Randomized Controlled Trial of Home Therapy With Caffeine Citrate in Moderately Preterm Infants With Apnea of Prematurity
Phase: PHASE3
Conditions: Apnea of Prematurity
Sponsor: NICHD Neonatal Research Network

MoCHA  
 
 
Randomized Controlled Trial of Home Therapy with Caffeine Citrate in Moderately 
Preterm Infants with Apnea of Prematurity  
 
Short Title: Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial 
 
ClinicalTrials.gov number: 
NCT###03340727 
 
 
Lead Study Investigator: 
Waldemar A. Carlo, University of Alabama at Birmingham 
 
Co-Investigators:           
                                                 
Eric C. Eichenwald, Children’s Hospital of Philadelphia 
                                                Anna Maria Hibbs, Case Western Reserve University 
                                                Ronald Goldberg, Duke University Medical Center 
                                                Abhik Das, RTI International 
Edward F. Bell, University of Iowa 
                                                Carl D’Angio, University of Rochester 
Martin Keszler, Brown University 
                                                Betty Vohr, Brown University 
Ravi M. Patel, Emory University 
Pablo Sanchez, Nationwide Children’s Hospital 
                                                Krisa Van Meurs, Stanford University 
                                                Nancy Newman, Case Western Reserve University 
Namasivayam Ambalavanan, University of Alabama at 
Birmingham  
Shirley Cosby, University of Alabama at Birmingham 
Michele Walsh, National Institute of Child Health and 
Development Neonatal Research Network 
 
 
 
 
Version 4.0 Date: 12/16/2021 
 

MoCHA 
 
 
Contents 
Section 1. 
Abstract ................................................................................................................... 1 
Section 2. 
Conflict of Interest Disclosures .............................................................................. 4 
Section 3. 
Statement of Problem .............................................................................................. 5 
3.1. 
Hypothesis................................................................................................... 5 
3.2. 
Specific Aims .............................................................................................. 5 
3.3. 
Background ................................................................................................. 6 
3.4. 
Justification for the Study ........................................................................... 8 
Section 4. 
Study Design ......................................................................................................... 10 
4.1. 
Primary Outcome ...................................................................................... 10 
4.2. 
Secondary Outcomes ................................................................................ 10 
4.3. 
Study Intervention ..................................................................................... 11 
4.4. 
Blinding/Masking ..................................................................................... 12 
4.5. 
Potential Risks and Benefits to Subjects ................................................... 12 
Section 5. 
Methods................................................................................................................. 16 
5.1. 
Study Population ....................................................................................... 16 
5.1.1. Inclusion Criteria .......................................................................... 16 
5.1.2. Exclusion Criteria ......................................................................... 16 
5.2. 
Detailed Study Procedures ........................................................................ 16 
5.2.1. Screening and Consent Procedures ............................................... 16 
5.2.2. Randomization Procedures ........................................................... 17 
5.2.3. In-hospital Procedures .................................................................. 17 
5.2.4. Post-hospital Procedures ............................................................... 19 
Section 6. 
Analytical Plan ...................................................................................................... 20 
6.1. 
Sample Size, Availability, and Projected Recruitement Time .................. 20 
6.2. 
Statistical Analysis Plan ............................................................................ 20 
6.3. 
Data Monitoring Plan ................................................................................ 21 
6.3.1. Monitoring for Side Efffects and Adverse Events ........................ 21 
 
 
6.3.2. Monitoring Drug Adherence/Compliance.....................................23 
6.3.3. Statistical Interim Monitoring and Stopping Rules ...................... 24 
 
Section 7 
Future Direction…………………………………………………………….……26  
Section 8 
Data Sharing…..…………………………………………………………….……26 
Section 9. 
Data Forms……………………...………………………………………….…….26 
Section 10. 
References ............................................................................................................. 27 
 

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SECTION 1. 
ABSTRACT 
Objective 
 
To evaluate the effect of continuing treatment with caffeine citrate in the hospital and at home in 
moderately preterm infants with resolved apnea of prematurity on days of hospitalization after 
randomization. 
 
Study Design  
 
Randomized, 1:1 allocation with parallel enrollment, double-blinded, placebo-controlled, 
multicenter trial.  
 
Primary Outcome  
 
The primary outcome of the study will be the number of days of hospitalization from 
randomization to discharge up to 48 weeks post-menstrual age (PMA), with censoring at time of 
transfer or death. 
 
Secondary Outcomes  
 
The secondary outcomes of the study will be: 
a. The number of days to physiologic maturity after randomization up to 48 wks PMA. 
 
Physiologic maturity will be defined as follows: 
i. 
Temperature: out of the incubator for at least 48 hours with normal body temperature 
ii. 
Feeding: oral feeding at a volume of at least 140 ml/kg/day or growing on less than 140 
ml/kg/day for at least 48 hours 
iii. 
Respiratory: apnea-free for at least 5 consecutive days 
 
b. Post menstrual age at discharge up to 48 wks PMA, censoring at time of transfer or death 
(status). 
c. The number of all cause readmissions, including apneic events and apparent life-threatening 
events (ALTE), to the hospital within the first four weeks, second four weeks, and first eight 
weeks combined after discharge from the hospital by 48 wks PMA.  
d. The number of all cause sick visits to urgent care, emergency room or health care provider 
office within the first four weeks, second four weeks, and first eight weeks combined after 
discharge from the hospital by 48 wks PMA.  
e. Safety outcome measures pre-hospital discharge 
• Weight gain from randomization until status (discharge up to 48 wks PMA, with 
censoring at time of transfer or death). The weight gain may also be assessed using 
percentiles including birthweight percentiles. 
• The number of days after randomization until status that infant had at least two 
consecutive heart rates >200 documented at least 3 hours apart (when infant not 
crying). 

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• Treatment for high blood pressure initiated after randomization until status. 
• The number of episodes between randomization and status that infant was placed NPO 
for ≥ 24 hours. 
• The use of anti-reflux medications started between randomization and status 
• The number of days that significant apnea/bradycardia, as defined by documentation of 
infant receiving any of the following between randomization and status: open label 
caffeine, other methylxanthines, doxapram, CPAP or ventilatory support for 
apnea/bradycardia. 
• The presence of documented and treated arrhythmias between randomization and 
status, not due to tachycardia or bradycardia. 
• The onset of documented seizures, as defined by treating with anti-convulsants, 
between randomization and status. 
 
f. Death  
 
Evaluation of infants during the first four weeks, second four weeks, and first eight weeks 
combined after discharge from the hospital is done to determine whether there is a difference in 
post-discharge secondary outcomes on caffeine (first four weeks), off caffeine (second four 
weeks), and in overall outcomes after discharge home (first eight weeks). 
 
A short discussion on the hypothetical cost-savings by the reduction in number of days of 
hospitalization as a financial benefit of the trial’s intervention (caffeine versus placebo) will be 
added to the discussion section of the manuscript at the conclusion of the trial.  
 
Eligibility Criteria  
 
Inclusion Criteria 
 
Inborn and outborn infants of 29 0/7 to 33 6/7 weeks gestational age at birth admitted to hospitals 
of the National Institute of Child Health and Human Development Neonatal Research Network 
(NRN) ≤ 72 hours of age and who at time of enrollment are:  
 
a. 33 0/7 - 35 6/7 weeks post-menstrual age at the time of randomization 
b. Receiving caffeine with plan to discontinue treatment or just discontinued caffeine treatment 
c. Receiving feeds at a volume of >120 ml/kg/day by oral and/or tube feeding 
d. Ability to start study medication within 72 hours after stopping caffeine 
 
Exclusion Criteria 
 
a. On respiratory therapy (oxygen more than room air equivalent for high altitude sites, nasal 
cannula, continuous positive pressure ventilation, and/or mechanical ventilation). 
b. Infants who would otherwise be discharged home on apnea monitor due to underlying 
disease or family history, including history of a sibling with sudden infant death syndrome 
c. Parental request for apnea monitor  
d. Congenital heart disease other than atrial septal defect, ventricular septal defect, or patent 
ductus arteriosus 

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e. Neuromuscular conditions affecting respiration 
f. Major congenital malformation and/or genetic disorder 
g. Plans to transfer to a non-NRN site before discharge 
h. Unable to obtain parental or guardian consent 
 
Study Intervention/Methods  
 
Study subjects will be patients in the NICU at one of the participating hospitals at a Neonatal 
Research Network site. Infants who meet the eligibility criteria will be randomized to either 
caffeine citrate at 10 mg/kg/dose (5 mg/kg caffeine base) or a placebo (equal volume of all the 
excipients except for the active ingredient, caffeine citrate) to be given daily, not less than 12 
hours between doses, beginning within 72 hours of open label caffeine discontinuation. The 
infant may still require hospitalization for observation after discontinuation of open label 
caffeine or for other discharge issues such as temperature control or feeding tolerance.  
 
Infants who will continue caffeine citrate or placebo at home for the first 28 days after hospital 
discharge, will have a weight obtained within 48 hours of discharge to be used for dosage 
calculation. On the day of discharge, the parent will be supplied with 28 numbered vials with 
oral caffeine citrate (intervention group) or placebo at an equivalent volume (placebo group).  
Oral syringes will be provided to the parents to draw up doses.  The parents will be educated by 
the research nurse, discharge nurse, physician, or pharmacist on storage and administration of 
study medication. A member of the research team will contact the parents to obtain post-
discharge information within 72 hours after discharge, once a week for the first 4 weeks, and 
biweekly during the weeks 5 to 8 after discharge.  
 
Sample Size  
 
To obtain a two-day difference in the outcome of median number of days of hospitalization after 
randomization, from 14 days to 12 days, with a power set at 90%, a significance of 0.05, and an 
attrition of 5%, the trial would require 587 infants per group for a total of 1174 infants.  At 80% 
power, the trial would require 479 infants per group for a total of 878 infants. The minimum 
required sample size for this trial will be 878 (439 in each treatment group), but enrollment will 
continue until either the presently-acquired supply of study drug is exhausted or expires in 
approximately August 2023 (accounting for full in-hospital and post-discharge follow-up), 
whichever comes first. The Neonatal Research Network gathers data on approximately 3000 
moderately preterm infants a year, with approximately 1000 treated with caffeine.  
 
Effect Size 
(days) 
Significance 
Power (%) 
Attrition (%) 
Sample Size 
14 to 10 
0.05 
80 
5 
226 
14 to 10 
0.05 
90 
5 
302 
14 to 12 
0.05 
80 
5 
878 
14 to 12 
0.05 
90 
5 
1174 

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SECTION 2. 
CONFLICT OF INTEREST DISCLOSURES 
Per Title 42, Code of Federal Regulations, Part 50, Subpart F (50.604 Responsibilities of 
Institutions regarding Investigator financial conflicts of interest), as amended, institutions and all 
sub-recipients are required to notify the grants officer of any financial conflicts of interest 
(FCOI) prior to expenditure of any funds and within 60 days of any subsequently identified 
FCOI. 
 

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SECTION 3. 
STATEMENT OF PROBLEM 
3.1. 
HYPOTHESES 
 
3.1.1. Primary Hypothesis 
The primary hypothesis is that in moderately preterm infants with resolved apnea of prematurity 
(AoP), continuing caffeine treatment compared to placebo will decrease the number of days of 
hospitalization from randomization to discharge up to 48 weeks post-menstrual age (PMA), with 
censoring at time of transfer or death.  AoP is a leading cause of prolonged hospitalization in 
these infants and, therefore, it is expected that caffeine therapy will shorten hospitalization. 
 
3.1.2. Secondary Hypotheses 
In moderately preterm infants with resolved AoP, continuing caffeine therapy for 28 days after 
hospital discharge compared to placebo will: 
 
a. decrease the number of days to reach physiologic maturity from randomization to discharge 
up to 48 wks PMA. 
b. decrease the number of readmissions to the hospital related to apneic or apparent life-
threatening events as well as all-cause readmissions within the first four weeks, second four 
weeks, and first eight weeks combined after discharge from the hospital by 48 wks PMA. 
c. decrease the number of sick visits related to apneic or apparent life-threatening events as well 
as all-cause sick visits to urgent care, emergency rooms, or health care providers within the 
first four weeks, second four weeks, and first eight weeks combined after discharge from the 
hospital by 48 wks PMA. 
d. be safe for continuing caffeine during the hospitalization and after discharge home without 
an increase in side effects or adverse events 
e. decrease the number of days of hospitalization from randomization to discharge, leading to a 
hypothetical cost-savings as a financial benefit of the trial’s intervention  
  
3.2. 
SPECIFIC AIMS 
 
3.1.3. Primary Specific Aim 
To evaluate the effect of continuing treatment with caffeine citrate in the hospital on number 
of days of hospitalization from randomization to discharge up to 48 wks PMA, with 
censoring at time of transfer or death. 
 
3.1.4. Secondary Specific Aims 
a. To evaluate the effect of continuing treatment with caffeine citrate in the hospital on number 
of days to reach physiologic maturity from randomization to discharge up to 48 wks PMA. 

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b. To evaluate the effect of treatment with caffeine until 28 days after hospital discharge on all-
cause readmissions to a hospital (including apneic and/or apparent life-threatening events) 
within the first 8 weeks after discharge by 48 wks PMA. 
c. To evaluate the effect of treatment with caffeine until 28 days after hospital discharge on the 
number of all-cause sick visits to urgent care, emergency rooms, or health care provider’s 
office (including apneic and/or apparent life-threatening events) within the first 8 weeks after 
discharge by 48 weeks PMA. 
d. To evaluate the side effects and adverse events of caffeine continuation in the hospital and 
after discharge up to 4 weeks post study drug administration. 
e. To assess the hypothetical cost-savings by the reduction in number of days of hospitalization 
as a financial benefit of the trial’s interventions.   
 
3.3. 
BACKGROUND 
 
AoP is a common diagnosis in moderately preterm infants, most exhibiting clinical signs of AoP 
as defined by the American Academy of Pediatrics [cessation of breathing for ≥ 20 seconds or < 
20 seconds if accompanied by bradycardia and/or cyanosis in infants <37 weeks gestational age 
(GA)]1.  Moderately 
preterm infants comprise 
one fourth of NICU 
admissions2,3. In a 
retrospective cohort study 
of moderately preterm 
infants, 92% (23/25) were 
diagnosed with AoP at 30 
weeks post-menstrual age 
(PMA). Even at 33 weeks 
PMA, 48% (59/122) of 
infants had AoP4, and 
apnea may persist beyond 
37 weeks, even until ~44 
weeks PMA5,6. PMA at the 
time of resolution of apnea 
is inversely proportional to 
the GA at birth7,8.  
Although respiratory 
maturation occurs with 
increased PMA4, there is 
uncertainty regarding the 
range of PMA at which 
there is complete resolution 
of AoP. This uncertainty 
can delay discharge, as 
sufficiently mature respiratory 
control is one of the essential 
Figure 1. Lorch SA, Srinivasan L, Escobar GJ. Epidemiology of apnea and 
bradycardia resolution in premature infants. Pediatrics 2011;128:e366-73 

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physiologic competencies before discharge of the infant as recommended by the American 
Academy of Pediatrics9. 
 
There is wide variability in practice among physicians regarding the timing of discharge. In a 
retrospective study of discharge timing that included 435 infants born at 30 to 34 6/7 weeks GA 
and admitted to one of 15 neonatal intensive care units, Eichenwald et al. noted that PMA at 
discharge ranged from 35.2 + 0.5 weeks to 36.5 + 1.2 weeks among the units despite similar 
criteria for discharge including full oral feeds, resolution of apneic episodes, and ability for 
thermoregulation4. In a large observational study, it was shown that even after infants had 
fulfilled other criteria for discharge, 15.8% (222/1403) of infants at 34 weeks’ PMA had 
recurrent apneic episodes7. Although apneic episodes decrease even without treatment with 
caffeine, many infants continue to have apneas many days (observation day on  Figure 1) after 
they are ready for discharge7. An intervention such as caffeine therapy that can decrease apneic 
episodes can potentially shorten the hospitalization of infants who are prone to apnea but 
otherwise ready for discharge. In a retrospective study of 164 infants, 41 (25%) were discharged 
with caffeine citrate continued at home10. The authors did not report any deaths or adverse 
events10. In addition, home caffeine therapy may reduce the number of apneic episodes at home, 
some of which can lead to readmission to the hospital or sick visits to the emergency room, 
urgent care, or health care provider.  
 
For many years, methylxanthines, primarily caffeine citrate, have been used to treat AoP11,12. 
Caffeine acts by inhibiting two of four adenosine receptors13,14 stimulating the infant to breathe 
and reducing apneic episodes12.  Furthermore, methylxanthines improve function of the 
respiratory musculature, including increased diaphragmatic contractions15-17. In multiple trials, 
methylxanthines have been shown to reduce AoP11,18. Caffeine decreases obstructive, central, 
and mixed apnea 19. A recent Cochrane review of five randomized controlled trials that included 
a total of 192 preterm infants indicated that methylxanthine treatment for apnea resulted in less 
treatment failures compared to placebo [RR 0.44 (95%CI 0.32 to 0.60), NNT 3 (95%CI 2 to 4)] 
as well as a decreased use of intermittent positive pressure ventilation [RR 0.34 (95% CI 0.12 to 
0.97), NNT 13 (95% CI 6 to 100)]18.  Tachycardia was the only side effect that was more 
common in the caffeine group18. A double-blind placebo-controlled trial showed that weight gain 
did not differ between intervention and placebo groups19.  In addition, a large randomized 
placebo-controlled trial of prolonged treatment with caffeine in extremely preterm infants 
showed short and long-term benefits of caffeine without evidence of side effects11,20. 
 
Three retrospective cohort studies of caffeine treatment at home for infants at risk for apnea and 
infants with apnea of infancy have been reported10,21,22. The median PMA at last dose of caffeine 
was 34.4 weeks in a large clinical trial11 while in another large multicenter study, the average 
PMA at discharge was 35.7 weeks (encompassing infants born at 30 to 33 weeks GA). This 
illustrates many infants continue to receive treatment late in their hospital course. As apnea can 
still occur past these PMAs, continuing caffeine beyond the usual duration of treatment through 
hospital discharge may decrease late episodes of apnea that occur in the hospital. Often, these 
late apneas can prolong hospital stay due to an additional period of monitoring for further apnea. 
In addition, continuation of caffeine beyond hospital discharge may prevent complications from 
AoP that lead to hospital readmission or unplanned healthcare visits. A trial investigating the use 
of prolonged caffeine citrate treatment would provide high level of evidence and generalizability 

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to determine the effects on length of hospitalization, readmissions, and sick visits in moderately 
preterm infants. The proposed trial will evaluate infants for eight weeks following discharge, 
since infants would have reached at least a PMA of 40 to 44 weeks at the end of the evaluation 
period. Thus, the number of events of apnea and bradycardia should not differ when compared to 
full term infants of the same PMA8,15,23. This is the reasoning for the eight week evaluation 
period following hospital discharge. 
 
3.4. 
Justification for the Study 
 
Moderately preterm infants represent a relatively large group of neonates who require admission 
to the NICU, but discharge can be delayed by AoP or other factors. According to the American 
Academy of Pediatrics guidelines for hospital discharge of preterm infants, infants must have 
sufficient respiratory control before discharge9, yet half of preterm infants were found in one 
study to continue to have apneic episodes at 33 weeks PMA2. According to a study by 
Eichenwald et al. apnea was one of the two most common factors responsible for prolonging 
hospitalization4.  Historically, there has been a fear of discharging preterm infants home too 
early, as they are at increased risk for continued AoP at home and potentially may experience an 
apparent life-threatening event21 requiring an emergency room visit and readmission related to 
apneic and bradycardic events after discharge. Caffeine treatment is effective in decreasing the 
episodes of apnea11,18. The current practice is to discontinue its use before discharge and evaluate 
for development of apneic episodes but this trial could change this paradigm and shorten 
hospitalization in a safe way by continuing caffeine treatment beyond discharge home.  
 
Apneic episodes frequently recur after discontinuation of caffeine treatment. Hypothetically, 
continuation of caffeine after resolution of apneas would prevent further apneas and allow for 
earlier discharge from the NICU, if other competencies of physiologic maturity have been 
achieved, including temperature regulation and feeding tolerance. Complete maturation of the 
respiratory center does not occur until as late as 44 weeks in preterm infants8. As the average age 
of discharge of moderately preterm infants is between 35 to 37 weeks4, apnea may still occur 
after discharge. Home therapy with caffeine can potentially decrease re-admissions to the 
hospital or sick visits due to AoP. To test these hypotheses, a randomized placebo-controlled trial 
of caffeine is proposed. The aim of this trial is to determine if continuing treatment with caffeine 
citrate in the hospital in moderately preterm infants with resolved apnea of prematurity instead of 
discontinuation of treatment in the hospital decreases hospital days. We will also determine if 
continuing caffeine at home decreases apneic episodes that may occur after discharge. The 
results of the trial could potentially transform how AoP is managed in moderately preterm 
infants during hospitalization as well as following discharge.  
 
A trial of continuing and discharging infants on home caffeine therapy is novel, but in several 
small retrospective reviews10,21,22 and a multicenter observational study4, a minority of the 
infants were discharged on methylxanthine treatment. However, there are no data on the 
effectiveness and safety of late hospital and home methylxanthine treatment. The proposed trial 
will be the first of its kind and will help determine if this management strategy is beneficial and 
safe.   
   

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To be able to carry out this multicenter trial, there is need to enroll a large number of moderately 
preterm infants. Approximately 3000 preterm infants of this gestational age group are admitted a 
year to the NRN NICUs, with approximately one-third receiving caffeine treatment. Given the 
vast experience of the study-site principal investigators in multicenter trials as well as the 
research infrastructure, with research nurses and pharmacists, we believe that the NRN is 
particularly suitable to successfully perform this multicenter trial. 
 
Potential challenges in performing this trial include: 
a. The administration of study medication at home by the parents without frequent missed doses  
b. Loss to follow up 
c. Inaccurate or missing information regarding re-admission to the hospital or to sick visits 
d. Inaccurate data collection on follow-up forms provided by the parents 
e. Side effects from the study medication  
 
The trial will be approved by each institutional review board (IRB). Parental consent will be 
obtained for each infant enrolled. Safety is of upmost importance and will be monitored by the 
Data Safety Monitoring Committee (DSMC) when 25%, 50%, and 75% of the subjects complete 
the eight-week follow up period (or are lost to follow up). The trial will record side effects and 
adverse events will be reported to the DSMC periodically. Expedited serious adverse events will 
be reported per local IRB guidelines and to the NICHD and NRN Data Coordinating Center at 
RTI. 
 

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SECTION 4. 
STUDY DESIGN 
4.1. 
PRIMARY OUTCOME 
 
The primary outcome of the study will be the number of days of hospitalization from 
randomization to discharge up to 48 weeks PMA, with censoring at time of transfer or death.  
 
4.2. 
SECONDARY OUTCOMES 
 
The secondary outcomes of the study will be: 
 
a. The number of days to physiologic maturity after randomization up to 48 wks PMA. 
Physiologic maturity will be defined as follows: 
i. 
Temperature: out of the incubator for at least 48 hours with normal body temperature 
ii. 
Feeding: oral feeding at a volume of at least 140 ml/kg for 48 hours or growing on less 
than 140 ml/kg/day for at least 48 hours  
iii. 
Respiratory: apnea-free for at least 5 consecutive days 
 
b. Post-menstrual age (PMA) at discharge up to 48 wks PMA, censoring at time of transfer or 
death (status). 
c. The number of all-cause readmissions, including apneic events and apparent life-threatening 
events (ALTE), to the hospital within the first four weeks, second four weeks, and first eight 
weeks combined after discharge from the hospital by 48 wks PMA.   
An apparent life-threatening event is defined by the American Academy of Pediatrics as 
an event that is perceived by the observer as life-threatening. This event can include 
apnea, color change (cyanosis), profound change in muscle tone (hypotonia), gagging, 
and/or choking24. 
d. The number of all-cause sick visits, urgent care, emergency rooms, or health care provider’s 
office, within the first four weeks, second four weeks, and first eight weeks combined after 
discharge from the hospital by 48 wks PMA.  
e. Safety measures pre-hospital discharge  
a. Weight gain from randomization until status (discharge up to 48 wks PMA, with 
censoring at time of transfer or death). The weight gain may also be assessed 
using percentiles including birthweight percentiles. 
b. The number of days after randomization until status that infant had at least two 
consecutive heart rates >200 documented at least 3 hours apart (when infant not 
crying). 
c. Treatment for high blood pressure initiated after randomization until status. 
d. The number of episodes between randomization and status that infant was placed 
NPO for ≥ 24 hours. 
e. The use of anti-reflux medications started between randomization and status 
f. The number of days that significant apnea/bradycardia, as defined by 
documentation of infant receiving any of the following between randomization 
and status: open label caffeine, other methylxanthines, doxapram, CPAP or 
ventilatory support for apnea/bradycardia. 

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11 
g. The presence of documented and treated arrhythmias between randomization and 
status, not due to tachycardia or bradycardia. 
h. The onset of documented seizures, as defined by treating with anti-convulsants, 
between randomization and status 
f. Death 
 
Apnea of prematurity (AoP) is defined by the AAP as cessation of breathing for ≥ 20 seconds or 
< 20 seconds if accompanied by bradycardia and/or cyanosis in infants <37 weeks GA24. 
However, individual study sites may vary in its definition, and for purposes of the study the 
diagnosis of AoP will be determined by the attending neonatologists in each hospital (apnea 
countdown as per local practice pre-specified for each hospital) and by the attending 
neonatologist on each specific infant.  For the purposes of this study, significant apnea episodes 
are defined as apnea events receiving treatment ordered by the attending physician (e.g. re-
starting caffeine, not just stimulation for example).  
 
Evaluation of infants during the first four weeks, second four weeks, and first eight weeks 
combined after discharge from the hospital is done to determine whether there is a difference in 
secondary outcomes on caffeine (first four weeks after discharge), off caffeine (second four 
weeks after discharge), and in overall outcomes after discharge home (first eight weeks after 
discharge). 
 
A short discussion on the hypothetical cost-savings by the reduction in number of days of 
hospitalization as a financial benefit of the trial’s intervention (caffeine versus placebo) will be 
done at the conclusion of the trial. 
 
4.3. 
STUDY INTERVENTION 
 
We propose enrolling moderately preterm infants who are between 33 0/7 and 35 6/7 weeks GA 
(inclusive) who are being treated with caffeine for AoP and for whom plans are to discontinue 
caffeine. Once the infant has been screened for eligibility, consented, and the neonatologist has 
determined that caffeine will be stopped, infants will be eligible to be randomized if they can be 
started on the study medication within 72 hours after stopping caffeine. They will be randomized 
either to continuing caffeine citrate at a dose of 10 mg/kg/dose (5 mg/kg caffeine base) given 
daily (treatment group) or an equal volume of  placebo given daily (placebo group), not less than 
12 hours between doses, to continue during the hospital stay and for 28 days after hospital 
discharge. In-hospital dosages will be adjusted weekly based on weight. Post-discharge dosage 
will be based on weight obtained within 48 hours of discharge. 
 
Trial Arms 
Trial Intervention 
Intervention Group 
Caffeine  
Caffeine citrate 10 mg/kg/day given once 
daily until 28 days after discharge  
Control Group 
Placebo 
Placebo contains all of the excipients except 
for the active ingredient, caffeine citrate (a 
volume equivalent to 10 mg/kg of caffeine 
citrate) given once daily for 28 days after 
discharge.  

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12 
 
The trial medication (caffeine citrate or placebo) will be weight-adjusted on a weekly basis until 
discharge. An apnea countdown will be done as per local practice before discharge. The duration 
of this countdown will be site dependent but pre-specified. Many infants may require 
hospitalization for observation after resolution of the apneas because of other discharge issues 
such as temperature control or feeding tolerance. If the attending neonatologist decides that re-
initiation of open-label caffeine is clinically indicated, caffeine/placebo treatment per 
randomization will be put on hold until the physician decides to discontinue open label caffeine 
at which time, the infant will be treated as per randomization within 24-72 hours after open label 
caffeine is stopped. Infants on study medication who are still in the hospital at 44 weeks PMA 
will have the caffeine/placebo discontinued.  
 
Prior to discharge, a weight obtained within the last 48 hours will be used to determine the post-
discharge dosage for those infants continuing with caffeine citrate or placebo at home. Once 
deemed ready for discharge, the parent will be supplied with 28 numbered vials with oral 
caffeine citrate (intervention group) or placebo at an equivalent volume (placebo group). The 
parents will be educated by the research nurse, discharge nurse, physician, or pharmacist on 
storage and administration of study medication. Infants will be continued at home on the same 
dose of caffeine citrate or placebo for the first 28 days after hospital discharge. A member of the 
research team will contact the parents to obtain post-discharge information within 72 hours after 
discharge, once a week for the first 4 weeks, and biweekly during the weeks 5 to 8 after 
discharge.  
 
4.4. 
BLINDING/MASKING 
 
Caffeine citrate therapy or placebo, depending on the randomized treatment allocation, will be 
prepared by the study pharmacist for administration in the NICU.  Study pharmacist will prepare 
daily doses of study drug (caffeine or placebo) for administration while in the hospital. At 
discharge, study pharmacist will dispense a 28-day supply of either caffeine or placebo vials for 
home administration.  All other research staff and all health care staff and family members will 
be blinded to the treatment allocation. The study medication can be prepared by the research 
pharmacist within 48 hours of anticipated discharge date.  
 
4.5. 
POTENTIAL RISKS AND BENEFITS TO SUBJECTS 
 
4.5.1. Current Standard of Care 
 
AoP is quite common in premature infants; 50% to 90% of infants with GA in the range of the 
proposed trial have AoP4. A review of 100 infants in the NICU at University of Alabama at 
Birmingham showed that 37% of infants within this cohort were treated with a methylxanthine. 
This is similar to Neonatal Research Network data from the Moderately Preterm Cohort Study, 
which showed that approximately one-third of infants received caffeine therapy. AoP can lead to 
intermittent hypoxemia, and if prolonged, can precipitate bradycardia and hypotension, which 
may lead to hypoxic-ischemic neurological injury25,26.  
 
 

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Initiating Caffeine Therapy  
 
Currently, infants of 29 0/7 to 33 6/7 weeks GA at birth are admitted to the NICU. There is some 
variation in the practice of treatment with caffeine for preterm infants. Caffeine treatment may be 
started prophylactically upon admission for some preterm infants. Data from the Cochrane meta-
analysis showed no differences in outcomes between prophylactic caffeine and placebo12. 
Another practice is to administer caffeine in preparation for extubation. This method was shown 
to reduce extubation failure (RR 0.48, 95% CI 0.32 to 0.71) within a week27. In general, multiple 
studies have shown the benefit of caffeine therapy in decreasing apneic episodes11,12,18,25-27. 
Therefore, the common practice is to give caffeine treatment to preterm infants who have apnea 
thought to be due to prematurity.  
 
Discontinuing Caffeine Therapy 
 
There is a wide variation in practices for discontinuing caffeine therapy. Caffeine has a half-life 
of approximately 4 days (~100 hours) in preterm infants28,29. After an infant no longer has apneic 
episodes for a variable amount of time, neonatologists opt to discontinue caffeine. Most 
neonatologists will observe infants in the hospital for at least five days following discontinuation 
of caffeine treatment, and this has been incorporated into this trial protocol.   
 
Discharge Home 
 
The American Academy of Pediatrics guidelines deem preterm infants ready to be discharged 
once they have achieved three main competencies: the ability to grow on full oral feeds, the 
ability to maintain body temperature in a simulated home environment, and sufficient maturity of 
respiratory control to allow for safe discharge9. However, even with these guidelines, there is 
still a wide variety of practice regarding discharge. In addition, although most infants have 
caffeine discontinued, there is still a subset of infants that are discharged home on caffeine. In a 
multicenter study by Eichenwald et al, 6% of infants aged 30-33 weeks PMA were discharged on 
methylxanthine treatment4. This trial will help answer whether the practice of discharging 
moderately preterm infants on caffeine shortens hospitalization and reduces readmissions and 
sick visits and whether other aspects of physiologic maturity are responsible for delays in 
discharge.  
 
4.5.2. Risks 
 
Neofax, a pharmaceutical reference source, includes side effects of caffeine citrate such as 
vomiting and restlessness, as well as functional cardiac symptoms, all based on low level of 
evidence studies32. In two randomized-controlled trials, the frequency of side effects between 
infants receiving caffeine and those in the placebo group did not differ11,19. Data on these 
measures are not collected usually in clinical care or trials so we will not collect them.  
 
In the largest caffeine trial to date, the Caffeine for Apnea (CAP) trial, decreased weight gain 
was reported in the caffeine group as compared to the placebo group in the first days of 
treatment. However, weight gain during the hospitalization did not differ between caffeine and 
placebo group infants11. In a recent large, randomized controlled trial of high-dose (caffeine 

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citrate 20 mg/kg, twice the dose planned for this trial) versus normal-dose caffeine (caffeine 
citrate 5 mg/kg), tachycardia was more frequent but still relatively uncommon occurring in 4% in 
the high-dose group. There was no difference in any other adverse effects between groups 
including feeding intolerance despite the use of doses much higher than those that will be used in 
the current trial33. Serious toxicity has been noted in patients who have inappropriately received 
overdoses of caffeine with blood levels exceeding 50 mg/L34 but are rare with correct dosing. 
The most recent Cochrane meta-analysis did not include an analysis of side effects related to the 
use of methylxanthines12.  
 
A small study of 16 premature infants evaluating the effects of caffeine citrate on cerebral blood 
flow showed that giving high doses (25 mg/kg/day; base 12.5 mg/kg caffeine) decreased cerebral 
blood flow as measured from the internal carotid artery, with a reduction of 17 % and 22% at 1 
hour and 2 hours post administration of caffeine, respectively10. Another study corroborated the 
findings of decreased cerebral blood flow with high doses but showed that at a dose of 10 
mg/kg/day or less of caffeine citrate there was no effect on cerebral blood flow35. The large 
Caffeine for Apnea trial which used doses up to 10 mg/kg/day showed that neurodevelopmental 
impairment was reduced with caffeine treatment21. The proposed trial will be using caffeine 
citrate doses of 10 mg/kg/day so there is no concern regarding alteration of cerebral blood flow. 
 
Premature infants are being discharged at an average PMA of approximately 36 weeks, 
according to a large multicenter study4. Although the majority of infants have resolution of apnea 
by 40 weeks PMA, some studies suggest late resolution of apneas, up to approximately 44 weeks 
PMA (accounting for maturation of the respiratory center)5,6. There is a possibility that sub-
clinical apneic episodes may occur at home and could potentially lead to re-admissions to the 
hospital or sick visits. This risk will be evaluated as a secondary outcome in the proposed trial. 
 
The review of the literature did not show increased risk of death from administration of caffeine 
citrate11,18. Infants enrolled in this trial will have the timing of discharge determined by the 
attending neonatologist. The trial will not deviate from the local practices in determining 
discharge criteria or discharge timing.  
 
Infants that qualify for this study are at increased risk for death, disability, and/or poor 
neurodevelopment given their underlying prematurity. They are also at risk for developing other 
conditions related to prematurity including but not limited to apnea, bradycardia, respiratory 
distress syndrome, intracranial hemorrhage, retinopathy of prematurity, feeding intolerance, 
infection, and bronchopulmonary dysplasia. These are existing risks of prematurity regardless of 
whether they participate in this study or not. 
 
We do not anticipate an increase in the risk of death or adverse outcomes for infants receiving 
either of the treatments provided in this study over and above those risks seen historically in 
similar infants. There may, however, be other unknown serious risks or risks associated with 
being in this study that we do not anticipate at this time.  
 
Infants and their families may experience stress and emotional distress from their time in the 
NICU and participation in the trial. There is a potential loss of confidentiality should the patient 
information be lost, stolen, or inadvertently distributed. 

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4.5.3. Benefits 
 
The American Academy of Pediatrics Committee on Fetus and Newborn supports a shorter 
hospital length of stay, as it benefits the family and infant, allowing for less separation as well as 
possibly decreasing the risk for hospital-acquired infections9. However, due to the uncertainty in 
the timing of resolution of apneic episodes in preterm infants, it is challenging for neonatologists 
to know when to discontinue caffeine and discharge patients home. A common problem is that 
even after infants have fulfilled other criteria for discharge, such as thermoregulation and full 
oral feeds, apnea may still be present and can prolong hospitalization, as was illustrated in a 
study where 15.8% (222/1403) of infants at 34 weeks’ PMA continued to have recurrent apneic 
episodes as the only reason for remaining hospitalized7.  
 
A potential benefit of trial participation and randomization to the Caffeine arm is that there may 
be fewer episodes of apneas in the NICU and the infant may be able to be discharged home 
earlier than those infants who receive placebo. This decreases the time that parents are stressed 
with a hospitalized infant as well as potentially decreasing the risk of intra-hospital acquired 
infections. In addition, with the administration of caffeine at home, there is the possibility of 
reducing apneic episodes that could lead to readmissions to the hospital or require sick visits to 
the health care provider, urgent care, or emergency room with further evaluation with x-rays and 
blood sampling. Also, the Caffeine for Apnea trial showed the benefits of caffeine use as it 
relates to patent ductus arteriosus, with a reduction in both medical (29.3% vs. 38.1%) and 
surgical (4.5% vs. 12.6%) treatment 11.  
 
Another potential benefit of the proposed trial would be the reduction of intermittent desaturation 
events in the infants continuing caffeine treatment. Intermittent desaturations, regardless of 
apneic episodes, may be related to neurodevelopmental impairment in premature infants36,37 as 
well as the development of retinopathy of prematurity38. A recent small randomized controlled 
trial compared the use of prolonged caffeine citrate versus no caffeine in infants between 34 and 
37 weeks GA to reduce intermittent desaturations. Infants of 35 weeks and 36 weeks GA in the 
caffeine group had a reduction in episodes of desaturations below 90% by 52% (95% CI, -70% 
to -22%) and 46% respectively (95% CI, -65% to -11%)39 but there was no reduction in 
desaturations from 37 weeks and beyond.  
 
This trial is testing caffeine treatment, which is used in NICUs throughout the world, with the 
main difference being the timing of discontinuation of treatment. As such, the subjects may 
receive no direct benefit from participating in this study. 
 
Infants receiving one treatment may have improved outcomes over those seen in the other 
treatment group. We do not know which treatment group will or will not show improvement and 
it is possible that the outcomes will be the same for the two treatment groups.  

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SECTION 5. 
METHODS 
5.1. 
STUDY POPULATION 
 
5.1.1 Inclusion Criteria  
 
Inborn and outborn infants of 29 0/7 to 33 6/7 weeks GA at birth and admitted to hospitals of the 
National Institute of Child Health and Human Development Neonatal Research Network ≤ 72 
hours of age will be eligible if they meet all of the following inclusion criteria at time of 
enrollment: 
 
a. 33 0/7 - 35 6/7 weeks PMA at the time of randomization 
b. Receiving caffeine with plan to discontinue treatment or just discontinued caffeine treatment 
c. Receiving full feeds (defined by a volume of >120 ml/kg/day) by oral and/or tube feeding 
d.   Ability to start study medication within 72 hours after stopping caffeine, 
 
5.1.2 Exclusion Criteria  
 
Any of the following criteria will exclude an infant from the trial: 
 
a. On respiratory therapy (oxygen more than room air equivalent for high altitude sites, nasal 
cannula, continuous positive pressure ventilation, and/or mechanical ventilation) 
b. Infants who would otherwise be discharged home on apnea monitor due to underlying 
disease or family history, including history of a sibling with sudden infant death syndrome 
c. Parental request for apnea monitor  
d. Congenital heart disease other than atrial septal defect, ventricular septal defect, or patent 
ductus arteriosus 
e. Neuromuscular conditions affecting respiration 
f. Major congenital malformations and/or genetic disorders 
g. Plans to transfer to a non NRN site before discharge 
h. Unable to obtain parental or guardian consent 
 
5.2. 
DETAILED STUDY PROCEDURES 
 
5.2.1. Screening and Consent 
 
Initially, the research nurses, coordinators, and physicians will identify all infants born between 
29 0/7 and 33 6/7 GA at birth. Consent can be obtained at any time. Evaluation for enrollment in 
the trial will be done once there are plans to discontinue caffeine treatment and the infant is 
between 33 0/7 and 35 6/7 weeks PMA (inclusive). Parents or a legal guardian of the infant who 
meets all the inclusion criteria and does not meet any of the exclusion criteria will be approached 
by the research nurse, coordinator, and/or physician for written informed consent. Infants who 
are deemed to require apnea monitoring at home after enrollment has occurred will be allowed 
its use and this will be noted on the Follow-up form.  
 
 

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5.2.2. Randomization Procedures 
 
When the attending neonatologist has discontinued clinical caffeine on an eligible and consented 
infant that is 33 0/7 - 35 6/7 weeks PMA, the infant can be randomized if it is possible to start 
study medication within 72 hours after stopping caffeine.   
 
Infants will be randomized 1:1 using a stratified permutated block design with a centralized 
procedure. Infants will be stratified by study center into two GA groups; infants born at 29 to 30 
6/7 weeks GA and 31 to 33 6/7 weeks GA. Randomization will occur through the Data 
Coordinating Center of RTI International (Research Triangle Park, North Carolina). Treatment 
allocation will be revealed only to the research pharmacy staff, who will prepare either caffeine 
citrate at 10 mg/kg (base of 5 mg/kg) or an equivalent volume of placebo to be administered 
once a day. The dosage will be based on the weight closest to randomization and then adjusted 
weekly for weight. Because both caffeine and placebo are colorless, they are indistinguishable 
and, therefore, blinding will be accomplished for all care providers and research staff. 
 
The oral delivery should begin as soon as clinically possible.  
 
Randomization of twins and higher order multiples (when eligible) will be done separately.  
 
5.2.3. In-hospital Procedures 
 
Study subjects are infants in the NICU at one of the principal or associated sites of the NRN. 
Once the attending physician has discontinued caffeine therapy, the infant will be randomized as 
described in section 5.2.2. The research pharmacist will be notified of enrollment and the infant 
will receive a once-a-day dose of caffeine citrate at 10 mg/kg/dose (5 mg/kg caffeine base) as 
part of the treatment group or receive placebo at the same volume and time every 24 hrs and not 
given less than 12 hours apart. The doses will be weight adjusted on a weekly basis. If the infant 
is later put NPO, the oral caffeine citrate or placebo will be held until feeding resumes and at the 
discretion of the attending neonatologist. 
 
In-hospital apnea and bradycardia events will be monitored using individual study site monitor 
devices. There are no universal definitions for apnea and bradycardia and therefore, diagnoses of 
these will be left at the discretion of each hospital group of neonatologists (pre-specified) and the 
neonatal team caring for the infant. The data on apnea and bradycardia will be used to determine 
physiologic maturity and for the local decision about discharging the babies home. The 
definitions of apnea and bradycardia will be decided locally.  However, for the purposes of this 
study, significant apnea/bradycardia will be defined as apnea/bradycardia events receiving 
treatment. Treatment is defined as ordered by the attending physician (e.g. re-starting caffeine, 
not just stimulation for example). Using local definitions will increase generalizability and 
interfere less with local decision making.  
 
Data will be collected from the infant's electronic or physical chart. The number of infants who 
receive CPAP, mechanical ventilation, and/or open label caffeine, other methylxanthine or 
doxapram for the treatment of apnea/bradycardia after randomization will be noted for the study.  
 

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The protocol will allow for individual study site centers to use their own discharge criteria, but 
for the purposes of the definition of secondary outcome of the trial, infants must have reached 
physiologic maturity, which includes a) out of an incubator for at least 48 hours, b) oral feeding 
at volume of at least 140 ml/kg/day or growing on less than 140 ml/kg/day for at least 48 hours, 
and be apnea-free for at least 5 consecutive days. Infants who are still in the hospital at 44 weeks 
PMA will have the study medication (caffeine/placebo) discontinued. Analysis will be done by 
intention to treat. If an infant is discharged before meeting the definition of physiologic maturity, 
it will be noted for analysis at the conclusion of the trial. The weight within 48 hours of 
discharge will be used for the caffeine/placebo home administration. The dose will not be 
adjusted for weight gain after discharge. The practice of discharging infants home on open-label 
caffeine will not be a part of the trial. However, should it occur, it will be noted as a protocol 
deviation and will be noted for subsequent analysis. 
 
Prior to discharge, a research nurse, physician, or pharmacist will educate the parents on storage 
and administration of the medication to the infant. Other instructions to the parents include 
preparation of daily dose and if a dose is missed, it may be given at any time on that day if the 
dose can be given at least 12 hours before the next day’s dose is due. If it was not given at all, the 
parents will be instructed to discard the entire vial that was missed and record it on the 
medication form. If an infant spits or vomits after a dose is given, another dose should not be 
given on the same day. Follow-up forms (Medication and Follow up Forms) will be supplied to 
allow the parents to keep track of daily medication administration and missed doses. The parent 
will be given a stamped envelope to return the forms to the NRN research coordinator at the end 
of the 8 weeks. If the study site allows for the use of a gift card, it will be mailed to the parent or 
guardian when the documents are returned to the research coordinator. The gift card will 
encourage the family member to return the follow up documents at the end of the 8-week follow 
up period. Because it will be supplied at the end of the study period, it will have no consequences 
to the enrollment or treatment of the infant. In addition, the gift card does not constitute payment 
to the family member for any service provided as part of the trial. 
 
Of note, infants who are deemed to require apnea monitoring at home after enrollment will be 
allowed its use and this will be noted on a follow-up form. Data from the home monitor 
recordings will not be used in the trial. 
 
The NRN research coordinator and staff will obtain maternal demographics data including age, 
race, education, marital status, and parity. In addition, infant data will also be recorded, including 
weight at birth, randomization, and status; length/head circumference at birth and status; date of 
status; date of last apnea episode recorded after randomization; use of CPAP or mechanical 
ventilation; date of last NPO episode lasting >24 hours as well as the number of episodes of NPO 
>24 hours following randomization; date of last orogastric or nasogastric feed; date of last day in 
incubator; dates of initiation and termination of open label caffeine therapy; and information 
related to side effects and adverse events. 
 

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5.2.4. Post-hospital Procedures 
 
Following discharge, the research team will contact the family within 72 hours after discharge, 
once a week for the first 4 weeks, and biweekly during the weeks 5 to 8 after discharge to ensure 
the study medication is being administered adequately and to gather information on doctor or 
hospital visits.  
 
Parents will be given a Health Care Provider Letter. A copy will also be sent directly to the 
Health Care Provider's office. The letter will clearly describe the trial goals and procedures, the 
dose of the study medication, and PI contact information. 
 
 

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SECTION 6. 
ANALYTICAL PLAN 
6.1. 
SAMPLE SIZE AND  AVAILABILITY  
 
To obtain a two-day difference in primary outcome of days from randomization to discharge, 
from 14 days to 12 days, with a power set at 90%, a significance of 0.05, and a 5% attrition, the 
trial would require 587 infants per group (intervention and placebo) for a total of 1174 infants, 
assuming a two-tailed non parametric test comparing median LOS in the two groups. With a 
power set at 80%, under the same assumptions and significance, the trial would require 439 
infants per group for a total of 878 infants. The minimum required sample size for this trial will 
be 878 (439 in each treatment group), but enrollment will continue until either the presently-
acquired supply of study drug is exhausted or expires in approximately August 2023 (accounting 
for full in-hospital and post-discharge follow-up), whichever comes first. There are 
approximately 3000 infants born between 290/7 and 33 6/7 weeks gestation per year in the NRN. A 
review of 100 infants in the NICU at one of the largest centers in the NRN showed that 37% of 
infants within this cohort were treated with a methylxanthine. This is similar to NRN data 
showing that approximately 1000 (one-third) of infants receive caffeine therapy. 
Effect Size 
(days) 
Significance 
Power (%) 
Attrition (%) 
Sample Size 
14 to 10 
0.05 
80 
5 
226 
14 to 10 
0.05 
90 
5 
302 
14 to 12 
0.05 
80 
5 
878 
14 to 12 
0.05 
90 
5 
1174 
 
 
6.2. 
STATISTICAL ANALYSIS PLAN 
 
The primary analysis will compare number of days of hospitalization from randomization to 
discharge, death, transfer or 48 weeks PMA, whichever occurs first between the intervention and 
control groups using median regression controlling for study center and GA group (the two 
stratification factors for this trial). Likewise, the treatment effect for the secondary outcomes 
(number of days to physiologic maturity after randomization, number of readmissions and 
number of sick visits) will be compared using either median regression or a Poisson regression 
model controlling for study center and GA group.  
 
Secondary analyses will evaluate whether other models better fit the distributions for these 
outcomes (for example, survival analysis models for the primary outcome and negative binomial 
or log linear models for the secondary outcomes).  
 
We will examine treatment heterogeneity for the primary outcome by adding interaction terms 
between treatment and study center, as well as treatment and GA group. If any of these 
interaction terms are close to statistical significance (p<0.1), for treatment heterogeneity by study 
center, we will attempt to identify centers where the treatment effect may be different (although 
the statistical power available to conduct such analyses will be fairly limited). If there is 

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indication of treatment heterogeneity by GA group, we will conduct stratified analyses by GA 
group to quantify the treatment effect separately by GA group. 
 
6.3. 
DATA MONITORING PLAN 
 
6.3.1.  Monitoring for Side Effects and Adverse Events 
 
Any infant that develops side effects or minor adverse effects related to the intervention can be 
continued on study medication at the discretion of the attending physician but the event will be 
recorded for the trial. If the infant demonstrates tachycardia of 220 beats per minute for greater 
than 60 minutes, the clinical team should hold the study drug for 24 hours.  If tachycardia 
resolves, the study drug may restart. 
 
Enrolled infants will have their inpatient record reviewed by research coordinators to obtain the 
following data: 
 
• Infant weight: at birth, day of randomization, and status  
• Heart rate: Number of days after randomization until status that there were at least two 
consecutive heart rates documented over 200 bpm (when infant was not crying) at least 3 
hours apart 
• Treatment for high blood pressure initiated after randomization until status 
• Gastrointestinal issues (NPO for more than 24 hours) 
• Use of reflux medications at status 
 
In the largest caffeine trial, the Caffeine for Apnea trial, initial decreased weight gain was 
reported in the caffeine group as compared to the placebo group but with continued caffeine 
treatment, long-term weight gain did not differ between caffeine and placebo group infants11. 
Differences in weight gain from the day of randomization, day of discharge (status), and at the 
infant’s well child visits (e.g. one and/or four week periods discharge) will be monitored 
 
Apnea/bradycardia: 
 
The trial will allow for individual study sites to continue their standard practice, and the 
definition of AoP will be left at the discretion of the neonatology staff treating the infant. If an 
infant develops apnea, treatment will be left at the discretion of the attending neonatologist or 
institution. The etiology of the ensuing event and its management (e.g. CPAP, mechanical 
ventilation, sepsis) will be recorded. Apnea and bradycardia are common in eligible infants even 
with caffeine treatment and will not be considered serious adverse events. 
 
Other complications of prematurity that are not likely to be related to the intervention will also 
be collected following randomization into this trial. These include development of necrotizing 
enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, late onset sepsis, and 
severe retinopathy of prematurity. 
 
In addition, the following data will be obtained from the family during follow-up calls and from 
returned mailed-in forms: 

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• Infant weights at all health care provider visits (well child and sick visits) 
• Reasons for sick visits to the Health Care Provider, urgent care, or emergency room 
• Reasons for admission to the hospital 
• Final diagnosis when discharged from the hospital 
 
A member of the research staff will be available during the day (8 am to 5 pm) for questions 
regarding the study medication and trial. If the infant requires medical attention, it should be 
addressed by the Health Care Provider or emergency medical care staff. The evaluating 
physician should treat the patient's medical needs, regardless of the involvement in the trial. 
Once the patient is stable, if the physician or parent/guardian requires further information related 
to the trial, a member of the research team may be contacted. Information obtained from the trial 
is unlikely to change the immediate care of the patient if sick.  
 
Expedited serious adverse events will be reported per local IRB guidelines, and to the NICHD 
and NRN Data Coordinating Center at RTI.  
 
The trial will record side effects and any study related serious adverse events will be reported to 
the DSMC periodically. Expedited serious adverse events will be reported per local IRB 
guidelines, and to the NICHD and the NRN Data Coordinating Center at RTI. All protocol 
deviations and violations will be reported.  
 
The following detail describes the action to be taken for each adverse event below: 
 
Arrhythmias and seizures 
 
Both arrhythmias (excluding those due to tachycardia or bradycardia) and seizures will be 
considered serious adverse events. Seizures have been reported with overdoses of caffeine 
(multiple doses of 20 mg/kg or more)10,16,17,19 and therefore would be unexpected. However, 
should seizures occur in the hospital, it will be evaluated and managed by individual study site 
policies or attending neonatologist. Infants whose medication is held or stopped based on 
decision made by the attending neonatologist will be included in the analysis as the design 
includes intention to treat analysis. Episodes of arrhythmia (excluding those due to tachycardia 
or bradycardia), seizure, and other unexpected, related serious adverse events will be 
documented for the results of the trial, and the outcome is to be reported to the NICHD and RTI.  
 
Hospitalization, sick visit to urgent care, emergency room or health care provider’s office 
related to apneic or apparent life-threatening event (ALTE)  
 
Hospitalization, sick visit to urgent care, emergency room or health care provider’s office related 
to apneic or apparent life-threatening event (ALTE) will be considered serious adverse events.   
Readmissions to the hospital and sick visits to urgent care, emergency rooms, or health care 
provider’s office related to apneic or apparent life-threatening event (ALTE) within the first 
eight weeks after discharge from the hospital will be collected for the results of the trial, and the 
outcome is to be reported to the NICHD and RTI  
 

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Infants will be monitored prospectively while in the NICU. Interim efficacy and safety will be 
formally evaluated by the independent Data Safety Monitoring Committee as specified in detail 
in Section 6.3.3.2.  
 
6.3.2. Monitoring Drug Adherence and Compliance 
 
Adherence to medication regimens is affected in a multi-factorial manner. A review of 51 studies 
with 19 chronic diseases found a wide range of factors for lack of compliance, falling within 
categories of socioeconomic, patient-related, and therapy-related determinants40. The conclusion 
of this large systematic review points to the use of multiple methods to better attain compliance 
with medications at home.  
 
For this trial, we will combine two recommended methods to assure adequate monitoring and 
improve compliance with medication administration: 
 
a. While the infant remains inpatient, the medication will be administered by the nurse as 
directed and the research nurse will perform a chart review at least twice a week to ensure 
study medication is being received after randomization and prior to discharge. 
 
b.   After discharge: 
 
i. 
A Medication form will be supplied to the parents. This will include a daily item to mark if 
medication was administered. In addition, parents can use this form to record sick visits to 
the Health Care Provider, emergency room, or hospitalizations as well as weights obtained 
during well-child or sick visits and missed doses of study medication. Any new 
medications prescribed will also be noted on this form.  
 
ii. 
A Follow-up form will be supplied. This will be similar to the Medication form, but will be 
used during the second four-week period discharge and will not include a medication 
administration section. Safety outcomes (such as Health Care Provider, Emergency visits, 
and re-admissions to a hospital) will be recorded on this form also.  
 
iii. 
A member of the research team will contact the parents within the first 72 hours after 
discharge to answer questions and assess medication compliance.  
 
iv. 
A member of the research team will contact the parents once a week during the first 4 
weeks and biweekly during weeks 5-8 to address concerns and evaluate medication 
compliance*. During this contact, the parents will be asked about any well or sick visits 
made to the health care provider, urgent care, emergency room, or hospital since the last 
contact and the reason for these visits.     
 
*To assure both safety and compliance, vials will be marked with a number corresponding to the 
beginning day of medication to be administered at home. For example, the next day after 
discharge, the parent is to administer the study drug from the vial marked #1 by oral syringe. The 
following day, the vial marked #2 should be given. This procedure, using an oral syringe, should 
be followed until day 28 after discharge when the last medication vial marked #28 should be 

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given. If a dose is missed, it may be given at any time on that day as long as it is given at least 12 
hours before the next dose is due the next day. If it was not given at all, the parents will be 
instructed to discard the dose that was missed and record it on the medication form. The schedule 
of medication administration will then continue with the next numbered vial. This information 
will be noted for further analysis at the conclusion of the trial. Because of the long half-life of 
caffeine, single missed doses will have little clinical effect. 
 
6.3.3. Statistical Interim Monitoring and Stopping Rules 
 
Statistical interim monitoring for this trial will be conducted by the independent Data Safety and 
Monitoring Committee using data and analyses provided by the NRN Data Coordinating Center 
at RTI. We recommend that the Data Safety and Monitoring Committee meet formally to review 
interim safety, efficacy and futility, as well as other aspects of accruing data (such as enrollment, 
data completeness and protocol compliance) four times during the study, after 100 infants 
complete the eight-week follow up and then roughly after 25%, 50% and 75% of subjects 
complete the eight week follow up. Formal Data Safety and Monitoring Committee reports will 
be prepared by the Data Coordinating Center for these meetings. These reports will include the 
following information: 
 
• Brief summary of the trial design, including primary and secondary hypotheses and  
outcomes, study population, inclusion and exclusion criteria, recruitment, screening, 
randomization and study intervention procedures, and statistical considerations for trial 
design and analysis 
• Interim monitoring plan 
• Enrollment, including screening, consent, randomization and study exit 
• Completeness of data and edit queries. Baseline study population characteristics, overall and 
by treatment group 
• Drug adherence and compliance   
• Primary efficacy outcomes by treatment group 
• Secondary efficacy outcomes by treatment group 
• Safety outcomes, including death, by treatment group 
• Protocol deviations and violations, overall and by treatment group. 
 
These Data Safety and Monitoring Committee reports will be blinded, with treatments labeled as 
group A and group B. As per the NRN Data Safety and Monitoring Committee Charter, the 
DSMC may, however, request to be un-blinded to perform their duties. If the Data Safety and 
Monitoring Committee recommends modification or cessation of the study protocol due to safety 
concerns, NIH will make the final determination. 
 
Interim Safety Monitoring 
Statistical interim safety monitoring will be conducted by the DCC after 100 infants complete the 
eight-week follow up and then after 25% (300), 50% (600), and 75% (900) of the infants 
enrolled complete the eight-week follow up period. Formal safety assessment will be based on 
the number of sick visits, emergency room visits, apparent life-threatening event episodes or 
hospitalizations related to AoP. Relatively liberal Pocock safety bounds based on 5 interim safety 
looks at the data will be constructed to guard against any occurrence of false positives while at 

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the same time allowing for stopping at reasonable levels of evidence. Thus, at each of these 
safety looks, an increased incidence of the above safety events in the Caffeine group with p < 
0.0158 will be considered as statistically significant evidence of harm that the Data Safety and 
Monitoring Committee can use to recommend suspension of the trial for safety reasons. In 
addition to the formal safety outcome, other safety outcomes collected in this trial (see section 
6.3.1) will also be examined by treatment group. If a death occurs in either of the groups, the 
Data Safety and Monitoring Committee will review the cause of death and determine if the cause 
is linked to the study intervention. If it is deemed to be related to the intervention as an increased 
risk, the Data Safety and Monitoring Committee may recommend stopping the trial. After the 
Data Coordinating Center conducts each of these interim safety analyses, it will inform the Chair 
of the Data Safety and Monitoring Committee (or her designee) if there is any suggestion of a 
trend in the safety data. The Data Safety and Monitoring Committee Chair will then determine 
any future course of action, including convening a meeting of the entire panel to discuss the 
safety data. 
 
Interim Efficacy Monitoring 
Statistical interim efficacy monitoring will be conducted by the Data Coordinating Center after 
25%, 50% and 75% of the babies enrolled into the trial complete eight-week follow up period. At 
each of these interim looks, the primary outcome will be compared by (blinded) treatment group 
as per the analysis plan in section 6.2. O’Brien Fleming stopping bounds for efficacy will be 
used to preserve an overall Type-I error rate of 0.05 for the primary outcome. Thus, stopping 
bounds for efficacy will be established if p < 5 X 10-5 at 25%, p < 0.004 at 50% and p < 0.018 at 
75% of interim data accrual. In the event that these stopping bounds are reached, the Data Safety 
and Monitoring Committee may recommend termination of the trial for efficacy. In addition to 
the primary outcome, secondary efficacy outcomes collected in this trial (see section 4.2) will 
also be examined by treatment group. 
 
Interim Futility Monitoring 
Statistical interim futility monitoring will be conducted by the Data Coordinating Center after 
50% and 75% of the babies enrolled into the trial complete the eight week follow up period. At 
each of these two looks, we will estimate conditional power, i.e., the probability to detect a 
statistically significant treatment effect for caffeine, given the observed data and the 
hypothesized treatment effect for the unobserved data. The Data Safety and Monitoring 
Committee may recommend suspension of the trial for futility if this probability is less than 15%. 
In addition to the conditional power analysis, the Data Safety and Monitoring Committee may 
also consider other pertinent aspects included in the interim report such as the quality of the data, 
protocol violations and treatment adherence, rate of enrollment, rate of attrition, in determining 
futility. 
 
SECTION 7. 
FUTURE DIRECTIONS 
This randomized, placebo-controlled, double-blinded, multicenter trial will inform us whether 
giving caffeine citrate throughout hospitalization will allow for decreased length of 
hospitalization of moderately premature infants as designed by an explanatory research method. 
The careful control of research subjects and variables in ideal conditions allows for efficacy in 

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clinical research. Possible future plans for this trial would be to determine if there are any 
differences in the neurodevelopmental outcomes at 22-26 months corrected age and at 5 years of 
age related to the use of prolonged caffeine at home in moderately preterm infants.   
 
SECTION 8. 
DATA SHARING 
Data collected for this study will be analyzed and stored at the Data Coordinating Center, RTI 
International. After the study is completed, the de-identified, archived data will be transmitted to 
the NICHD Data and Specimen Hub (DASH), for use by other researchers including those 
outside of the study. Permission to transmit data to DASH will be included in the informed 
consent. 
 
SECTION 9. 
DATA FORMS  
9.1. 
Screening Log 
9.2. 
Eligibility and Consent Form 
9.3. 
Randomization Form 
9.4. 
Baseline Form 
9.5. 
In-hospital Study Drug Administration Form  
9.6. 
Open Label Treatment for Apnea Form 
9.7. 
Pharmacy Drug Accountability Form 
9.8. 
In-hospital Outcomes Form  
9.9. 
Adverse Events Form  
9.10. Protocol Deviation/Violation Form (S) – Masked and Unmasked Staff 
9.11. Post-discharge Study Drug and Medical Visit Form 
9.12. Post-discharge Status Form 
 

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