Conditions: Apnea of Prematurity
Keywords: Moderate preterm infant Caffeine citrate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 827
Healthy volunteers: no

Brief summary:
The objective of this study is 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.

Detailed description:
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 or placebo (equal volume of all the excipients except for the active ingredient, caffeine citrate) to be given daily 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.

Once deemed ready for discharge, infants will be continued at home on the same dose of caffeine citrate or placebo for the first 28 days after hospital discharge. 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).

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.

Arms:
arm 1: Caffeine citrate at 10 mg/kg/dose (5 mg/kg caffeine base) daily, in hospital. Infants will continue at home on the same dose of caffeine citrate for the first 28 days after hospital discharge. arm 2: Placebo contains all of the excipients except for the active ingredient, caffeine citrate, (a volume equivalent to 10 mg/kg of caffeine citrate) and given daily. Infants will be continued at home on the same dose of placebo for the first 28 days after hospital discharge.

Interventions: intervention 1: Caffeine Citrate intervention 2: Placebo
Intervention descriptions: intervention 1: The study intervention is caffeine citrate given once daily at 10 mg/kg/day. It is given orally, before hospital discharge and 28 days after discharge. intervention 2: The study intervention is placebo given once daily at a volume equivalent to 10 mg/kg of caffeine citrate. It is given orally, before hospital discharge and 28 days after discharge.

Protocol document:
SAP_002.pdf: 
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STATISTICAL ANALYSIS PLAN 
Randomized Controlled Trial of Home Therapy with Caffeine Citrate in Moderately 
Preterm Infants with Apnea of Prematurity 
(NCT03340727) 
 
SAP VERSION: 
1.0 
 
SAP DATE: 
December 12, 2022 
 
SPONSOR: 
NICHD Neonatal Research Network 
 
PREPARED BY: 
RTI International. 
 
 
3040 Cornwallis Rd 
 
 
Research Triangle Park, NC 27709-2104 
 
AUTHOR (S): 
Benjamin Carper 
 
 
Abhik Das 
 
 
 
 
 
 


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Contents 
1 BACKGROUND 
5 
2 PURPOSE OF THE ANALYSIS 
5 
3 STUDY AIMS AND OUTCOMES 
5 
3.1 STUDY AIMS 
5 
3.1.1 Primary Aim 
5 
3.1.2 Secondary Aims 
5 
3.2 OUTCOMES 
6 
3.2.1 Primary Outcome 
6 
3.2.2 Secondary Outcomes 
6 
4 STUDY METHODS 
7 
4.1 OVERALL STUDY DESIGN AND PLAN 
7 
4.2 STUDY POPULATION 
8 
4.3 PARTICIPANT CHARACTERISTICS 
8 
4.4 STUDY ARM ASSIGNMENT AND RANDOMIZATION 
8 
4.5 MASKING AND DATA LOCK 
9 
4.6 GENERAL MASKING PROCEDURES 
9 
4.7 DATABASE LOCK 
9 
4.8 IN-HOSPITAL AND POST-HOSPITAL PROCEDURES 
9 
5 ANALYSIS POPULATIONS 
10 
6 SAMPLE SIZE DETERMINATION 
11 
7 STATISTICAL/ANALYTICAL ISSUES 
11 
7.1 GENERAL RULES 
11 
7.2 ADJUSTMENTS FOR COVARIATES 
12 
7.3 HANDLING OF DROPOUTS AND MISSING DATA 
12 
7.4 INTERIM ANALYSES AND DATA MONITORING 
12 
7.5 MASKED DATA REVIEW 
14 
7.6 MULTICENTER STUDIES 
14 
7.7 MULTIPLE COMPARISONS AND MULTIPLICITY 
14 
7.8 EXAMINATION OF SUBGROUPS 
14 
8 STUDY PARTICIPANT CHARACTERIZATION 
14 
8.1 PARTICIPANT DISPOSITION 
14 
8.2 PROTOCOL DEVIATIONS 
14 
8.3 STUDY DRUG EXPOSURE AND COMPLIANCE 
15 
8.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
15 


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9 EFFICACY ANALYSES 
16 
9.1 OVERVIEW OF EFFICACY ANALYSIS METHODS 
16 
9.2 EFFICACY VARIABLES 
16 
9.3 PRIMARY ANALYSIS METHODS 
18 
9.4 SECONDARY ANALYSIS METHODS 
18 
9.5 EXPLORATORY ANALYSIS METHODS 
18 
10 SAFETY ANALYSES 
18 
10.1 OVERVIEW OF SAFETY ANALYSIS METHODS 
19 
10.2 SAFETY VARIABLES 
19 
10.3 ADVERSE EVENTS 
20 
10.4 DEATHS AND SERIOUS ADVERSE EVENTS 
20 
11 ANALYSIS OF OTHER OUTCOMES 
20 
12 REPORTING CONVENTIONS 
20 
13 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
20 
14 REFERENCES 
21 
15 LIST OF POTENTIAL DISPLAYS 
21 
 
 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation: Deciphered: 
AE 
Adverse Event 
ALTE 
Apparent Life-Threatening Event 
AoP 
Apnea of Prematurity 
BPM 
Beats per Minute 
CPAP 
Continuous Positive Airway Pressure 
DCC 
Data Coordinating Center 
DSMC 
Data Safety and Monitoring Committee 
GA 
Gestational Age 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LOS 
Length of Stay 
NICHD 
National Institute of Child Health and Human Development 
NICU 
Neonatal Intensive Care Unit 
NIH 
National Institutes of Health 
NPO 
Nothing by Mouth 
NRN 
Neonatal Research Network 
PI 
Principal Investigator 
PMA 
Post-menstrual Age 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
 
 
 


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1 BACKGROUND 
Apnea of Prematurity (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)].  Moderately preterm infants comprise one fourth of NICU admissions. 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 AoP, and 
apnea may persist beyond 37 weeks, even until ~44 weeks PMA. PMA at the time of resolution of 
apnea is inversely proportional to the GA at birth.  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 physiologic competencies before discharge of the infant as recommended by the 
American Academy of Pediatrics9. 
 
Three retrospective cohort studies of caffeine treatment at home for infants at risk for apnea and 
infants with apnea of infancy have been reported. The median PMA at last dose of caffeine was 34.4 
weeks in a large clinical trial 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 
thus provide high level of evidence and generalizability to determine the effects on length of 
hospitalization, readmissions, and sick visits in moderately preterm infants. This 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 PMA. This is the reasoning for the 
eight-week evaluation period following hospital discharge. 
2 PURPOSE OF THE ANALYSIS 
This statistical analysis plan (SAP) contains detailed information about statistical analysis to be 
performed 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. 
3 STUDY AIMS AND OUTCOMES 
3.1 Study Aims 
3.1.1 Primary Aim 
To determine efficacy of continuing treatment with caffeine citrate compared to placebo in the 
hospital and at home in moderately preterm infants with resolved apnea of prematurity for the 
reduction in days of hospitalization after randomization. 
3.1.2 Secondary Aims 
1. 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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2. 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. 
3. 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 wks PMA. 
4. 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. 
5. To assess the hypothetical cost-savings by the reduction in number of days of hospitalization as a 
financial benefit of the trial’s interventions.  
3.2 Outcomes 
3.2.1 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.  
3.2.2 Secondary Outcomes 
1. The number of days to physiologic maturity after randomization up to 48 wks PMA. Physiologic 
maturity will be defined as follows: 
a) Temperature: out of the incubator for at least 48 hours with normal body temperature 
b) 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 
c) Respiratory: apnea-free for at least 5 consecutive days 
2. Post menstrual age at discharge up to 48 wks PMA, censoring at time of transfer or death (status). 
3. 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.  
4. 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.  
5. Safety outcome 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, continuous positive airway pressure (CPAP) or ventilatory 
support for apnea/bradycardia. 
g) The presence of documented and treated arrhythmias between randomization and status, not 
due to tachycardia or bradycardia. 


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h) The onset of documented seizures, as defined by treating with anti-convulsants, between 
randomization and status. 
6. Death 
4 STUDY METHODS 
4.1 Overall Study Design and Plan 
This study will enroll moderately preterm infants who are between 330/7 and 356/7 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.  
 
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.  
 
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 


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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, 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. 
4.2 Study Population 
4.3 Participant Characteristics 
The study population is defined by the following eligibility criteria: 
 
Inclusion Criteria: 
1. 330/7 - 356/7 weeks PMA at the time of randomization 
2. Receiving caffeine with plan to discontinue treatment or just discontinued caffeine treatment 
3. Receiving full feeds (defined by a volume of >120 ml/kg/day) by oral and/or tube feeding 
4. Ability to start study medication within 72 hours after stopping caffeine 
 
Exclusion Criteria: 
1. On respiratory therapy (oxygen more than room air equivalent for high altitude sites, nasal 
cannula, continuous positive pressure ventilation, and/or mechanical ventilation) 
2. 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 
3. Parental request for apnea monitor  
4. Congenital heart disease other than atrial septal defect, ventricular septal defect, or patent ductus 
arteriosus 
5. Neuromuscular conditions affecting respiration 
6. Major congenital malformations and/or genetic disorders 
7. Plans to transfer to a non NRN site before discharge 
8. Unable to obtain parental or guardian consent 
4.4 Study Arm Assignment and Randomization 
When the attending neonatologist has discontinued clinical caffeine on an eligible and consented 
infant that is 330/7 - 356/7 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 randomly 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 (DCC) 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 independently. 


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4.5 Masking and Data Lock 
4.6 General Masking Procedures 
This is a double-blind, placebo-controlled clinical trial. As such, neither site staff nor the 
parent/guardians that administer the study drug to the patient will be aware of the treatment 
assignment. Only the research pharmacists at the clinical sites and designated personnel at the DCC 
(Study Manager, Data Manager and Study Statistician) will be unblinded. All clinical caregivers and 
investigators, including the DCC PI will remain masked to the study drug assignment. Any 
intentional or unintentional unmasking will be reported as a protocol deviation in the data 
management system. 
4.7 Database Lock 
The database will be locked after all enrolled infants have completed their post-discharge follow-up, 
died or transferred, or reached 48 wks PMA. Randomization assignment will not be unmasked until 
after database lock is finalized. Data cleaning and edit check may continue after the database lock and 
final versions of the analysis files will be archived. 
4.8 In-hospital and Post-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 hours 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.  
 
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 


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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 to 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. 
 
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.  
5 ANALYSIS POPULATIONS 
Intention-to-Treat Population (ITT) 
The intention-to-treat population will comprise of all randomized participants who have at least one 
efficacy measurement. Participants who receive study drug but do not complete the study will be used 
in all analyses for which data are available. Participants who are withdrawn for further follow-up will 
be treated as lost to follow-up at the time that consent was withdrawn, and data will be used up to the 
time of study withdrawal (unless parents/guardians expressly forbid use of any collected data). 
 


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Safety Population 
The safety population will comprise of all randomized participants regardless of treatment received or 
collection of efficacy information. 
6 SAMPLE SIZE DETERMINATION 
To obtain a two-day difference in the 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 available 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. The following table shows 
scenarios for approximate time to completion of the trial as a function of consent rate and NICHD 
center involvement: 
 
Consent Rate (%) 
Time to Completion (mo), all sites 
Time to Completion (mo), half sites 
50 
24 
48 
60 
20 
40 
70 
18 
36 
80 
15 
30 
 
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 
7 STATISTICAL/ANALYTICAL ISSUES 
7.1 General Rules 
All statistical computations performed and data summaries created will be accomplished using SAS 
9.4 or higher. If additional statistical packages are required, these will be discussed in the study 
report. For summaries of study data, categorical measures will be summarized in tables listing the 
frequency and the percentage of subjects in each study arm; continuous data will be summarized by 
presenting mean, standard deviation, median and range; and ordinal data will be summarized by only 
presenting median and range.   


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7.2 Adjustments for Covariates  
Indicator variables for the study stratification of site and gestational age will be included as covariates 
in most efficacy analyses performed for this study. Additionally, demographic and baseline 
characteristics for subjects will be compared between study arms using analysis of covariance 
techniques for continuous measures, Mantel-Haenszel mean score test using standardized mid-rank 
scores for ordinal measures, and Cochran Mantel-Haenszel chi-square tests for general association for 
categorical measures. If sample sizes allow, these analyses will control for the study stratification 
factors. If these analyses suggest that substantial differences exist among arms, the use as covariates 
of these parameters on which the arms differ will be explored in exploratory analyses of the efficacy 
data. 
7.3 Handling of Dropouts and Missing Data 
Missing data will be monitored in real-time. In the event an assessment or data form is missed, DCC 
staff will contact site coordinators to enter the required information from the in-hospital portion of the 
study as quickly as possible. For the post-hospital data collection, missing data will be queried by 
DCC staff to determine if the site has collected the desired information from the parents/guardians. 
Given that recruitment into the study and the primary outcome are all performed/collected during the 
initial hospital stay, it is not anticipated that there will be any missing data for the length-of-stay 
primary outcome. 
7.4 Interim Analyses and Data Monitoring 
Statistical interim monitoring for this trial will be conducted by the independent NRN Data Safety 
and Monitoring Committee (DSMC) using data and analyses provided by the NRN DCC at RTI. We 
recommend that the DSMC 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 DSMC reports will be 
prepared by the DCC 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 DSMC reports will be blinded, with treatments labeled as group A and group B. As per the 
NRN DSMC Charter, the DSMC may, however, request to be un-blinded to perform their duties. If 
the DSMC recommends modification or cessation of the study protocol due to safety concerns, 
NICHD will make the final determination. 
 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
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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 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 DSMC 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 
DSMC 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 DSMC may recommend 
stopping the trial. After the DCC conducts each of these interim safety analyses, it will inform the 
Chair of the DSMC (or her designee) if there is any suggestion of a trend in the safety data. The 
DSMC 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 DCC 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 using the methods outlined in 
Section 9. 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 DSMC may recommend termination of the trial for efficacy. 
In addition to the primary outcome, secondary efficacy outcomes collected in this trial will also be 
examined by treatment group. 
 
Interim Futility Monitoring 
Statistical interim futility monitoring will be conducted by the DCC 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 
DSMC may recommend suspension of the trial for futility if this probability is less than 15%. In 
addition to the conditional power analysis, the DSMC 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. 
 
Additional Data Monitoring 
Additional monitoring of data for this study will occur in real-time and will include study drug and 
home kit reconciliation with randomization, pharmacy log reconciliation with patient administration 
log, missing and incomplete forms, tracking of primary and secondary outcomes, and reporting of 
protocol deviations and adverse events.  
 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
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Expedited serious adverse events will be reported per local IRB guidelines, and within 24 hours to the 
NRN DCC 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 
within 24 hours to the NRN DCC at RTI. All protocol deviations and violations will be reported.  
 
Infants will be monitored prospectively while in the NICU. Interim efficacy and safety will be 
formally evaluated by the independent DSMC. 
7.5 Masked Data Review 
A masked data review of the primary outcome and secondary outcomes for this study will be 
performed by the protocol team. This review will occur prior to completion of the primary analyses 
prior to any official unblinding. This will include a presentation of descriptive statistics (e.g., means, 
standard deviations, percentiles for continuous variables and counts and percentages of categorical 
variables) of the selected outcomes and model predictor variables. 
7.6 Multicenter Studies 
For this multicenter study, randomization of study participants is stratified within center and by 
gestational age. Consequently, for all model-based primary and secondary analyses, center will be 
included as a fixed effect in the models. As an ancillary analysis associated with the primary 
outcome, we will examine descriptively whether the treatment effect varies across sites; however, no 
other analyses will assess site differences in treatment effect because sample sizes are inadequate to 
support evaluation of site-level effects. 
7.7 Multiple Comparisons and Multiplicity 
The primary hypothesis will be tested at a nominal two-sided type I error of 0.05. All p-values for any 
baseline and demographic characteristic comparisons, secondary outcomes, and safety parameters 
will be for descriptive purposes only. 
7.8 Examination of Subgroups 
Treatment heterogeneity by hospital center, gestational age, and sex will be examined as part of the 
primary analysis. If any interaction effects are determined to be significant, subgroup analysis will be 
performed to assess the treatment effects in the appropriate subpopulations. See Section 9.3 for more 
details.  
8 STUDY PARTICIPANT CHARACTERIZATION 
8.1 Participant Disposition 
Participant eligibility status will be summarized, and overall disposition of study participants will be 
described using a standard CONSORT diagram. The number of participants randomized and those 
completing or discontinuing from study therapy will be summarized. Reasons for study withdrawal 
will be listed. 
8.2 Protocol Deviations 
Protocol deviations will be listed with information such as type of deviation, time of occurrence, and 
reason. Depending on the number of deviations reported, the number of protocol deviations will also 
be summarized overall and for each protocol deviation category.  


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8.3 Study Drug Exposure 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 ensure 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 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. 
8.4 Demographic and Baseline Characteristics 
Demographic and baseline clinical characteristics for the study participants will be summarized by 
study arm using the general analysis rules describe above. Variables of interest include mother 
demographics, gender, gestational age, race and ethnicity, and in-hospital clinical outcomes at the 
time of birth. 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
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9 EFFICACY ANALYSES 
9.1 Overview of Efficacy Analysis Methods 
• 
All efficacy analyses will be performed on the ITT population. 
• 
All efficacy variables will be summarized by treatment group. Count (N), mean, standard 
deviation, minimum, and maximum will summarize continuous efficacy variables (e.g., post-
menstrual age); median, 1st quartile, 3rd quartile, minimum, and maximum will be calculated for 
count efficacy variables (e.g., number of days of hospitalization); whereas number and percent 
will summarize categorical efficacy variables (e.g., death).  
• 
Analyses of the primary outcome are separately discussed in Section 9.3. Analyses of other 
dichotomous outcomes will be performed using robust Poisson regression models, with both log 
and linear link functions, to estimate adjusted relative risks and risk differences. Efficacy models 
will be adjusted for stratification by clinical site and gestational age. Unless otherwise noted, all 
analyses of continuous efficacy variables will be performed using median or robust Poisson 
regression.  
 
Models will be adjusted for clinical site and gestational age. If there are not enough patients per 
clinical site to include the variables in the models as fixed effects, clinical site will be included as 
a random intercept to account for correlation between outcomes of patients treated by the same 
clinical site or similar sites will be combined.  
9.2 Efficacy Variables 
Primary and secondary efficacy variables are described in the table below. 
 
Variable 
Type 
Definition 
Primary Outcome 
Number of days of 
hospitalization 
Count 
The number of days between randomization and 
hospital discharge. This outcome is censored at 48 
weeks PMA and at time of transfer or death 
Secondary Outcomes 
Number of days to 
physiologic maturity 
Count 
Physiologic maturity is defined: 
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 
This outcome is censored at 48 weeks PMA. 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
 Page 17  
 
Variable 
Type 
Definition 
Number of days to 
physiologic maturity - 
Temperature 
Count 
Physiologic maturity is defined: 
i. 
Temperature: out of the incubator for at 
least 48 hours with normal body 
temperature 
This outcome is censored at 48 weeks PMA. 
Number of days to 
physiologic maturity – 
Feeding 
Count 
Physiologic maturity is defined: 
i. 
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  
This outcome is censored at 48 weeks PMA. 
Number of days to 
physiologic maturity - 
Respiratory 
Count 
Physiologic maturity is defined: 
i. 
Respiratory: apnea-free for at least 5 
consecutive days 
This outcome is censored at 48 weeks PMA. 
Post-menstrual age at 
discharge 
Continuous 
The post-menstrual age of the infant at discharge 
censored at 48 weeks PMA and at time of transfer 
or death 
Number of all-cause 
readmissions within first 4 
weeks post-discharge 
Count 
Number of hospital readmissions including apneic 
events and apparent life-threatening events during 
first 4 weeks following hospital discharge. The 
outcome is censored at 48 weeks PMA. 
Number of all-cause 
readmissions within second 4 
weeks post-discharge 
Count 
Number of hospital readmissions including apneic 
events and apparent life-threatening events during 
second 4 weeks following hospital discharge. The 
outcome is censored at 48 weeks PMA. 
Number of all-cause 
readmissions within first 8 
weeks post-discharge 
Count 
Number of hospital readmissions including apneic 
events and apparent life-threatening events during 
first 8 weeks following hospital discharge. The 
outcome is censored at 48 weeks PMA. 
Number of all-cause sick 
visits within first 4 weeks 
post-discharge 
Count 
Number of all cause sick visits, urgent care, 
emergency room, or other non-scheduled/routine 
health care provider office visits during first 4 
weeks following hospital discharge. The outcome 
is censored at 48 weeks PMA. 
Number of all-cause sick 
visits within second 4 weeks 
post-discharge 
Count 
Number of all cause sick visits, urgent care, 
emergency room, or other non-scheduled/routine 
health care provider office visits during last 4 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
 Page 18  
 
Variable 
Type 
Definition 
weeks following hospital discharge. The outcome 
is censored at 48 weeks PMA. 
Number of all-cause sick 
visits within first 8 weeks 
post-discharge 
Count 
Number of all cause sick visits, urgent care, 
emergency room, or other non-scheduled/routine 
health care provider office visits during first 8 
weeks following hospital discharge. The outcome 
is censored at 48 weeks PMA. 
All-cause Mortality 
Categorical 
Demise of Infant 
9.3 Primary Analysis Methods 
For the primary analysis, the number of days of hospitalization between randomization and discharge 
will be compared between the caffeine citrate and placebo groups using either median or robust 
Poisson regression models. The model will include a fixed effect for treatment group. The model will 
also be adjusted for the design effect of stratification by site and gestational age. Estimates, p-values 
and 95% confidence intervals will be presented for treatment group comparisons. In an intent-to-treat 
fashion, all data will be included in the primary model based on their randomized treatment, 
regardless of the treatment administered to the patient. If there are important baseline characteristics 
that differ between randomized treatment groups by chance, additional sensitivity analyses may be 
conducted to evaluate the impact of those imbalances. 
 
We will examine treatment heterogeneity for the primary outcome by adding interaction terms 
between treatment and study center, as well as treatment and gestational age group, and following 
NIH guidelines, treatment and sex. 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 indication of treatment heterogeneity by GA group and/or sex, we 
will conduct stratified analyses by GA group and/or sex to quantify the treatment effect separately by 
GA group/sex. 
9.4 Secondary Analysis Methods 
Secondary outcomes will be compared between treatment groups using models similar to the primary 
outcome for continuous measures and analogous generalized linear models for categorical outcomes.  
 
Additionally, secondary analyses will evaluate whether other models better fit the distributions for 
both the primary and secondary outcomes (for example, survival analysis models for the primary 
outcome and negative binomial or log linear models for suitable secondary outcomes).  
9.5 Exploratory Analysis Methods 
Not Applicable.  
10 SAFETY ANALYSES 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
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10.1 Overview of Safety Analysis Methods 
All safety analyses will be performed using all participants who were randomized and evaluated 
based on the treatment they received. The frequency of toxicities potentially attributable to study 
treatment will be determined. Treatment and resolution of all safety endpoints will also be 
documented. Treatment groups will be compared for incidence of events with a chi-squared or 
Fisher’s exact test, and incidence density (events per person-months of exposure) will be calculated. 
10.2 Safety Variables 
Safety outcome variables are described in the table below. 
 
Variable 
Type 
Definition 
Safety Outcomes 
Weight gain from 
randomization until status 
Continuous/
Categorical 
Change in weight between randomization and 
in-hospital status. Outcome is censored at 48 
weeks PMA and time of transfer or death. May 
also be assessed using percentiles. 
Number of days after 
randomization until status 
that infant had at least two 
consecutive heart rates >200 
documented at least 3 hours 
apart 
Count 
Number of days between randomization and status 
with at least 2 consecutive heart rates > 200 bpm at 
least 3 hours apart. Outcome excludes when infant 
was crying. 
Treatment for high blood 
pressure initiated after 
randomization until status 
Categorical 
Presence of treatment for high blood pressure that 
was started between randomization and status. 
Number of episodes between 
randomization and status that 
infant was placed NPO for ≥ 
24 hours 
Count 
Number of days between randomization and status 
in which infant was placed NPO for at least 24 
hours 
Use of anti-reflux 
medications between 
randomization and status 
Categorical 
Presence of use of anti-reflux medication that were 
started between randomization and status. 
Number of days of 
significant apnea/bradycardia 
between randomization and 
status 
Count 
Number of days between randomization and status 
with infant showing significant apnea/bradycardia. 
Significant apnea/bradycardia documented by 
infant receiving open label caffeine, doxapram, 
other methylxanthines, CPAP or ventilatory 
support for apnea/bradycardia 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
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Variable 
Type 
Definition 
Presence of documented and 
treated arrhythmias between 
randomization and status 
Categorical 
Presence of treated arrhythmias between 
randomization and status. Outcome excludes 
arrhythmias due to tachycardia or bradycardia 
Onset of documented 
seizures between 
randomization and status 
Categorical 
Presence of documented seizures between 
randomization and status. Documented seizures are 
defined by treating with anti-convulsants. 
10.3 Adverse Events 
Per the protocol, specific adverse events will be collected on an adverse event log. Adverse events 
will be listed and summarized by event type. Summaries will be of the number of events and number 
of individuals experiencing events by treatment group and will be created for all adverse events, by 
severity, and by relationship to treatment.  
10.4 Deaths and Serious Adverse Events 
A serious adverse event (SAE) is any event that is life threatening, results in death, causes or prolongs 
hospitalization, leads to a disability or birth defect, or requires an intervention to prevent a disability. 
SAEs will be listed, and SAEs and treatment-related SAEs will be summarized in the manner 
mentioned in Section 10.3 if there are enough events to summarize. Deaths will be listed.
11 ANALYSIS OF OTHER OUTCOMES 
At this time, there are no other outcomes under consideration. Additional analyses motivated by 
observations in the final outcome data may be conducted, but these will be clearly identified as post-
hoc analyses in any publication and will not be specifically addressed via updates to the SAP. 
12 REPORTING CONVENTIONS 
Unless required otherwise by FDA standards, the following rules are standard: 
• 
Moment statistics including mean and standard deviation will be reported at 1 more significant 
digit than the precision of the data.  
• 
Order statistics including median, min and max will be reported to the same level of precision as 
the original observations. If any values are calculated out to have more significant digits, then the 
value should be rounded so that it is the same level of precision as the original data. 
• 
Following SAS rules, the median will be reported as the average of the two middle numbers if the 
dataset contains even numbers. 
• 
Test statistics including t and z test statistics will be reported to two decimal places.  
• 
P-value will be reported to 3 decimal places if > 0.001. If it is less than 0.001 then report 
‘<0.001’. Report p-values as 0.05 rather than .05. 
• 
No preliminary rounding should be performed, rounding should only occur after analysis. To 
round, consider digit to right of last significant digit: if < 5 round down, if >=5 round up. 
13 CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
None at this time. Additional analyses motivated by observations in the final outcome data 
may be conducted, but these will be clearly identified as post-hoc analyses in any publication 
and will not be specifically addressed via updates to the SAP. 


MoCHA Statistical Analysis Plan 
 
 
 
 
  
Final 2022-12-12 
 Page 21  
 
14 REFERENCES 
None. 
15 LIST OF POTENTIAL DISPLAYS  
Data displays may be added, deleted, rearranged or the structure may be modified after finalization of 
the SAP. Such changes require no amendment to the SAP as long as the change does not contradict 
the text of the SAP.  
 
Tables 
Demographic and Baseline Characteristics (Demographic and baseline summaries mothers and 
infants) 
Participant Disposition (Number of individuals consented, randomized, and completing in-
hospital and post-discharge, as well as final disposition based on final study status.)  
Dosing Summary (Number of doses taken in hospital, proportion of expected doses taken post-
discharge missed) 
Primary Efficacy Model Results 
Secondary Efficacy Model Results 
Exploratory Efficacy Model Results 
Safety Summary 
Figures 
CONSORT Diagram 
Boxplots of numbers of days  
Survival plot for primary outcome by treatment arm 
Effect estimates and 95% confidence intervals summarizing treatment heterogeneity for primary 
outcome by GA group and sex 
Additional figures may be produced for manuscripts.  
Data Listings will be created for all critical study variables 
 
 

ICF_003.pdf: 
 
MoCHA 
 
Moderately Preterm Infants with Caffeine At Home for Apnea (MoCHA) Trial 
 
Eunice Kennedy Shriver NICHD 
Neonatal Research Network 
 
 
 
NCT03340727 
 
 
 
Version 4.0  
December 16, 2021


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
1 
 
Appendix L 
Informed Consent Statement for: 
MOCHA 
You are being asked to allow your baby to be in a research 
study which will look at the use of caffeine in the hospital 
and after discharge. Caffeine is a medicine commonly used 
to treat apnea of prematurity.  Babies who were born 
between 29 and 33 weeks gestational age and have a 
history of apnea will be part of this study. 
It is important for you to understand why we are doing this 
research and what it means for your baby to be a part of 
the study. You may discuss this information with relatives, 
friends and others who help you make important decisions. 
If you have any questions about this research, please ask us.  
This study is sponsored by the Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
(NICHD), which is part of the National Institutes of Health 
(NIH), and is being done at XXXXX by XXXXX (name of site 
and PI). 
What is Apnea of Prematurity? 
Apnea of prematurity is a common problem in babies who are born before their due date.  Apnea is 
when babies stop breathing for a short period of time.  Apnea may also cause slowing of their heart 
rate (bradycardia).  Babies usually stop having apnea around the time of their due date. However, for 
some babies, apnea may last past this time and may delay discharge. The doctors worry that if 
premature babies go home before they stop having apnea they are at greater risk for having an 
“apparent life-threatening event” (ALTE).  An ALTE is an apnea event with slowing of the heart rate 
(bradycardia) that is serious and may need emergency room care.  Sometimes babies will be admitted 
to the hospital if they have apnea and bradycardia after going home.  However, most doctors wait 
before sending premature babies home until they have not had apnea and/or bradycardia events for 5-
7 days. 
Why is Caffeine Used? 
Caffeine is used to treat apnea in premature babies in the newborn intensive care units (NICUs). 
However, studies have shown that some babies still may have apnea after getting caffeine.   
 
Investigator 
 
Location 
 
Telephone 
 
Protocol Title 
Randomized Controlled Trial of 
Home Therapy with Caffeine Citrate 
in Moderate Preterm Infants with 
Apnea of Prematurity (MoCHA) 
(Cooperative Multicenter Neonatal 
Research Network) 
 
 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
2 
 
Why is this study being done?  
The purpose of this research study is to find out 
if using caffeine until discharge and after 
discharge at home will help us send babies 
home sooner.   
There are two main purposes for this study: 
1. To find out if using caffeine until 
discharge will allow babies to go home 
sooner.  
2. To find out if using caffeine during the 
first month after discharge can prevent 
or decrease apnea.  
How many babies will take part 
in this study?  
There will be 1200 babies enrolled from 
approximately 15 centers across the United 
States. XX hospital plans to enroll about XX 
babies.  
How long will my baby be a part 
of this study? 
Your baby will begin the study close to the time 
of discharge from the hospital and will continue 
to be a part of it for the first 56 days following 
discharge. 
What will happen if my baby 
joins this study? 
Babies that go into this study will be randomly 
assigned (like the toss of a coin) to one of two 
groups. There is an equal chance of being in 
either group. 
 
Caffeine 
Group 
Receives 
caffeine 
medication. 
Placebo 
Group 
Receives 
solution 
without 
caffeine. 
 
The study will begin when your baby is close to 
discharge and the doctors decide your baby no 
longer needs caffeine. At this time your baby 
will be randomly assigned to receive either 
caffeine or a placebo ( solution without 
caffeine). This study medication (caffeine or 
placebo) will be given each day until discharge. 
You will then receive the same study 
medication to give your baby daily for the first 
28 days after he/she goes home.  
Neither you nor your baby’s doctors or nurses 
will know which group your baby is in. While in 
the hospital, your baby’s nurses will give the 
study medication once a day. The dose of the 
study medication will be based on your baby’s 
weight. 
On the day of discharge, you will be given 28 
small vials (bottles) of the same study 
medication. The vials will be numbered 1-28, 
and one vial will be used each day.  We will 
teach you how to fill a small syringe with the 
correct amount of study medication each day.  
We will teach you how to give your baby the 
study medication once a day by mouth for the 
first 28 days after your baby goes home. We 
will also teach you how to properly store the 
study medication.  
At discharge, we will give you a diary to fill out 
during the time your baby is in the study at 
home. The diary will have a place each day for 
you to mark that you gave your baby the study 
medication. It will also have spaces to write 
down things such as forgetting to give the 
medication, any regular doctor visits, 
unexpected doctor or emergency room visits or 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
3 
 
any hospital admissions. We need you to fill 
this out every day for the first 28 days.  
The last part of the diary will be used for the 
second month after discharge. We will need 
you to write down your baby’s regular doctor 
visits, unexpected doctor or emergency room 
visits or any hospital admissions during this 
time. 
We will keep in touch with you after your baby 
is discharged from the hospital. We will call   
about three days after discharge, once a week 
for the first four weeks, and then at about six 
and eight weeks after discharge. We will ask 
about what you have written on the diary. 
There will be no extra clinic visits for this study. 
Besides this study medication, your baby will 
have all the usual care given to premature 
babies while in the hospital.   
As part of the study, we will collect information 
from your baby’s medical chart. This may 
include birth weight, gestational age, sex, 
problems he/she had while in the hospital, 
medications received and test results while in 
the hospital.  
If your baby is transferred to another 
participating hospital before going home, all 
parts of the study will continue if possible, 
including the medical chart review.  
If your baby is transferred to another NON-
participating hospital before going home, all 
parts of the study will discontinue.  
We will also collect information about you 
(mother), such as age, your years of education, 
marital status, race/ethnicity, type of insurance 
and health issues during your pregnancy.  We 
will ask for your address, phone numbers, and 
email address so we can contact you when your 
baby goes home from the hospital. 
We may contact you in the future for further 
long term follow up for this study. 
What are the risks and possible 
discomforts from being in this 
research study? 
Because of being born early, your baby has a 
greater risk of having poor developmental 
outcomes, disabilities, or even death.  Some 
babies have apnea and are at higher risk for an 
apparent life-threatening event (ALTE).  These 
risks are the same whether or not your baby is 
in this study.   
There may be other risks related to being in this 
study.   
Caffeine is a commonly used drug which has a 
few side effects.  Possible side effects may 
include: 
• Slow weight gain 
• Irritability or jitteriness 
• Seizures or convulsions 
• Irregular heart rate 
• Higher heart rate  
• Higher blood pressure 
These side effects occur in about 1 to 5 of every 
100 babies taking caffeine.  These side effects 
are temporary and usually go away after 
stopping the medication.  Your baby has 
already been given caffeine in the hospital and 
has been watched for these side effects. There 
are no known side effects for the babies who 
get the placebo. 
Your baby will be put into a study group by 
chance. One group may be less effective or 
have more side effects than the other study 
treatment or other available treatment. 
 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
4 
 
 
Unknown Risks 
There may also be risks that are unknown at 
this time. You will be given more information if 
other risks are found. 
Confidentiality 
Another possible risk of being part of this study 
is loss of confidentiality or privacy.  
What are the benefits of joining 
this study?  
There may be benefit if the study shows that 
babies in the group that gets caffeine go home 
sooner and have less apnea after discharge.  
This may prevent unexpected visits to the 
doctor or to the emergency room for problems 
with apnea.    
All babies enrolled in this study, whether they 
are in the group that gets caffeine or placebo, 
may benefit from the closer monitoring by the 
study staff. Study staff will be contacting you 
often to check on you and your baby. 
One treatment may have better outcomes than 
the other treatment. It is possible that neither 
group will show any improvement.  
It is also possible that your baby will not get any 
benefit from being in this study. However, 
information that we learn from this study may 
help us to better care for premature babies in 
the future. 
What other choices do I have if I 
do not allow my baby to be in 
this study?  
You have the choice to not allow your baby to 
be in this study. If you choose not to allow your 
baby to join, he/she will receive the usual care 
given in the hospital and after discharge. This 
care may include keeping your baby in the 
hospital until all apnea has stopped, discharge 
with an apnea monitor and/or treatment with 
caffeine after discharge. 
Will my baby’s medical 
information be kept 
private/confidential? 
<insert standard institutional language about 
confidentiality. Following is a sample> 
Information obtained about your baby for this 
study will be kept confidential to the extent 
allowed by law. However, research that 
identifies your baby may be shared with people 
or organizations for quality assurance or data 
analysis, or with those responsible for ensuring 
compliance with laws and regulations related to 
research. They include: 
• <Insert your institution. Following is a 
sample> UAB Institutional Review Board 
(IRB). An IRB is a group that reviews the 
study to protect the rights and welfare 
of research participants. 
• Eunice Kennedy Shriver National 
Institute of Child Health and Human 
Development (NICHD) 
• Research Triangle Institute (RTI), the 
data coordinating center for the study 
• Food and Drug Administration (FDA) 
• Office for Human Research Protections 
(OHRP) 
The information from the research may be 
published for scientific purposes; however your 
baby’s identity will not be given out. A copy of 
the consent form will be placed in your baby’s 
medical record at <Insert your institution. 
Following is a sample> UAB Health System or 
Children’s of Alabama. This may include either 
a paper medical record or electronic medical 
record (EMR). An EMR is an electronic version 
of a paper medical record of your baby’s care 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
5 
 
within this health system. The EMR may 
indicate that your baby is on a clinical trial and 
provide the name and contact information for 
the principal investigator. 
Results of research tests or procedures may be 
placed in your baby’s medical record. All 
information within your medical record can be 
viewed by individuals authorized to access the 
record. Information relating to the study, 
including name, date of birth and social security 
number, may be shared with the billing offices 
of <Insert your institution. Following is a 
sample> UAB and UAB Health System affiliated 
entities, along with Children’s of Alabama and 
its billing agents so costs for clinical services can 
be appropriately paid for by either the study 
account or by your insurance. 
Information about your baby that we collect for 
this study will be kept in a locked filing cabinet 
in our clinical research office, and on password-
protected computers. This office is protected 
by security staff 24 hours a day, 7 days a week. 
Information collected from your baby’s chart 
for this study will be labeled with coded study 
identification (ID) number. The log book 
connecting the code number with your baby’s 
identity will be kept locked in a filing cabinet in 
our clinical research office, available only to 
research staff working on the study.  
Coded information will be sent to the NICHD 
Neonatal Research Network’s Data 
Coordinating Center at Research Triangle 
Institute (RTI) in Research Triangle Park, North 
Carolina.  Information from this research study 
will be kept by <Local Research Institution> and RTI 
International and may be shared for future 
research in accordance with the NIH Public 
Access Policy and NIH Data Sharing Policy. 
Information released under this policy will not 
identify your baby or his/her participation in 
this research study. 
A description of this research study will be 
available on ClinicalTrials.gov, ID number NCT 
03340727, as required by United States law. 
This website will not include information that 
can identify you or your baby. The website will 
include a summary of the results of this study. 
You can search this website at any time. 
This research study has a Confidentiality 
Certificate that protects your child’s privacy. If a 
legal matter happens, researchers may not use 
any information that might identify your child 
unless you give your okay.  You may give 
information about your child or this study to 
anyone you wish. If an insurer or employer 
learns that your child is in a study and you 
agree to share study data with them, the 
researcher will do so. This means that you must 
also guard your child’s private information. The 
researcher may give information to authorities 
to prevent serious harm to you, your child, or 
others. 
 
What are the costs of taking 
part in this research study?  
You will not be billed, nor will your insurance 
company be billed, for any test, treatment or 
visit that is done only for this study. The parts 
of your baby’s care that would normally be 
done as usual treatment, including (but not 
limited to) treatment with a mechanical 
ventilator, antibiotics, feeding by vein, or blood 
pressure medications, will be billed to you or 
your insurance company as usual. The study 
will pay for all parts of your baby’s care that are 
done only for the study. 
Will I be paid for taking part in 
this research study?  
You will not be paid for your baby taking part in 
this study while your baby is in the hospital.  
However, after the diary is completed, and the 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
6 
 
phone calls with study staff are done, you will 
receive a $30 gift card in the mail. 
What happens if my baby is 
injured as a result of taking part 
in this research study?   
In the event of physical injury to your baby 
resulting from their participation in this 
research, necessary medical treatment will be 
provided to your baby and billed as part of their 
medical expenses.  Costs not covered by their 
insurance will be your responsibility.  Also, it is 
your responsibility to determine the extent of 
your baby’s health care coverage.   
There is no program in place for other payment 
for such injuries.  However, you and your baby 
are not giving up any legal rights or benefits to 
which you are otherwise owed.     
Is participation in this study 
voluntary? 
Yes, whether or not you allow your baby to be 
in this study is your choice. There will be no 
penalty if you decide not to allow your baby to 
be in the study. If you decide not to allow your 
baby to be in the study, your baby will not lose 
any benefits otherwise owed. You are free to 
withdraw your baby from the study at any time. 
Refusing to let your baby be in this study or 
deciding to take them out of it will not affect 
your relationship with this institution.  
New Information 
You will be told by the study doctor or study 
staff if new information is learned that might 
affect your choice to allow your baby to stay in 
the study.  If you decide to take your baby out 
of the study at that time, the research doctor 
will make arrangements for your baby’s 
medical care to continue as usual. If you decide 
to allow your baby to stay in the study, you will 
be asked to sign a new consent form.  
Right of Investigator to 
Withdraw Participants 
Your baby may be removed from the study 
without your permission if the sponsor ends 
the study or if the study doctor decides it is not 
in the best interest of your baby’s health. Some 
reasons for taking your baby out include risks of 
being in the study are more than the benefits 
or if your baby develops a severe problem. 
If I have questions or concerns 
about this research, whom can I 
contact?   
If you have any questions, complaints, or 
concerns about the study you can contact the 
investigator (Dr. ___), the co-investigators (Drs. 
___ or ___) or their staff by calling the 
University Paging Operator: (xxx) xxx-xxxx, the 
University NICU (xxx-xxx-xxxx or the ____ NICU 
(xxx) xxx-xxxx 24 hours a day. If you think your 
baby may have been harmed from being in this 
study, you can contact the same people. 
 
Institutional Review Board 
Contact the Institutional Review Board (IRB) if 
you have questions about your baby’s rights 
when he/she takes part in research. Also, 
contact the IRB if you have questions, 
complaints or concerns that you do not feel you 
can talk about with the investigator. The 
University IRB may be reached by phone at 
(xxx) xxx-xxxx or by e-mail at irb@xxxxx.edu.   
We are always available to answer your 
questions. If you have any questions that come 
up during this study, please be sure to ask us 


Moderately Preterm Infants with Caffeine at Home for Apnea (MoCHA) Trial  Manual of Operations  
 
 
 
STATEMENT OF CONSENT 
I have read this Informed Consent document and have had the opportunity to ask questions.  I will be 
given a signed copy of this form to keep. 
I, as the parent or guardian, agree to let my baby to take part in this research study and allow you to 
use and collect and share health information about my baby for this study, as you have explained in 
this form. 
 
_________________________________ 
Baby’s Name 
 
_________________________________ 
Parent/Guardian’s Name 
 
_________________________________ 
 
 
 
____________ 
Parent/Guardian’s Signature 
 
 
 
 
 
Date 
 
_________________________________ 
Relationship to Baby for Parent/Guardian 
 
_________________________________ 
Name of Person Obtaining Authorization and Consent 
 
 
_________________________________ 
 
 
 
____________ 
Signature of Person Obtaining Authorization and Consent 
 
Date 
 
 
 

Prot_000.pdf: 
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 
 


MoCHA  
1 
 
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). 


MoCHA  
2 
 
• 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 


MoCHA  
3 
 
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 


MoCHA  
4 
 
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. 
 


MoCHA  
5 
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. 


MoCHA  
6 
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 


MoCHA  
7 
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 


MoCHA  
8 
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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9 
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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14 
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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15 
 
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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20 
 
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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