birth weight counterparts but has not been studied as extensively regarding caffeine’s benefits. This study aims to assess the effectiveness of caffeine in this specific group to determine its potential role in improving the duration of respiratory support. 

b)          Research gap:

Caffeine citrate primarily used for apnea of prematurity

Even though pharmacological action of caffeine explains likelihood of its beneficial effect as an adjunct to respiratory support.

But, there are limited research on the use of caffeine citrate for respiratory support

c)             Problem statement:

Preterm neonates weighing between 1250 and 2000 grams are at increased risk for respiratory complications, including respiratory distress syndrome (RDS), which often necessitates prolonged respiratory support. Current therapeutic interventions, such as caffeine citrate, have shown promise in reducing apnea episodes and facilitating the transition from invasive to non-invasive respiratory support. However, the specific efficacy of caffeine citrate in decreasing the duration of respiratory support for this particular weight category remains inadequately explored.

d)             Rationale:   

Caffeine has been shown to decrease apnea frequency, enhance respiratory mechanics, and potentially reduce the incidence of bronchopulmonary dysplasia (BPD) and other complications associated with prolonged mechanical ventilation. Given that RDS is a leading cause of morbidity and mortality among preterm infants, optimizing caffeine therapy likely to facilitate early weaning from respiratory support, this could significantly improve clinical outcomes, reduce hospital stays, and lower healthcare burdens.

e)           Novelty:

This study aims to provide novel insights into the role of caffeine citrate specifically for preterm neonates weighing between 1250 to 2000 grams, a group that has not been extensively studied compared to those under 1250 grams.

1.     To date, there has been only one published study worldwide on the effects of caffeine citrate on the duration of respiratory support in preterm neonates weighing between 1250 and 2000 grams. This study is expected to be the first of its kind conducted from the Indian subcontinent, aimed at generating further evidence.

2.     The previous study conducted in Iran in 2022 focused exclusively on neonates receiving nasal continuous positive airway pressure (CPAP). In contrast, our study aims to include all neonates requiring any form of respiratory support, encompassing both invasive and non-invasive modes.

f)              Expected outcome and application:

Caffeine citrate is expected to reduce the duration of respiratory support in preterm neonates weighing between 1250 to 2000 grams. Consequently, it is likely to decrease associated morbidities and shorten hospital stays.

3.     Research question(s):

Can oral caffeine citrate reduce the duration of respiratory support in inborn preterm neonates (gestational age: 30-36⁺⁶ weeks) weighing between 1250 to 2000 grams, requiring respiratory support since birth for more than six hours ?

Respiratory support:

Non-invasive respiratory support [Nasal Cannula, Nasal Continuous Positive Airway Pressure (nCPAP), Nasal Intermittent Positive Pressure Ventilation (NIPPV), Heated Humidified High Flow Nasal Cannula (HHHFNC)] and,

Invasive respiratory support [Synchronized intermittent mandatory ventilation (SIMV), High frequency oscillatory ventilation (HFOV)]

4.   Research hypothesis(es), if any:

a.     Null hypothesis (H0):

The use of oral caffeine citrate in preterm neonates requiring respiratory support does not reduce the duration of respiratory support.

b.    Alternate hypothesis (H1):

The use of oral caffeine citrate in preterm neonates requiring respiratory support reduces the duration of respiratory support.

5.     Aim and objectives:

a.     Aim of the study:

To evaluate the efficacy of oral caffeine citrate compared to placebo on the duration of respiratory support in preterm neonates (gestational age: 30-36⁺⁶ weeks) weighing between 1250 to 2000 gram, requiring respiratory support since birth for more than six hours.

b.     Primary Objective:

To compare the duration (in hours) of respiratory support requirement among the intervention and control groups

c.     Secondary Objectives:

1.     To compare the duration (in completed days) of NICU stay among the intervention and control groups.

2.     To compare proportions of neonatal death by day 7 and day 28 of life among the intervention and control groups (all cause).

3.     To compare the proportion of neonates with feed intolerance among the intervention and control groups.

1.     Methodology:

a.     Study design: Double arm, blinded, parallel group randomised control trial

b.    Study settings: Level III NICU, AIIMS Patna

c.     Study duration: March, 2025 to Dec, 2026

d.    Study participants:

a.     Inclusion criteria:

All inborn neonates with a gestation age of  between 30 to 36⁺⁶ weeks

AND

Birth weight between 1250 to 2000 gram

AND

Requiring respiratory support since birth for a duration of more than 6 hours.

b.    Exclusion criteria:

1.     Major congenital anomalies and chromosomal disorder

2.     Hypoxic ischemic encephalopathy stage II or above

3.     Neonates kept nil per mouth beyond 24 hours of life

4.     Neonates on multiple (≥2) inotropes

e.     Sampling

a.     Sampling population: All inborn neonates admitted in NICU fulfilling the inclusion criteria will be included in the study.

b.    Sampling technique: Consecutive  type

c.     Sample size(n) calculation:                                                                                        The study conducted by Ramin et al. (2022) on the effect of prophylactic caffeine on noninvasive respiratory support in preterm neonates weighing between 1250 and 2000 grams found that the caffeine group had a significantly shorter duration of nasal CPAP support compared to the control group [41.53 hrs (43.25) vs 78.48 hrs (114.25); mean difference: -36.9 hrs (87)] (21).

Based on these findings, the calculated sample size is approximately 86 participants in each group (total of 172 participants) to detect a minimum mean difference of 36.9 hours between the groups, assuming a population standard deviation of 86. This calculation considers a superiority trial with 80% power and a 5% alpha error, using Open epi Software, Version 3, Open-source calculator.

f.       Randomization details (for interventional studies)

Intervention details with standardization techniques (drugs / devices / invasive procedures / non-invasive procedures / others):

1)    Randomization:

Random sequences with variable block sizes of 4, 6, and 8 will be generated using sealed envelope, a web-based, open-access application. An independent investigator, who will not be involved in the study, will prepare the randomization sequence.

2)    Preparation of the drugs:

·      Oral caffeine citrate is commercially available as a colorless, transparent liquid oral solution. Each milliliter (ml) contains 20 mg of caffeine citrate, equivalent to 10 mg of caffeine base IP and water for injection as a sufficient quantity (q.s). This will serve as the intervention agent.

·      Sterile water for injection is also available as a colorless, transparent solution. This will serve as the control agent.

3)    Storage of the drugs:

These two medications will be drawn into identical 2 ml syringes and labelled as either Drug A or Drug B by a senior nursing officer who will not be involved in the clinical care of the enrolled neonate, under the guidance of the Head of the Department of Pharmacology. Fresh preparations will be made each day and stored in the refrigerator (lower self) for use.

4)    Time of administration:

The first loading dose will be administered as soon as possible after enrolment, and no later than 24 hours of life (in cases where the baby is kept nil-per-mouth for the initial few hours).

Subsequent maintenance doses will be administered at 24-hour intervals.

5)    Mode of administration: Enteral route – either via an orogastric tube or through katori-spoon (K/S) feeding, mixed with expressed breast milk.

6)    Duration of therapy: The intervention will continue until the neonate has been off respiratory support for at least 24 hours.

g.     Study procedure:

1.     Ethical Clearances and CTRI Registration:

Ethical clearances will be obtained from the institution and CTRI registration will be done before the commencement of this study.

2.     Recruitment:

The neonates eligible for inclusion in the study will be identified, and their parents will be approached and informed about the study. Parents will have the opportunity to ask questions regarding the study and will be provided with a Participant Information Sheet (PIS). Following this, parents will be approached for informed consent.

3.     Informed Consent:

Written consent will be sought from either parent or the available local guardian after they have received a full verbal and written explanation of the trial. The written explanation will be provided through the Participant Information Sheet (PIS) (Annexure B). Written informed consent from the parents will be obtained through dated signatures on a Parent Informed Consent Form (PICF) (Annexure C), which will also include the signature of the principal investigator. A copy of this form will be given to the parents, and another copy will be attached to the baby’s medical records.

4.     Enrolment:

Neonates whose parents have provided informed consent will be enrolled in the study, excluding those who meet the exclusion criteria.   

5.     Preparation of drugs:

Oral caffeine citrate is commercially available as a colourless, transparent liquid oral solution under the brand name CAPNEA, manufactured by CIPLA Pharmaceuticals. Each millilitre(ml) contains 20 mg of caffeine citrate, equivalent to 10 mg of caffeine base IP, with water for injection as a sufficient quantity (q.s).

Sterile water for injection is also available as a colourless, transparent solution. These two medications will be drawn into 2 ml syringes and labelled as either Drug A or Drug B by a senior nursing officer who will not be involved in the clinical care of the enrolled neonate, under the guidance of the Head of the Department of Pharmacology. Fresh preparations will be made each morning and stored in the refrigerator for use.

6.     Randomization:

Random sequences with variable block sizes of 4, 6, and 8 will be generated using sealed envelope, a web-based, open-access application. An independent investigator, who will not be involved in the study, will prepare the randomization sequence. A consecutive sampling strategy will be followed.

7.     Allocation concealment:

All enrolled neonates will be randomly assigned to either the intervention or control group (1:1) using serially numbered opaque and sealed envelopes. The independent investigator who prepared the randomization sequence will code the study groups as either Group A or Group B, and this coding will remain confidential until the completion of the study. These envelopes will be opened by the bedside nurse/resident doctor, within 1 hour of enrolment, in the absence of principal investigator

8.     Blinding & Matching:

The drugs will be supplied in identical 2 cc syringes labelled as “Drug A” for Group A and “Drug B” for Group B. Both the drug solutions are similar in colour, consistency, and appearance, ensuring effective blinding.

Additionally, both the drugs will be administered in the same doses, which include an initial loading dose of 1 ml/kg and subsequent maintainace doses of 0.5 ml/kg, allowing us to maintain matching between the groups.

9.     Intervention:

Neonates assigned to Group A will receive Drug A, while those in Group B will receive Drug B. The first loading dose of 1 ml/kg will be administered via the enteral route, either using an orogastric tube or by katori-spoon feeding mixed with expressed breast milk, as soon as possible after enrolment, and no later than 24 hours of life (in cases where the baby is kept nil-per-mouth for the initial few hours) by the bed side nurse/ resident doctor. Subsequent doses of 0.5 ml/kg will be given through the same route, with a 24-hour interval between doses. The intervention will continue until the neonate has been off respiratory support for at least 48 hours.

10.  Interim Exit criteria:

                                            i.         Developed Central/Mixed Apnea with Gestational age of < 34 week

                                          ii.         Requiring NPO (nil by mouth) for 24 hours or more during the study period post enrolment

11.  Data collection and Analysis:

The total duration of respiratory support in hours and the total duration of hospitalization in days will be recorded for each participant. Additionally, neonatal deaths by day 7 and 28 (all-cause), and prevalence of feeding intolerance will be recorded for each participant. The type of drugs received will also be documented for each participant. The outcome variables will be compared between the two groups: those who received Drug A and those who received Drug B. A subgroup analysis will be conducted, including neonates weighing between 1250 grams and 1500 grams, as well as those weighing between 1500 grams and 2000 grams.

12.  Unblinding and Dissemination:

Once the analysis is complete, the unblinding process will take place to identify which group received the intervention and which served as the control. Subsequently, the final results will be published.

a.     Data Collection and Statistical Analysis Plan:

Analysis will be conducted based on an intention-to-treat (ITT) principle. All data will be recorded in a pre-piloted online data collection sheet, and subsequently entered into an MS Excel sheet (version 2019). The data will be statistically analyzed using JAMOVI software (version 2.3).

Categorical variables will be presented as proportions, while continuous variables will be reported as means and standard deviations (SD) or medians and interquartile ranges (IQR). The distribution of continuous variables will be assessed using the Shapiro-Wilk test and visual inspection of Q-Q plots.

For categorical variables, intergroup differences will be compared using the Chi-square test or Fisher’s exact test, as applicable. Risk ratios will be calculated for categorical outcomes, and logistic regression analysis will be performed if necessary.

For continuous variables, intergroup differences will be compared using the independent Student’s t-test for normally distributed data or the Mann-Whitney U test for non-normally distributed data.

All statistical analyses will be carried out at a 95% confidence interval, with significance attributed to a p-value of < 0.05.

b.    Limitations of the study:

1.     Long-term follow-up is not feasible within the limited timeframe of this study, therefore long-term outcomes of the interventional drug could not be assessed.

2.     It is a single centre study

c.     List risks and benefits of the study:

Benefits: 

1.     Caffeine citrate can be a low-cost intervention for neonates weighing between 1250 to 2000 grams who require respiratory support, potentially reducing the duration of that support. This, in turn, may decrease the complications associated with prolonged respiratory support (Nasal septal injury/ Ventilator induced lung injury)

2.     Caffeine citrate can also shorten the duration of hospital stays, thereby reducing the financial burden on parents due to treatment costs and lost wages, as well as minimizing the utilization of healthcare resources.

Risks:

The risks associated with the study primarily involve the side effects of caffeine administration. Caffeine has a favorable safety profile and is a commonly prescribed medication in neonatology. It is even recommended for prophylactic use in very preterm neonates weighing less than 1250 grams. Therefore, the likelihood of additional risks associated with its use is minimal.