Clinical trial NCT03576885
Conditions: Pulmonary Hypertension Bronchopulmonary Dysplasia
Sponsor: AdventHealth
Start date: 2019-07-15; Completion date: 2023-10-09
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Inhaled nitric oxide (iNO) is an effective treatment for pulmonary hypertension (PH) in term and near-term infants. Preterm infants are at risk for early PH that is associated with high risk for bronchopulmonary dysplasia or death. In multiple clinical trials, iNO treatment was not effective for BPD prevention. However, infants were not screened for PH and iNO treatment was not targeted for PH. iNO treatment for PH in preterm infants is controversial due to lack of evidence. The study team hypothesizes that early diagnosis of PH (72-96 hours of life) and iNO treatment will decrease the incidence of death and bronchopulmonary dysplasia and improve oxygenation in extremely preterm infants.

1. To determine if iNO treatment of extremely preterm infants with early pulmonary hypertension as established with echocardiographic evidence at 72-96 hours of age will decrease incidence of death or BPD.
2. To determine if iNO treatment of extremely preterm infants with early PH will decrease the pulmonary artery pressure and improve oxygenation within 72 hours of intervention.

Detailed description:
This is a single center, blinded, randomized control clinical trial to evaluate the effects of inhaled nitric oxide on the outcome of survival and incidence of bronchopulmonary dysplasia. This trial has a planned enrollment of 138 infants with 68 infants with delayed pulmonary transition assigned to either the treatment or placebo group. There is no enrollment restriction based on gender, ethnicity, or race. Enrollment is expected to take 36 months with an additional 12 months for data analysis.Infants with early pulmonary hypertension will be randomized to the treatment or placebo group. Treatment will continue until resolution of pulmonary hypertension or through Day 14, whichever comes first. Serial echocardiograms will be performed every 48 hours +/-12 hours until Day 14. Oxygen saturation levels will be averaged every 24 hour period following enrollment. This study will provide evidence for the beneficial effects of early diagnosis and treatment of pulmonary hypertension in preterm infants.

Arms: arm 1: inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. arm 2: Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. arm 3: Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension
Interventions: intervention 1: inhaled nitric oxide intervention 2: Placebo
Intervention descriptions: intervention 1: inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension intervention 2: placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol Title: 
Treatment of Delayed Pulmonary Transition in Extremely Preterm 
Infants & 
Bronchopulmonary Dysplasia 
 
NCT # NCT03576885 
Date of Document - 10SEP2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Protocol Title: 
Treatment of Delayed Pulmonary Transition in Extremely Preterm Infants & Bronchopulmonary 
Dysplasia 
 
Study Sponsor:   
AdventHealth  
 
Principal Investigator: 
Principal investigator: Hussnain Mirza, MD 
 
 
 


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List of Abbreviations: 
BPD Broncho-pulmonary dysplasia 
GBS Group B streptococcus 
HBs Hepatitis B surface antigen 
iNO Inhaled nitric oxide 
IVH Intraventricular hemorrhage 
NEC Necrotizing enterocolitis 
PAP Pulmonary arterial pressure 
PDA Patent ductus arteriosus 
PH Pulmonary hypertension 
PVL Periventricular leukomalacia 
RCT Randomized Controlled Trials 
ROP Retinopathy of Prematurity 
RT Respiratory Therapist 
sBP Systemic blood pressure 
sPO2 Pulse oximeter 
VP Ventriculoperitoneal 
 
 
 
 


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Introduction 
This document is a protocol for a human research study. This study is to be conducted in 
accordance with applicable Federal regulations and institutional research policies and 
procedures. 
 
Background Information and Scientific Rationale 
Bronchopulmonary Dysplasia (BPD) is the most common morbidity in extremely preterm infants 
affecting approximately 15,000 infants annually in the United States. Up to 70% of extremely 
preterm infants who require mechanical ventilation beyond 7 days of life can develop BPD.1 It is 
considered a major contributor to the $22 billion annual cost of prematurity.2 BPD increases the 
risk of mortality especially after respiratory syncytial viral infection. Although clinical symptoms 
may improve with time, pulmonary reserve are always restricted. Up to 50% infants with BPD may 
die within 2 years if the disease is complicated by late pulmonary hypertension.3 There is no cure 
for BPD; however, reducing its incidence and ameliorating its severity is possible by minimizing 
the underlying contributing risk factors. 
 
In an animal model, West et al. showed significant lung injury secondary to the elevated 
pulmonary capillary pressure up to 40 mmHg for as little as 4 minutes.4 Multiple prospective 
clinical studies have shown a significant association between early PH and BPD.5-7  Incidence of 
early PH in preterm infants has been reported in 6-42% range. However, time for early PH 
screening was variable (1-6 weeks of life). As the natural history of postnatal cardiopulmonary 
adaptation in extremely preterm infants was never studied before, the optimal time for early PH 
screening was unknown.8  
 
iNO is an effective treatment for pulmonary hypertension in term and near-term infants. 
There is no randomized controlled trial to determine the efficacy of iNO to treat early PH in 
extremely preterm infants9, 10 but the treatment can be effective when used in appropriate 
subjects.11, 12 Safety of iNO treatment in preterm infants is well established in multiple RCTs.2, 13-
16 American Academy of Pediatrics (AAP)17 and National Institute of Child Health (NICHD)18 do 
not recommend routine iNO treatment to prevent BPD/death in preterm infants. However, these 
organizations recognize the potential benefit of iNO treatment for preterm infants with PH and 
encourages future research. Similarly, American Heart Association and American Thoracic 
Society also favor the iNO treatment for preterm infants with documented PH.19 Using a case 
control study design Seth et al. have recently reported higher risk for BPD and intraventricular 
hemorrhage (IVH) among preterm infants with early PH. iNO treatment of early PH was 
associated with improved clinical outcomes and survival compared to the infants in the untreated 
group.20  
 


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Prophylactic iNO treatment of preterm infants did not decrease the risk of BPD in several 
randomized clinical trials.21, 22 23 However, these trials were done without echocardiographic 
screening for PH24 to selectively enroll high risk infants who may benefit from iNO intervention. 
Thus, a likely explanation for the negative outcome of efficacy is the enrollment of generic nature 
of study subjects that may have diluted the beneficial effect of iNO intervention.  For these infants, 
iNO treatment continued for 7-14 days without monitoring hemodynamic changes. Prolonged iNO 
treatment may cause the formation of unmeasured toxic radicals such as peroxynitrite that can 
induce surfactant dysfunction, cause membrane damage by lipid peroxidation and increase the 
risk for BPD.25 It is very important to identify PH in preterm infants and monitor pulmonary 
hemodynamic changes following the initiation of iNO treatment to prevent unnecessary and 
prolonged exposure to iNO.26  In the presence of hemodynamically significant PDA, iNO treatment 
can increase left to right shunting by causing pulmonary vasodilatation.26 
 
Based on the current literature and our preliminary data 27(presented below), we 
hypothesized that “iNO treatment of extremely preterm infants with delayed postnatal 
cardiopulmonary transition defined as presence of early pulmonary hypertension (PH) at  - 96 
hours of age will decrease the incidence of death or BPD”.   
 
 If our hypothesis is correct, this study will provide evidence for beneficial effects of early 
diagnosis and treatment of pulmonary hypertension in preterm infants to minimize the risk of BPD. 
Our proposed RCT may lead to change in clinical practice.  
 
Study Objectives 
 
Primary Objective/Aim/Goal/Hypothesis: 
 
Primary objective of this study is to show that iNO treatment of extremely preterm infants with 
early Pulmonary Hypertension (PH) defined as echocardiographic evidence of PH at 48-96 hours 
of age will decrease the incidence of death or BPD.  
 
Secondary Objective/Aim/Goal/Hypothesis: 
 
Secondary objective is to show that iNO treatment of extremely preterm infants with early 
PH will decrease the pulmonary artery pressure and improve the oxygenation within 72 
hours of intervention. The change in pulmonary artery pressure and oxygenation from 


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initiation of treatment () to 3 days later (approximately 72 hours later) will be compared 
for the two treatment arms. 
 
Study Design 
Research Design 
This research will be carried out as a masked randomized controlled trial. Randomization 
will be designed by our study statistician (Dr. Julie Pepe).  Study population will be 
extremely preterm infants with early pulmonary hypertension diagnosed by 
echocardiography at 48- 96 hours of age. They will be randomized to either iNO or 
placebo.  
 
Study Agent, Device, and/or Intervention Description  
 
Inhaled nitric oxide (iNO) will be used as the intervention agent. This therapy is 
currently used in infants with late pulmonary hypertension that developed as a 
complication of BPD. Mallinckrodt Corporation, the manufacturer and supplier of 
iNO has agreed to provide the iNO as well as the placebo gas tanks at no cost for 
the study. 
 
 
Applicable to: 
FDA Regulation 
IND Studies 
IDE studies 
Abbreviated 
IDE studies 
21 CFR 11 
X 
X 
 
21 CFR 54 
X 
X 
 
21 CFR 210 
X 
 
 
21 CFR 211 
X 
 
 
21 CFR 312 
X 
 
 
21 CFR 812 
 
X 
X 
21 CFR 820 
 
X 
 
 


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An IND for this study has been approved by the FDA. The PI, Hussnain Mirza, 
MD, is the holder of the IND, #139794. This study will comply with all FDA 
requirements, IRB requirements, and ICH-GCP guidance. 
 
iNO and placebo devices will be stored separate from our clinical equipment in 
NICU. The clinical team will not have access to the study devices. Trained, 
unblinded respiratory therapists will obtain the study devices after study consent 
is signed and randomization has occurred.  The study will be conducted per GCP 
and FDA requirements. 
 
Study Site(s)/Location(s) and Number of Subjects 
 
This is a single site clinical study to be conducted at the Neonatal Intensive Care 
Unit of AdventHealth for Children. A total of 136 infants will be enrolled in the trial, 
and 68 of those infants will be randomized (34 in each arm). Screen failures, which 
are defined as infants who were consented but the echocardiogram showed no 
PH, will be enrolled into the comparison group and no further intervention will 
occur for them. To compare the incidence of death or BPD, outcome data will 
continue to be collected on the comparison group for the duration of their hospital 
stay. 
 
Subject Selection 
 
Vulnerable Populations  
This research involves Neonates of Uncertain Viability.  If this population was not included, the 
validity of the study would be compromised because the hypothesis is based on the uniquely high 
incidence of early pulmonary hypertension (PH) in this group which in turn is associated with a 
very high risk for bronco-pulmonary dysplasia (BPD), a very serious morbidity with extremely high 
probability of death and neurodevelopmental impairment if survived. We aim to provide 
intervention in the form of inhaled nitric oxide to alleviate PH and reduce the incidence of BPD. A 
successful trial will change practice and improve the clinical outcome of this population  
 
We would like to point out that the survival rate of this vulnerable population (extremely preterm 
infants, gestational age between 23-29 weeks) has improved remarkably in the U.S. during the 
past decade (based on National Institute of Child Health, Neonatal Research Network statistics) 
because of extensive clinical trials and intervention conducted by clinical investigators in the U.S. 
and globally. These studies were all approved by the local IRBs with the notion that research such 
as our proposed trial will provide evidence to guide our practice in enhancing the rate of intact 
survivors among this vulnerable population. 


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Our neonatologists do not determine the viability of any newborn in the delivery room or during 
the code. We make all decisions to offer limited life support or comfort care well before the 
delivery if any fetus has known congenital anomaly that will not be compatible with life. We also 
offer limited or comfort care only for infants born before 24 weeks gestation if the family make 
that decision during perinatal consultation with the neonatologist. For infants that code in the 
delivery room or in the unit, Neonatal Resuscitation Program (NRP) Guidelines are followed. The 
entire team (MD, ARNP, RN, RT) is involved when resuscitation is decided to be ineffective and 
is stopped.  
 
Withdrawal of life support is an extremely rare occurrence in our NICU that requires two 
neonatologists to independently assess the clinical status of an infant. Dr. Mirza, will not 
participate in determining the withdrawal of life support or DNR for any infant enrolled in this 
study.  
 
Inclusion Criteria 
There will be two steps of inclusion and exclusion criteria: 
 
Step 1: 
Inclusion Criteria: 
These infants are eligible for echocardiographic screening of early pulmonary hypertension: 
1. Extremely preterm infants born at 230/7-296/7 weeks gestation admitted to our neonatal ICU 
2. Positive pressure ventilation at 48-96 hours of age, irrespective of oxygen concentration 
via ETT or CPAP 
Exclusion Criteria:  
1.Death prior to the 48 hours of age  
2.Chromosomal or major congenital anomalies 
3. Myocardial Dysfunction seen on screening echocardiogram 
4. Infants dependent on right to left shunting of blood or any complex cardiac defect 
5. Mother is COVID-19 positive 
 
Step 2: 
 


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Inclusion criteria  
• 
Infants with early pulmonary hypertension will be randomized to iNO treatment or placebo 
at 48 -96 hours of age. 
Exclusion criteria: 
Infants whose echocardiogram done at 48-96 hours shows at least one of the following: 
• 
PH exclusively due to excessive pulmonary blood flow (left to right shunting due to large 
PDA and normal septal position and no significant TR without bidirectional shunt)  
• 
Pulmonary blood flow obstruction secondary to pulmonary vein stenosis, mitral valve 
stenosis, cor triata, and aortic valve atresia.  
 
Resources Available  
 
The PI will meet with the research team prior to commencement of the study to discuss the 
protocol and address any questions about the protocol or individual duties and functions. Team 
members will meet as needed for the duration of the study to address any questions or concerns 
that may arise. Research personnel in the study have completed all training requirements to 
participate in research as required by AdventHealth. The study will be conducted in accordance 
with the protocol and Institutional Review Board (IRB). 
 
The PI and Co-Is have worked together in conducting the observational study that successfully 
obtained the preliminary data for the current randomized controlled trial.  
The experience enhances the successful implementation of the current research application. In 
regard to the patient resource, in 2016, our NICU admitted 132 extremely preterm infants. Over 
a three-year proposed study period, we will have 362 available subjects for enrollment into our 
trial.  
We will secure the collaboration of our Echocardiography department in conducting the 
echocardiograms as described in the protocol.  
We have received three years of funding for this study from the Thrasher Foundation. 
 
Study Procedures 
 
Subject Recruitment and Screening 
The study will commence after IRB approval and OSP clearance and full execution of agreements 
with Thrasher Foundation and Mallinckrodt. The research team members indicated on the 


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delegation log will screen the NICU census daily for infants who may be eligible for the study. If 
an infant is identified as potentially eligible through review of the medical records, permission will 
be sought from the attending neonatologist to approach the parents about study participation. 
After informed parental consent by a research team member, all eligible infants (per step 1 
inclusion criteria above) will be screened by echocardiography at 48-96 hours of life to identify 
infants with early PH. If an echocardiogram is ordered by the clinical team at this time point, a 
study echo will not be performed and the data will be retrieved from the clinically indicated echo. 
If an infant is critically ill and unable to tolerate the procedure as determined by attending 
clinicians, echocardiogram can be delayed up to 96 hours of age. Any significant clinical finding, 
e.g. pericardial effusion, large PDA, ventricular dysfunction or any major structural anomaly will 
be disclosed to the clinical care team.  All infants will be managed by the clinical teams in NICU. 
Eligible infants (per step 2 inclusion /exclusion criteria cited above) will be enrolled in the 
randomized controlled trial for treatment with iNO or placebo as shown in Figure 1. Infants who 
have no evidence of pulmonary hypertension on the screening echocardiogram will have no 
further research intervention activity, but their data will be collected (comparison(reference) 
group). 
 
Figure 1: Study Enrollment Plan 
 
 
Diagnosis of PH will be based on peak velocity of tricuspid regurgitation (TRmax), PDA gradient or 
end systolic interventricular septal position.5 We will calculate right   ventricular (RV) pressure 
gradient by modified Bernoulli equation (RV pressure = 4 x (TR max2). Pulmonary artery pressure 


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(PAP) will be estimated by adding 5 to the RV gradient (to adjust for right atrial pressure). In the 
absence of measurable TRmax, PAP can be estimated by calculating the PDA gradient and 
measuring the concurrent systemic blood pressure (sBP) i.e. sBP- (4 x PDAmax2) for left to right 
shunting across PDA or sBP+ (4 x PDAmax2) for right to left or bidirectional shunting. In the 
absence of TRmax or PDA, PAP can be estimated by the end systolic interventricular septal 
configuration at the papillary muscle level in short axis view from multiple acoustic windows i.e. 
left parasternal, right high parasternal and subcostal. PH will be categorized as moderate if 
estimated pulmonary artery pressure (PAP) is more than half but less than systemic systolic blood 
pressure or if the septal position is flat. PH will be considered severe if PAP > sBP or septal 
position is paradoxical.  
 
Data Collection: 
Demographic and clinical data will be prospectively collected from maternal and neonatal charts 
along with data from serial echocardiograms. Following variables will be included in the database 
• 
Maternal Data: Age, ethnicity, educational level, smoking, alcohol or illicit use of drugs, 
medication history, any medical or surgical problem, antenatal screening lab results (GBS, 
HIV, HBs Ag, RPR) maternal UTI, chorioamnionitis, rupture of membrane, vaginal bleeding 
or discharge, antenatal antibiotics, steroids, indomethacin or magnesium.  
• 
Neonatal Data: BPD our primary outcome is  determined based on the need for 
positive pressure ventilation or supplemental oxygen after room air challenge test  
Gestation, Gender, mode of delivery, Apgar scores, IUGR, Birth Weight, Surfactant, 
Ventilation, pulmonary hypertension (early, intermittent or late), use of supplemental 
oxygen, culture proven infections, blood transfusions, Cardiotropic medication, bicarb 
infusion, saline boluses, use of indomethacin, PDA treatment/ ligation, use of diuretics, 
use of postnatal steroids, IVH, PVL, Post IVH hydrocephalus, NEC,  ROP, ROP requiring  
treatment, VP shunt, Tracheostomy, Gastrostomy tube, home oxygen, home ventilation, 
length of hospital stay and death. 
 
Consent Process  
All consent form processes will adhere to HRP 802 and 803 guidance. This study will be 
explained to the parent/s and all questions will be answered. The study team member will 
ensure the parent/s understand the information and have sufficient time to review the 
consent.  The signing of the consent will be as indicated on the signature page of the full 
consent, with a parent or LAR signing on the first line and the signature of a second parent 
signing unless one of the indications of why a second parent is not signing is checked, as 
is standard on the consent template for pediatric studies. The parent/s or LAR will be given 
a copy of the signed consent. 
 


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Non-English-Speaking Subjects 
In the event a non-English speaking family is identified as having a child who is a 
potential candidate, the IRB Short Form procedures will be initiated. A certified 
interpreter will be used to discuss the study with the parents or legal guardian. The 
consent form has been translated into Spanish and Creole and will be used to enroll 
Spanish/Creole speaking subjects.  
 
Documentation of Informed Consent Process 
Documentation of the informed consent process is required to establish that the subject 
was accurately and adequately informed and that no study-related procedures were 
initiated prior to obtaining informed consent.  A research team member will note in the 
source documentation the consent process, date consent was obtained, and that consent 
was obtained prior to initiating any research procedures. 
 
Waiver of Written Documentation of Consent or Waiver of Consent  
N/A 
 
          Randomization 
Randomization into 2 groups will be done using statistical software (SAS or Excel). To 
keep the balance between treatment and placebo groups, we will use stratified permuted 
block randomization. Randomization will be stratified by gestational age (23 0/7-25 6/7 
weeks, 26 0/1-29 6/7 weeks) and severity of PH (moderate & severe). Because the number 
of enrolled infants per stratification group is unknown at the start of the study, additional 
envelopes will be generated with randomization sequences of various block sizes 
balanced between placebo and treatment. The envelopes will remain sealed until the 
infant has been enrolled in the study. The envelopes will be kept in a secured office in the 
RT department that will be accessible to only trained, unblinded RT personnel. Documents 
regarding the randomization process will be kept in the RT department. The randomization 
envelope will be pulled by one of the trained, unblinded RT personnel who will obtain the 
corresponding treatment/placebo tank prior to the initiation of intervention. 
 
Study Visits:   
Infants with early pulmonary hypertension will be randomized to the treatment group or 
the placebo group (see randomization plan). iNO or placebo treatment will start at 20 ppm. 
Treatment will continue for 2 weeks or until resolution of pulmonary hypertension, 
whichever comes first. 
 
 


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To ensure the safety and evaluate the clinical response to iNO treatment, we will perform 
serial echocardiograms as shown in figure 2.  
 
 
 
 
 
Figure 2 
 
 
Since the data of SpO2 & FiO2 are available in all infants, their ratios (SF ratio) will be 
calculated as markers of improved oxygenation.  SF ratio has the advantage of avoiding 
invasive arterial blood sampling in situation when umbilical arterial line is unavailable. It is 
a reliable noninvasive surrogate for PaO2: FiO2 ratio to identify children with severe lung 
disease.28, 29 Respiratory Severity Score (RSS= FiO2 X Mean airway pressure (MAP)) will 
be monitored for infants on mechanical ventilation since the data of mean airway pressure 
will be available. Significant response to iNO treatment will be defined as 20% 
improvement in SF ratio or resolution of pulmonary hypertension (assessed by echo) 
within 72 hours.  Serial echocardiograms will be performed every 24-48 ± 12hours until 14 
days of life irrespective of the length of treatment. 
 


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If PH is resolved during the 2-week treatment window or after the completion of the 2-
week treatment protocol, we will start weaning the iNO dose by decreasing to 15 ppm. 
Weaning will continue to 10, 5, 4, 3, 2 and 1 ppm every 4 hours. During the weaning 
process if SF ratio decreased by 20%, iNO /Placebo dose will be increased to the minimum 
dose where FiO2 and PaO2 were stable. Weaning can be resumed after 12 hours following 
the above guidelines. The iNO weaning process described above is the current standard 
of care in our NICU for infants with PH. If pulmonary hypertension recurs in the first 2 
weeks of life after stopping the treatment, iNO/Placebo treatment will be resumed based 
upon the randomization at the time of enrollment. 
 
About 1/3 of term and near-term infants with pulmonary hypertension may not respond to 
iNO. We will evaluate the effectiveness of iNO treatment by recording changes in serial 
echocardiogram and in mean airway pressure (MAP), FiO2, SpO2/FiO2 ratio, and 
oxygenation index (OI) before and at 24 + 6, 48 + 6, and 72 +12 hours after beginning 
therapy. Non-responders will be defined as no improvement in pulmonary artery pressure 
or cardiac function on three serial echocardiograms and lack of 10% improvements from 
baseline for MAP, FiO2, SpO2/FiO2 ratio and OI at 72 + 12 hours after starting treatment. 
Once an infant is identified as a non-responder, we will start weaning treatment (iNO or 
placebo) as described in our iNO weaning plan given below. It is important because even 
in “non-responders,” one can still see significant rebound pulmonary hypertension with 
iNO discontinuation. If pulmonary hypertension is noted on subsequent echocardiograms, 
study intervention will not be resumed for non-responders. However, there is no restriction 
on clinical team to start iNO if needed based on clinical criteria.   
 
During the course of hospitalization, all infants will receive standard of care and will be 
monitored as per NICU monitoring. Per AdventHealth NICU standardized guidelines, 
target oxygen saturations for ≤ 32 weeks PMA is 86-92%. We will follow these guidelines 
while the subject is receiving supplemental oxygen.  
 
Study Duration 
The study will commence as soon as we receive IRB approval and OSP clearance. The 
project enrollment period will last approximately three years with one year to clean the 
data and analyze results.  
 
Study Outcome Measures (Endpoints) 
• 
Maternal demographics (listed under the data collection section of the protocol) 
• 
Infant measures (listed under the data collection section of the protocol) 


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• 
Incidence of death or BPD measured at 36 weeks post menstrual age (yes or no) 
o BPD will be defined as need for supplemental oxygen for at least 28 days. 
Severity of BPD will be determined at 36 weeks postmenstrual age. Infants 
with no need for supplemental oxygen will be classified as mild BPD. 
Continued requirement for supplemental oxygen (<0.3 FiO2) will be 
considered moderate BPD. Infants requiring >0.3 FiO2 and or positive 
pressure respiratory support will be diagnosed with severe BPD. The need 
for continuing oxygen therapy will be determined by a room air challenge. 
We will prospectively collect data that will allow us to define BPD as 
recommended by the 2018 NICHD report 
• 
Pulmonary arterial pressure based on serial echocardiograms) 
• 
Oxygen saturation level (average for each 24-hour period after enrollment) 
• 
Arterial pressure and oxygen saturation will be measured up to 2-weeks or until 
the treatment is discontinued, whichever is shorter. 
 
Data Management and Quality Plan 
Data de-identification   
Each subject will be assigned a unique study identification number (001, 002, 003, etc.) 
for data collection. A master list will be created to link the subject’s MRN with the study 
number. The master list will be saved electronically in a password protected file on an 
AdventHealth server accessible only to study team members.  
 
Data Confidentiality, Storage, and Retention 
Study documentation and paperwork will be stored in the locked Pediatric Research office 
and access will be restricted to the research team. The data file will be stored electronically 
on a password protected secure server at AdventHealth accessible only to the study team. 
Study documentation will be retained for 7 years after completion of the study. After that 
period, paper records will be placed in hospital approved shred bins. Electronic records 
will be placed in a computer electronic trash bin followed by immediate emptying of the 
electronic trash bin. 
 
Data Quality  
 
Quality control procedures for this research study include source data verification by 
randomly selecting 10% of subject records with comparison between the paper case 
report form (CRF) and the electronic database record of those same data.  If errors are 
common, data will be completely checked prior to data analysis.   


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Data Sharing  
N/A 
           
 Sample Size Determination 
 
Sample size was calculated based on our pilot study showing that the incidence of death 
or BPD among extremely preterm infants with early pulmonary hypertension was 80%.  
Assuming a 30% relative decrease of the incidence we came up with a sample size of 34 
infants in each arm with 80% power and alpha of 0.05. 
 
Statistical Analysis Plan 
 
Primary Objective Analysis 
Data will be analyzed to define the demographic and clinical characteristics of the two 
study cohorts (iNO and placebo) and the infants without early PH (not enrolled for 
treatment, please see Fig. 1). Chi square test for categorical variables and student’s t test 
or non-parametric equivalent test for continuous variables will be used. Relative Risk (with 
95% CI) for death or BPD will be calculated for the placebo and iNO treatment groups. 
The outcomes of infants without early PH will also be compared with the two study cohorts 
(iNO and placebo). Logistic regression will be performed to adjust for significant co-
variables if needed (unlikely because of randomization and stratification). Similarly, 
treatment and placebo groups will be compared to determine the short-term benefits of 
iNO treatment for PH in preterm infants. 
 
Secondary Objective Analysis 
We will analyze the change in pulmonary arterial pressure by serial echo within 72 hours 
of initiation of iNO. We will also compare the pulse oximeter to inspired oxygen ratio. 
 


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Potential Risks and Benefits 
Potential Benefits 
If our primary hypothesis is correct, the infant enrolled in the iNO arm may have the benefit of 
being a survivor without BPD. The infant in the placebo arm will have the same risk of surviving 
with BPD as in current standard of care.  
   
Potential Risks:   
A potential risk associated with iNO is methemoglobinemia. This risk is minimal as 
we are using low concentrations of iNO. Occasionally an extremely preterm infant is 
unstable and performing echocardiogram could cause oxygen desaturation and a 
temporary increase in FiO2 requirement. Heart failure has been described as a potential risk 
for iNO treatment. However, this complication is noted only among the patients with ischemic 
heart disease or myocardial dysfunction. No severe side effects of iNO have been reported at the 
starting dose of 20 ppm.30 We will not include any infants with myocardial dysfunction noted on 
the initial echocardiogram. We will start weaning iNO treatment if worsening of hemodynamic 
status is noted on serial echocardiograms based upon the recommendations of our cardiologists. 
Very rarely, nitric oxide can chemically react with oxygen to make nitrogen dioxide (NO2) that 
can cause inflammation of the airways if the level exceeds beyond 5 parts per million.  
 
 
Mitigation of Risks:  
We will measure levels of methemoglobin with blood gases as is current standard of 
care in the NICU. The first methemoglobin level will be checked within 4-8 hours of 
treatment initiation, and then repeated every 24-48 hours during the intervention. 
Methemoglobinemia can be reversed by stopping the iNO. 
 
Our device has an alarm set at 0.7ppm for live monitoring of NO2 that is set well below the threshold 
for any adverse effect. 
 
Study team will seek clearance from the clinical team before performing echocardiogram to 
ensure the safety of the infant. If an infant is clinically unstable, study echocardiogram can be 
delayed or cancelled 
 
During the course of study, the attending clinicians may request unmasking of intervention (iNO 
or placebo) only if oxygenation index is higher than 40 for at least 4 hours or if there is risk of 


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death due to hypoxic respiratory failure without starting iNO. If the infant is on iNO, treatment will 
continue. If the infant is on placebo, iNO treatment may be allowed. The PI will be notified 
immediately. A protocol violation will be filed and intention to treat principle will apply.  
 
Provisions to Protect the Privacy Interest of Subjects  
Subjects will be assigned a study number for collecting data. All precautions will be taken to make 
sure that only authorized individuals will have access subject research records.  The collection of 
sensitive information about subjects will be limited to the minimum necessary to achieve the aims 
of the research and no unnecessary sensitive information will be collected.  
 
Early Withdrawal of Subjects 
Investigator Withdrawal of Subjects  
. 
A. The following stopping criteria will be followed: Patient experiences a serious adverse event 
(defined per regulation) related to study drug  
B. Patient experiences any one of the following: 
I. 
Pulmonary edema due to worsening of left ventricular dysfunction  
II. 
Elevated met Hb level (>5%) on 2 samples 6 hours apart or > 7.5% on a single reading 
III. 
If nitrogen di-oxide (NO2) concentration is more than 3 ppm for 6 hours or more than 5 
ppm on a single reading 
C. Investigator judgement 
 
Subject Request for Withdrawal from Study 
If a parent would like to withdraw their infant from the study, the Withdraw from Study form 
will be given to the parent/s to complete and the infant will be removed from the study.  
 
Criteria for Cessation of Enrollment Pending DSMB Review of Safety Data 
1. Two or more infants experience an SAE related to iNO treatment 
2. Two or more infants are discontinued from the study due to safety concerns 
 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who are withdrawn from the study will not be included in the final analysis. All 
AEs and SAEs will continue to be collected on withdrawn subjects throughout 
hospitalization, and that data will be reviewed by the DSMB when necessary. 


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Adverse Event Reporting  
 
An adverse event is defined as “any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related.”  
 
A serious adverse event is defined as an adverse event “if, in the view of the investigator, 
it results in any of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.” 
Adverse events that meet criteria for reporting will be submitted to the FDA and/or IRB as 
applicable. Given this high-risk patient population, a number of adverse events are 
expected. The key monitoring function will be to assess whether evidence is accruing that 
suggests a differential adverse event rate associated with treatment. AE’s collected 
include elevated met hemoglobin or nitrogen dioxide, rebound pulmonary hypertension 
after discontinuing iNO, myocardial dysfunction/heart failure, hypotension, pulmonary 
hemorrhage, pneumothorax, PDA (if treated), NEC (stage 2b or 3), culture proven sepsis 
(treated with antibiotics ≥ 5 days), IVH (grade III or IV), ROP (severe), death, cardiac arrest 
or other life-threatening events. These adverse events will be collected from the time the 
subject starts intervention or placebo through the end of study participation (at 36 weeks 
corrected gestational age) and will be documented in the subject’s chart.  
 
Serious Adverse Events (SAE) and Adverse Events related to iNO Treatment: 
 
Severe adverse events of special interest include one or any combination of the 
following 
1. Pulmonary edema due to worsening of left ventricular dysfunction (occur when infants with 
pre-existing LV dysfunction are treated with iNO) 


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2. Elevated met Hb level (>5%) on 2 samples 6 hours apart or > 7.5% on a single reading 
3. If nitrogen di-oxide (NO2) concentration is more than 3 ppm for 6 hours or more than 5 
ppm on a single reading 
 
Methemoglobinemia and elevated NO2 levels are dose dependent adverse events seen among 
infant treated with higher dose (>20ppm) 
 
Adverse Events of Special Interest related to iNO treatment will be defined as one or any 
combination of the following 
1. Rebound Pulmonary Hypertension Syndrome: This is seen after the abrupt withdrawal of iNO. 
Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, 
systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary 
Hypertension occurs, reinstate iNO therapy immediately. 
2. Other rare adverse events may include thrombocytopenia (Platelets <50,000), hypokalemia 
(< 2.5 mEq/dl), hyperbilirubinemia while on study intervention (at phototherapy threshold for 
age and gestation) in absence of other known risk factors, atelectasis while on study 
intervention (as noted on chest x ray with lung collapse) and hypotension (below 5th centile 
for age and gestation) 
 
Severity Grading School for Adverse Events: 
Adverse event severity will be graded as below 
 
 
Classification  
Examples 
Mild (Grade 1) infants are 
asymptomatic or have mild 
symptoms associated with study 
intervention that require clinical or 
diagnostic observations only; no 
intervention indicated. 
• Methemoglobinemia >2% 
• NO2 > 1.5 
• Hypokalemia <3 
• Left Ventricular Dysfunction: Ejection Fraction decrease 
by 20% 
• Thrombocytopenia: Platelets <100,000 
• Hyperbilirubinemia in the absence of other known risk 
factors that requires single phototherapy 
• Mild Hypotension (mean BP < # gestation weeks) that 
requires no treatment 
Moderate (Grade 2) if infants 
have moderate symptoms that 
require discontinuing study 
intervention, non-urgent 
treatment or intervention 
• Methemoglobinemia >3% 
• NO2 > 2 
• Hypokalemia <2.7 
• Left Ventricular Dysfunction: Ejection Fraction decrease 
by 30% 
• Thrombocytopenia: Platelets <50,000 


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• Hyperbilirubinemia in the absence of other known risk 
factors that requires double phototherapy 
• Moderate Hypotension (mean BP < # gestation weeks) 
that requires IV fluid boluses after starting intervention 
Severe (Grade 3): Infants 
developed severe or medically 
significant symptoms that is not 
immediately life threatening but 
require treatment or 
intervention. 
• Methemoglobinemia >5% 
• NO2 > 3 
• Hypokalemia <2.5 
• Left Ventricular Dysfunction: Ejection Fraction decrease 
by 40% 
• Thrombocytopenia: Platelets <30,000 
• Hyperbilirubinemia in the absence of other known risk 
factors that requires triple phototherapy 
• Severe Hypotension (mean BP < # gestation weeks) that 
require single cardiotropic infusion after starting the study 
intervention 
Life Threatening (Grade 4): A 
complication that is life 
threatening and requires urgent 
intervention 
• Methemoglobinemia >7.5% 
• NO2 > 5 
• Hypokalemia <2 
• Left Ventricular Dysfunction: Ejection Fraction decrease 
by 50% 
• Thrombocytopenia: Platelets <30,000+ skin or mucosal 
bleeding 
• Hyperbilirubinemia in the absence of other known risk 
factors that requires exchange transfusion 
• Severe Hypotension (mean BP < # gestation weeks) that 
require multiple cardiotropic infusions after starting the 
study intervention 
Death (Grade 5): Any death that 
is directly related to study 
intervention 
• Any death that cannot be explained by the existing clinical 
status (Sepsis/ resistant respiratory failure etc.) and 
directly related to iNO toxicity (all points mentioned 
above) 
 
Relatedness/Causality of an adverse event will be determined and classified below 
 
Classification 
Definition 
 
Related 
 
There is an association between the event and the administration of 
investigational study drug, plausible mechanisms for the event to be related to 
the investigational study drug and causes other than the investigational study 
drug have been ruled out, and/or the event reappeared on re-exposure to the 
investigational study drug. 
 
Possibly related 
 
There is an association between the event and the administration of the 
investigational study drug and there is a plausible mechanism for the event to 
be related to investigational study drug, but there may also be alternative 


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etiology, such as characteristics of the subject’s clinical status or underlying 
disease.  
Unlikely related 
 
The event is unlikely to be related to the investigational study drug and likely 
to be related to factors other than investigational study drug.  
Not related 
 
The event is related to an etiology other than the investigational study drug 
(the alternative etiology will be documented in the study subject’s medical 
record).  
 
 
All SAEs should be reported to the PI and study Coordinator within 48 hours. Deaths should be 
reported to the PI and study Coordinator within 24 hours. The medical monitor will then be notified 
and will review the event. After review, additional notifications will be made to the DSMB, IRB, 
and FDA as necessary. When deemed necessary by the medical monitor, the DSMB will be 
notified of any significant events immediately and a meeting will take place to determine 
appropriate actions. 
 
Known Safety Profile of iNO: 
 
Controlled studies have included 325 patients on iNO doses of 5 to 80 ppm and 251 patients on 
placebo. Total mortality in the pooled trials was 11% on placebo and 9% on iNO. In both the 
NINOS and CINRGI studies, the duration of hospitalization was similar in iNO and placebo-treated 
groups. From all controlled studies, at least 6 months of follow-up is available for 278 patients 
who received iNO and 212 patients who received placebo. Among these patients, there was no 
evidence of an adverse effect of treatment on the need for rehospitalization, special medical 
services, pulmonary disease, or neurological sequelae. In the NINOS study, treatment groups 
were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV 
hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant 
therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage. In CINRGI, the only adverse 
reaction (>2% higher incidence on iNO than on placebo) was hypotension (14% vs. 11%).  
 
Nitrogen dioxide (NO2) forms in gas mixtures containing iNO and O2. Nitrogen dioxide may cause 
airway inflammation and damage to lung tissues. If the concentration of NO2 in the breathing 
circuit exceeds 5 ppm, decrease the dose of iNO. During iNO treatment, NO2 shall be 
continuously monitored. Methemoglobinemia is a function of time and nitric oxide dose in 
neonates. The methemoglobin (MetHb) concentration and time profiles during the first 12 hours 
of exposure to 0, 5, 20, and 80 ppm of iNO are shown below. 
 


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Safety Monitoring Plan   
 
Safety Monitoring 
A head ultrasound will be completed prior to the initiation of the study product. As standard of care 
in our NICU for this population, head ultrasound will be performed for intraventricular hemorrhage 
(IVH) screening at approximately 7 days  of life and at approximately 36 weeks corrected 
gestational age. or prior to discharge. Real time monitoring for NO2 will be available. 
Methemoglobin level will be checked within 4-8 hours from initiation of intervention and then every 
24-48 hours during the intervention. In addition to the primary and secondary study outcomes, we 
will monitor all infants for AE’s as defined above. 
 
Data and Safety Monitoring Board (DSMB) or Equivalent 
 
A data safety monitoring committee (DSMC) will be established for this trial. Safety data 
will be monitored by this committee at 50% enrollment, and AEs will be reviewed by the DSMC 
during the meeting. The DSMC will review the event information and determine if any action is 
necessary. The DSMC may stop the study or put the study on hold pending further review. 
 
Ethical Considerations N/A 
 
Sharing of Results with Subjects N/A 
 
 
Funding Source: We received a grant from Thrasher Foundation to support this study. 
We have also received iNO and placebo gas tanks for the study from Mallinckrodt 
Pharmaceuticals. 
 
Subject Stipends or Payments N/A 
 


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Publication Plan 
At the completion of the trial, we will prepare an abstract for presentation at a national 
pediatric meeting and then a manuscript will be prepared for submission to a peer review 
journal. 
 
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