Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary Dysplasia
Phase: PHASE2
Conditions: Bronchopulmonary Dysplasia
Sponsor: University of North Carolina, Chapel Hill

 
Safety of Furosemide in Premature Infants at Risk of 
Bronchopulmonary Dysplasia 
 
 
Study Protocol 
 
NCT number NCT02527798 
Document Date as Amended by Addendum V001 09/27/2019 
Document Date Protocol V6.0 03/22/2017 
 
 
 

NICHD-2014-FUR01 – FUROSEMIDE Addendum 001 
 
Version 1.0  
IND # 120933 
27 September 2019 
 
CLIENT CONFIDENTIAL 
Protocol Addendum 001 
27 September 2019 
 
Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary 
Dysplasia  
Follow-Up Hearing Test Results 
NICHD-2014-FUR01 
 
Summary:  
This document is an addendum to the Safety of Furosemide in Premature Infants at Risk of 
Bronchopulmonary Dysplasia (NICHD-2014-FUR01) protocol. The purpose of this addendum 
is to collect additional hearing test results from the subset of FUR01 participants who meet the 
eligibility criteria outlined below. We will record results from hearing tests that were conducted 
as part of standard care after completion of final FUR01 study assessments up to and including 
when the participant passes a hearing test (both ears), or until the participant reached 1 year of 
age, whichever comes first. 
 
Rationale: 
Infants born prematurely with documented failed or equivocal hearing tests typically have 
follow-up testing as part of their routine medical care through the first year of life. Follow-up 
testing typically reveals that a substantial number of these infants have normal hearing. Results 
of these follow-up hearing tests in FUR01 participants with a failed or equivocal hearing test 
reported at final study assessments prior to discharge, are important to collect to add to the 
safety profile of furosemide in previously premature infants at risk of bronchopulmonary 
dysplasia. 
 
Inclusion Criteria: 
1. Participated in the FUR01 Study 
2. Documented hearing test result (for either ear) was categorized as fail or equivocal at 
final FUR01 study assessments reported prior to discharge 
3. Documented informed consent, or waiver of informed consent, as determined by the 
ruling IRB 
 
Exclusion Criteria: 
1. Informed consent was withdrawn during FUR01 study participation 
 
Events of Interest: 
Failed hearing test (in either ear) identified by standard of care hearing screen (e.g. BAER), as 
determined by clinical care provider. 
 
 

NICHD-2014-FUR01 – FUROSEMIDE Addendum 001 
 
Version 1.0  
IND # 120933 
27 September 2019 
 
CLIENT CONFIDENTIAL 
Follow-Up Hearing Assessment / Data Collection 
 
For eligible participants, the study staff will continue to collect results from standard of care 
hearing tests, if available, until and including when the participant passes a hearing test 
(both ears) or until the participant is 1 year of age, whichever came first.  
 
Data collection will occur via medical record review.  
 
Analysis Plan: 
The analyses described in the protocol and Statistical Analysis Plan will be conducted using the 
follow-up hearing test results. 

NICHD-2014-FUR01 – FUROSEMIDE 
 
 
 
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Pediatric Trials Network 
 
Safety of Furosemide in Premature Infants at Risk of Bronchopulmonary 
Dysplasia  
 
NICHD-2014-FUR01 
 
Phase 2 Trial 
 
 
Funding Sponsor: 
The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) 
 
Funding Mechanism:  Task Order 
Protocol Date: 
22-Mar-2017 
Protocol Version: 
6.0  
IND Number: 
120,933 
Principal Investigator (IND Sponsor): 
 
Matthew M. Laughon, MD, MPH 
Professor 
The University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7596 
Office: 984-974-7851 
E-mail: matt_laughon@med.unc.edu 
 
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NICHD-2014-FUR01 – FUROSEMIDE 
 
 
 
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Statement of Compliance 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP): Consolidated Guideline, and 
the applicable regulatory requirements from the United States Code of Federal Regulations 
(CFR), including 45 CFR 46 (human subjects protection), 21 CFR 312 (Investigational New 
Drug), 21 CFR part 50 (informed consent), and 21 CFR part 56 (institutional review board [IRB]) 
as well as international regulatory requirements if applicable. 
 
All individuals responsible for the design and/or conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting this research. 
 
 
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SITE PRINCIPAL INVESTIGATOR STATEMENT 
 
I have read the protocol, including all appendices, and the investigator brochure or product 
label, and I agree that it contains all necessary details for my staff and me to conduct this study 
as described. I will personally oversee the conduct of this study as outlined herein and will make 
a reasonable effort to complete the study within the time designated. I agree to make all 
reasonable efforts to adhere to the attached protocol. 
 
I will provide all study personnel under my supervision with copies of the protocol and access to 
all information provided by the sponsor or the sponsor’s representative. I will discuss this 
material with study personnel to ensure that they are fully informed about the effectiveness and 
safety parameters and the conduct of the study in general. I am aware that, before beginning 
this study, the institutional review board responsible for such matters must approve this protocol 
in the clinical facility where it will be conducted. 
 
I agree to provide all participants with informed consent forms, as required by government and 
International Conference on Harmonisation regulations. I further agree to report to the sponsor 
or its representative any adverse events in accordance with the terms of this protocol and the 
U.S. Code of Federal Regulations, Title 21, part 312.64 as well as international regulatory 
requirements if applicable. 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
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STUDY PRINCIPAL INVESTIGATOR / IND SPONSOR SIGNATURE 
 
The signature below documents the review and approval of this protocol and the attachments 
(e.g., package inserts), and provides the necessary assurances that this clinical study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality and according to local legal and regulatory requirements and to the principles 
outlined in applicable U.S. federal regulations and ICH guidelines. 
 
 
Matthew M. Laughon, MD, MPH 
 
 
Pediatric Trials Network Study Principal 
Investigator Name  
 
 
 
 
 
 
 
Signature 
 
Date 
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Table of Contents 
 
 
page 
Statement of Compliance ............................................................................................................. i 
Signature Pages ......................................................................................................................... ii 
List of Abbreviations .................................................................................................................. vii 
Protocol Synopsis ...................................................................................................................…ix 
 
1 
Key Roles ......................................................................................................................... 11 
2 
Background Information and Scientific Rationale.............................................................. 13 
2.1 
Background Information ........................................................................................ 13 
2.2 
Scientific Rationale ............................................................................................... 13 
2.2.1 
The safety and pharmacokinetics of furosemide in premature infants is 
limited. There have been 4 studies of the pharmacokinetics of furosemide in 
premature infants. ..................................................................................... 16 
2.3 
Potential Risks and Benefits ................................................................................. 19 
2.3.1 
Potential Risks .......................................................................................... 19 
2.3.2 
Potential Benefits ...................................................................................... 19 
3 
Objectives ........................................................................................................................ 20 
3.1 
Study Outcome Measures .................................................................................... 20 
3.1.1 
Primary Outcome Measures ...................................................................... 20 
3.1.2 
Secondary Outcome Measures ................................................................. 20 
3.1.3 
Other safety and efficacy outcomes .......................................................... 20 
4 
Study Design .................................................................................................................... 22 
5 
Study Population .............................................................................................................. 23 
5.1 
Selection of the Study Population ......................................................................... 23 
5.2 
Inclusion/Exclusion Criteria ................................................................................... 23 
5.3 
Treatment Assignment Procedures ....................................................................... 23 
5.3.1 
Additional Participants ............................................................................... 23 
5.3.2 
Randomization Procedures ....................................................................... 24 
5.3.3 
Masking Procedures .................................................................................. 24 
5.3.4 
Reasons for Participant Withdrawal ........................................................... 24 
5.3.5 
Termination of Study ................................................................................. 25 
6 
Study procedures ............................................................................................................. 26 
6.1 
Summary of Procedures ....................................................................................... 26 
6.2 
Screening ............................................................................................................. 26 
6.3 
Enrollment/Baseline .............................................................................................. 26 
6.4 
Treatment Period .................................................................................................. 27 
6.5 
Follow-up Period ................................................................................................... 27 
6.6 
36-week PMA Assessment ................................................................................... 27 
6.7 
Final Study Assessment ....................................................................................... 28 
6.8 
Respiratory Assessment ....................................................................................... 28 
6.9 
Laboratory Evaluations ......................................................................................... 28 
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Table of Contents continued 
 
6.10 
PK Sampling ......................................................................................................... 29 
6.10.1 Minimizing Blood Loss ............................................................................... 29 
6.10.2 Specimen Preparation, Handling, and Shipping ........................................ 30 
6.11 
Adverse Event ...................................................................................................... 30 
7 
Study Product Description ................................................................................................ 31 
7.1 
Dosage and Study Drug Information ..................................................................... 31 
7.2 
Formulation, Packaging, and Labeling .................................................................. 32 
7.3 
Preparation and Administration of Study Intervention/Investigational Product ....... 32 
7.4 
Product Storage and Stability ................................................................................ 32 
7.5 
Concomitant Medications/Treatments ................................................................... 32 
8 
Assessment of Safety ....................................................................................................... 34 
8.1 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters 34 
8.1.1 
Adverse Event ........................................................................................... 34 
8.1.2 
Unexpected Adverse Event ....................................................................... 34 
8.1.3 
Identification of Events and Timeframe for Reporting ................................ 34 
8.1.4 
Follow-up of Adverse Events ..................................................................... 35 
8.1.5 
Guidelines for Assessing Intensity of an Adverse Event ............................ 35 
8.1.6 
Guidelines for Determining Causality......................................................... 35 
8.1.7 
Discontinuation of a Participant Due to Adverse Events ............................ 35 
8.1.8 
Reporting Procedures ............................................................................... 36 
8.2 
Serious Adverse Events ........................................................................................ 36 
8.3 
Regulatory Reporting ............................................................................................ 36 
8.4 
Safety Oversight ................................................................................................... 36 
8.5 
Dose Escalation and Halting Criteria: Safety Concerns ......................................... 36 
9 
Clinical Monitoring ............................................................................................................ 38 
10 
Statistical Considerations ................................................................................................. 39 
10.1 
Study Endpoints .................................................................................................... 39 
10.2 
Sample Size Considerations ................................................................................. 39 
10.3 
Interim Safety Analysis ......................................................................................... 39 
10.4 
Analysis Plan ........................................................................................................ 39 
11 
Participant Confidentiality ................................................................................................. 41 
12 
Informed Consent Process ............................................................................................... 42 
13 
Source Documents and Access to Source Data/Documents ............................................ 43 
14 
Quality Control and Quality Assurance ............................................................................. 44 
15 
Ethics/Protection of Human Participants ........................................................................... 45 
15.1 
Ethical Standard ................................................................................................... 45 
15.2 
Institutional Review Board .................................................................................... 45 
15.3 
Informed Consent ................................................................................................. 45 
15.4 
Participant Confidentiality ..................................................................................... 45 
15.5 
Study Discontinuation ........................................................................................... 46 
16 
Data Handling and Record Keeping ................................................................................. 47 
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Table of Contents continued 
 
16.1 
Data Management Responsibilities ....................................................................... 47 
16.2 
Data Capture Methods .......................................................................................... 47 
16.3 
Timing/Reports ..................................................................................................... 47 
16.4 
Study Records Retention ...................................................................................... 48 
16.5 
Protocol Deviations ............................................................................................... 48 
16.6 
Participant Privacy/Authorization .......................................................................... 48 
17 
Publication Policy ............................................................................................................. 49 
18 
Appendix A: Laboratory Values ........................................................................................ 50 
19 
Literature References ....................................................................................................... 51 
 
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List of Abbreviations 
 
AE 
Adverse Event 
AUC0-24 
Area Under the Concentration Time Curve 0-24 hours 
AUCss 
Area Under the Concentration Time Curve at Steady State  
BAER 
Brainstem Auditory Evoked Response 
BPD 
Bronchopulmonary Dysplasia 
BUN 
Blood Urea Nitrogen 
BW 
Birth Weight 
CA 
Calcium 
CFR 
Code of Federal Regulations 
CL 
Clearance 
Cmax 
Maximum Concentration 
CR 
Central Review 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DCF 
Data Collection Form 
DCRI 
Duke Clinical Research Institute 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
FiO2 
Fraction of Inspired Oxygen 
FDA 
Food and Drug Administration 
GA 
Gestational Age 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
Potassium 
Kg 
Kilogram 
L 
Liter 
LPM 
Liters per Minute 
MedDRA  
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mcg 
Microgram 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
Na 
Sodium 
NCPAP 
Nasal Continuous Positive Airway Pressure  
NICU 
Neonatal Intensive Care Unit 
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List of Abbreviations – continued 
 
NIH 
National Institutes of Health 
NRN 
Neonatal Research Network 
PDA 
Patent Ductus Arteriosis 
PI 
Principal Investigator 
PICU 
Pediatric Intensive Care Unit 
PNA 
Postnatal age 
PMA 
Postmenstrual age (gestational age plus postnatal age) 
PK 
Pharmacokinetics 
PO 
By mouth 
PTN 
Pediatric Trials Network 
RANTES 
Regulated on Activation, Normal T Cell Expressed & Secreted 
SAE 
Serious Adverse Event 
TORO 
Transfer of Regulatory Obligations 
t1/2 
Half-life 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 
 
 
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Protocol Synopsis 
Protocol Title: 
Safety of Furosemide in Premature Infants at Risk of 
Bronchopulmonary Dysplasia (BPD) 
Phase: 
2 
Product: 
Furosemide 
Objectives: 
Primary: Describe the safety of furosemide in premature infants at risk of 
BPD 
Secondary: Preliminary effectiveness and pharmacokinetics (PK) of 
furosemide 
Study Design: 
Multi-center, randomized, placebo-controlled, dose escalating, double 
masked, safety study  
Study Population: 
Inclusion Criteria 
1. Documented informed consent from legal guardian, prior to study 
procedures  
2. Receiving positive airway pressure (nasal continuous airway 
pressure, nasal intermittent positive pressure ventilation, or nasal 
cannula flow > 1LPM) or mechanical ventilation (high frequency or 
conventional) at time of randomization. 
3. < 29 weeks gestational age at birth 
4. 7-28 days postnatal age at time of randomization 
Exclusion Criteria 
1. Exposure to any diuretic ≤ 72 hours prior to randomization 
2. Previous enrollment and dosing in current study, “Safety of 
Furosemide in Premature Infants at Risk of Bronchopulmonary 
Dysplasia” 
3. Hemodynamically significant patent ductus arteriosus, as 
determined by the investigator 
4. Major congenital anomaly (e.g. congenital diaphragmatic hernia, 
congenital pulmonary adenomatoid malformation) 
5. Meconium aspiration syndrome 
6. Known allergy to any diuretic 
7. Serum creatinine >1.7 mg/dl < 24 hours prior to randomization 
8. BUN >50 mg/dl < 24 hours prior to randomization 
9. Na <125 mmol/L < 24 hours prior to randomization  
10. K ≤2.5 mmol/L < 24 hours prior to randomization 
11. Ca ≤ 6 mg/dL (or ionized calcium ≤ 3.2 mg/dl) < 24 hours prior to 
randomization   
12. Indirect bilirubin > 10 mg/dl < 24 hours prior to randomization*.  
13. Any condition which would make the participant, in the opinion of 
the investigator, unsuitable for the study. 
 
*If total bilirubin is measured without the differentiated (conjugated 
(direct) and unconjugated (indirect) fractions and is ≤10mg/dl, this 
value can be accepted for determination of indirect bilirubin ≤10mg/dl. 
Number of Participants: 
120 
Number of Sites: 
Approximately 30 sites 
Duration of 
Participation: 
Up to 35 days (28 days of study drug plus 7 days of safety monitoring). 
Information about hospitalization will be collected at 36 weeks post 
menstrual age and/or at discharge. 
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Dose Schedule: 
Table. N and dosing scheme 
 
 
N 
Furosemide 
(IV) 
Furosemide  
(enteral) 
N 
Cohort 
N 
Cohort 1 
Placebo 
10 
1 mg/kg q 24 
hours 
2 mg/kg q 24 
hours 
30 
40 
Cohort 2 
Placebo 
10 
1 mg/kg q 6 
hours 
2 mg/kg q 6 hours 
30 
40 
Cohort 3 
Placebo 
10 
2 mg/kg q 6 
hours 
4 mg/kg q 6 hours 
30 
40 
 
 
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1 
KEY ROLES 
For questions regarding this protocol, contact: 
 
Study Principal Investigator/ 
Matthew M. Laughon, MD, MPH 
IND Sponsor:  
Professor 
 
 
The University of North Carolina at Chapel Hill\ 
 
Chapel Hill, NC 27599-7596 
 
Telephone: (984) 974-7851 
 
E-mail:  matt_laughon@med.unc.edu 
 
 
 
Study Protocol Chair (Duke PI) 
Jason E. Lang, MD, MPH 
 
Associate Professor 
 
Duke Clinical Research Institute 
 
Duke University School of Medicine 
 
Durham, NC  27705 
 
Telephone: (919) 684-8657 
 
Email: Jason.Lang@duke.edu 
 
 
Sub-Investigators: 
Sub-investigators are included in the signature log and 
 
consent form(s) at each clinical site. 
 
 
 
Medical Monitor: 
Robert Lindblad, MD Chief Medical Officer 
 
The Emmes Corporation 
 
401 N. Washington Street, Suite 700 
 
Telephone: 301-251-1161 
 
Rockville, MD 20850 
 
Email: bpcasafety@emmes.com 
 
 
BPCA DCC Principal Investigator: 
Ravinder Anand, PhD  
 
Vice President 
 
 
The Emmes Corporation 
 
401 N. Washington Street, Suite 700 
 
Telephone: 301-251-1161 
 
Fax: 1-800-784-9044 
 
Rockville, MD 20850  
 
Email: furo@emmes.com 
 
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NICHD Contract Officer Representative: David Siegel, MD 
 
National Institutes of Health 
 
Eunice Kennedy Shriver 
 
National Institute for Child Health and Human 
 
Development 
 
BG 6710B RM 2327D 
 
6710B Rockledge Drive 
 
Bethesda, MD  20817 
 
Telephone: 301-594-8670 
 
Fax: 301-480-3876 
 
Email:  siegelda@mail.nih.gov  
 
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2 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
2.1 
Background Information 
The Best Pharmaceuticals for Children Act (BPCA) mandates the National Institutes of Health 
(NIH) to prioritize therapeutic areas in critical need for pediatric labeling, sponsor pediatric 
clinical trials, and submit these data to FDA for consideration for labeling changes.  This study 
will be conducted in accordance with Section 409l of the Public Health Service Act; as such, the 
results from this research may be submitted to the FDA for review and use in negotiated 
labeling changes.  This research study is contractually supported by the NICHD.  The NICHD 
awarded a contract to Duke University which established a Pediatric Trials Network (PTN) 
through its Duke Clinical Research Institute (DCRI) in order to facilitate trial design for studies 
supported by NIH.  A separate contract was awarded to The Emmes Corporation (Rockville, 
MD) to serve as the BPCA Data Coordinating Center (DCC). 
2.2 
Scientific Rationale 
Bronchopulmonary dysplasia (BPD) is defined by the NIH as mild, moderate, or severe 
based on required respiratory support at 36 weeks postmenstrual age.1 An NIH workshop 
proposed a severity-based definition that classifies BPD into mild, moderate or severe based on 
either postnatal age (PNA) or postmenstrual age (PMA) (Table 2-1). Ehrenkranz et al2 validated 
the NICHD severity-based definition of BPD by comparing it to the more traditional definitions of 
BPD such as supplemental oxygen at 28 days and at 36 weeks PMA. The NICHD consensus 
severity based scale better identified infants who are at most risk for poor pulmonary outcomes 
as well as neurodevelopment impairment than the traditional definitions.2 
 
Table 2-1. NICHD severity-based definition of BPD for premature infants at 36 weeks 
post-menstrual age (or discharge) 
 
No BPD 
Receiving > 21% supplemental oxygen (O2) for ≤28 days and not at 36 weeks PMA 
Mild BPD 
Receiving > 21% O2 for ≥28 days but not at 36 weeks PMA 
Moderate BPD 
Receiving > 21% O2 for ≥28 days  plus treatment with <30% O2 at 36 weeks PMA 
Severe BPD 
Receiving > 21% O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36 weeks PMA 
 
BPD is characterized by clinical signs and symptoms as well as pathologic findings in 
the lung.  The most common form of BPD is mild or moderate BPD. Animal studies suggest 
that the histology of infants with mild or moderate BPD have diffuse disease, minimal areas of 
lung hyperinflation, and most strikingly a reduction in alveoli and capillaries with little fibrosis.3,4 
Premature infants with severe BPD are generally exposed to prolonged mechanical ventilation 
and oxygen-often for weeks to months. These infants have characteristic areas of hyperinflation 
alternated with areas of focal collapse, as well as hyperplasia of the bronchial epithelium.5,6 
Radiography of these infants showed areas of heterogeneity throughout the lung fields and 
coarse scattered opacities in the most severe of infants.7  
 
Approximately 17,500 premature infants develop BPD each year in the US.  Although rare 
in the general population, BPD is the most common pulmonary morbidity associated with 
prematurity and is increasing.  Approximately 50,000 infants are born at ≤ 28 weeks gestational 
age each year in the US and ~35% develop BPD. The incidence of BPD varies widely between 
centers even after adjusting for potential risk factors. Data from 2010 from the Vermont Oxford 
Network shows the rates of BPD vary from 12% to 32%, depending on center, among infants 
born less than 32 weeks gestation. The rising number of infants with BPD might be due to the 
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improvement in the survival of extremely low gestational age infants that leads to an increase in 
the numbers of preterm infants who survive with BPD.8,9 With increased survival of more very 
low birth weight infants, due to several pre- and post-natal interventions, the number of infants 
at risk for developing BPD is increasing.10   
 
BPD is associated with life-long problems. Premature infants with BPD have a longer initial 
hospitalization than their peers without BPD,11 and BPD remains a substantial lifelong burden. 
Premature infants with severe BPD are particularly challenging for clinicians and frequently 
suffer from multiple morbidities such as pulmonary hypertension, prolonged hospitalization and 
death.12,13,14 The costs of the disorder are both social and economic and are measured in 
impaired childhood health and quality of life, family stress and economic hardship, and 
increased healthcare costs.15,16,17  
 
The strongest risk factor for BPD is prematurity. Epidemiologic studies of cohorts of 
premature infants consistently find that lower gestational age and lower birth weight are 
associated with an increased risk of BPD.18,19 Rojas et al20 identified low birth weight, presence 
of a patent ductus arteriosus (PDA) as risk factors for BPD in premature infants between 500 
and 1000 g. Marshall et al21 identified gestational age, birth weight, nosocomial infection, fluid 
intake on day 2, PDA, and ventilation at 48 hours of life as risk factors for BPD. A secondary 
analysis of the Neonatal Research Network Glutamine trial identified lower birth weight, lower 
gestational age, male, lower 1 and 5-minute Apgar Scores, higher oxygen requirement at 
24 hours of age, longer duration of assisted ventilation, use of postnatal steroids for BPD, 
presence of severe intraventricular hemorrhage, proven necrotizing enterocolitis, patent ductus 
arteriosus, and late onset sepsis as risk factors for BPD22 In preterm infants with respiratory 
failure enrolled in the Neonatal Research Network inhaled nitric oxide trial, the authors found 
that the risk of BPD was associated with lower birth weight, higher oxygen requirement, male 
gender, additional surfactant doses, higher oxygenation index and outborn status.23 Until 
recently, using these risk factors for prediction of BPD has been challenging.23 
 
Accurate prediction of BPD risk is now possible: The NICHD Neonatal Research Network 
recently developed an online, publicly available BPD prediction tool 
(https://neonatal.rti.org/index.cfm?fuseaction=BPDCalculator.start) (or enter NICHD BPD 
estimator in a search engine) that accurately predicts the risk of developing BPD by postnatal 
day using only 7 readily available variables: postnatal day, gestational age, birth weight, sex, 
race/ethnicity, ventilator support, and FiO2. Previous BPD prediction scoring systems have not 
been widely adopted, and each has had significant limitations. Some have satisfactory 
sensitivity and specificity but use a now outdated definition of BPD as oxygen therapy at 28 
postnatal days.24,25,26 Some include radiographs as part of the scoring system, which introduces 
subjectivity and reduces generalizability. Other limits to the utility of these models are the 
inclusion of ventilated infants only, the lack of categorization of BPD by severity, the exclusion of 
infants who die, and under-utilization of antenatal corticosteroids and surfactant 
therapy.27,28,29,30,31,32,33,34 Most importantly, none examined models by postnatal day through the 
first 28 postnatal days. The prediction tool is internally and externally validated and the models 
classify infants in the internal validation sample into the correct level of BPD or death in more 
than 8 out of 10 cases.  
 
There are no FDA indicated therapies that prevent BPD or are available to treat BPD 
symptoms.  To date, only vitamin A and caffeine prevent BPD without known significant long 
term adverse events.35,36  Postnatal steroids reduce BPD, but increase the risk of cerebral 
palsy.37,38  Although inhaled nitric oxide is beneficial in term infants with hypoxic respiratory 
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failure, the majority of studies demonstrate that it does not prevent BPD in premature infants, 
although there was a great deal of heterogeneity in the patient populations, dose, and duration 
of inhaled nitric oxide.39 One problem with the vast majority of trials of drugs to prevent BPD is 
that they did not establish the safety, preliminary effectiveness, PK, pharmacodynamics, or dose 
prior to implementation of phase III randomized, controlled trials.40 
 
Previous trials of diuretics, including furosemide, are limited to respiratory outcomes 
after one week of exposure. Two Cochrane reviews examine the use of loop diuretics such as 
furosemide and diuretics acting on the distal renal tubule.41,42 They include small studies of 
single dose or short course therapy and report short-term improvements in extubation rates, 
lung compliance, and fraction of inspired oxygen.  The incidence of BPD was not reported in 
these studies. Thus, there is biologic plausibility and physiologic studies that demonstrate 
improvement in lung function, but it is not known if furosemide prevents BPD.43 Prevention of 
BPD is an urgent, unmet public health need. 
 
Neonatologists are using furosemide without efficacy or safety data. Neonatologists 
commonly use diuretics, with furosemide being the most common by far (93% of diuretic use), in 
premature infants.44 Despite neonatal medicine’s long history of catastrophic adverse events 
resulting from inadequate study of drugs prior to their widespread use, the majority of drugs 
used in premature infants have undergone insufficient study to receive FDA labeling, including 
diuretics. Extrapolating diuretic safety, effectiveness, and dosing from adults underestimates the 
complicated physiology of premature infants, who have (1) larger extracellular fluid volume per 
unit body weight, (2) immature renal and hepatic function, and (3) a unique blood-brain barrier, 
each of which can alter drug disposition and clearance.45,46,47 Improper use of drugs in these 
vulnerable patients leads to increased rates of treatment failure, adverse events, mortality, and 
long-term morbidities.47 Diuretic studies specifically designed for premature infants are urgently 
needed. 
 
Furosemide is consistently in the top 10 among all medications reported in all 
hospitalized infants in the NICU: We reviewed data from the Pediatrix Data Warehouse from 
2005-2010 that includes information from ~20% of all infants admitted each year to the NICU in 
the US. Furosemide was the 7th most commonly used drug overall in the NICU from 2005-2010, 
and 5th most commonly used in extremely low birth weight infants (<1000 g; Table 2-2).48 
81 out of every 1000 hospitalized infants are exposed to furosemide. (668 infant-days per 1000 
infants).  
 
Table 2-2. Most common drugs in the NICU reported from 887,910 infants 
Medication 
% exposed 
FDA labeling for premature 
Ampicillin 
68 
None 
Gentamicin 
63 
Dosing information 
Caffeine 
14 
None for <28 weeks 
Vancomycin 
9 
Dosing information 
Beractant 
9 
Yes 
Cefotaxime 
8 
Dosing information 
Furosemide 
8 
None 
Fentanyl 
6 
None 
Dopamine 
6 
None 
Midazolam 
5 
Yes 
 
 
 
 
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Furosemide is the most common diuretic used: Among the 39,357 infants < 32 weeks and < 
1500 g who received diuretics, 93% (36,759) received furosemide (Table 2-3).44 
Table 2-3. Infants <32 weeks and <1500 g exposed to diuretics by type 
Diuretic1 
N (%)2 
Exposure3 
Courses3 
Days  
of exposure4 
 
Total N=39,357 
 
 
 
Furosemide 
36,759 (93) 
342 
784 
66 
Spironolactone 
9577 (24) 
86 
109 
3 
Chlorothiazide 
8309 (21) 
77 
98 
29 
Hydrochlorothiazide 
2473 (6) 
22 
26 
7 
Bumetanide 
1443 (4) 
13 
17 
2 
Acetazolamide 
1131 (3) 
11 
18 
2 
1 metolazone (n=147), hydrochlorothiazide/spironolactone (n=87), diazoxide (n=64), 
ethacrynic acid (n=61), mannitol (n=8), and amiloride (n=3) exposure was minimal 
2 infants could be exposed to more than one diuretic 
3 per 1000 infants (all infants) 
4 per 1000 infant-days (all infants) 
Furosemide clinical pharmacology:  Furosemide is a loop diuretic that acts in the proximal 
and distal tubules, as well as in the loop of Henle; it inhibits reabsorption of sodium and chloride 
at these sites. Furosemide is indicated in adults and pediatric patients for the treatment of 
edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, 
including the nephrotic syndrome. It is also indicated as adjunctive therapy in acute pulmonary 
edema in adults. 
2.2.1 The safety and pharmacokinetics of furosemide in premature infants is limited. 
There have been 4 studies of the pharmacokinetics of furosemide in premature 
infants.  
Table 2-4. Demographics of premature infants and dosing in furosemide studies 
 
N 
BW 
GA 
Postnatal 
age 
Dose 
Route 
Frequency of 
administration 
 
 
g 
weeks 
weeks 
mg/kg 
 
hours 
Aranda 197849 
8 
2391+/-290 
35+/-1.8 
1.6+/-0.8 
1-1.5 
IV 
Single dose 
Peterson 198050 
14 
1270+/-169 
30+/-0.8 
1.4+/-0.3 
1 
IV 
Single dose 
Vert 198251 
8 
1326+/-352 
29+/-2 
3.1+/-3 
0.29-1.48 
IV 
Single and multiple doses 
Mirochnick 198852 
10 
829+/-217 
26.6+/-2.9 
2.4+/-1 
1; 2-3 
IV; enteral 
12 
 
Table 2-5. Pharmacokinetics of furosemide in premature infants 
 
Volume of distribution 
Clearance 
 
Half-life 
 
L/kg 
ml/kg/hour 
hours 
Aranda 197849 
0.829+/-0.118 
81.6+/-15 
7.7+/-1 
Peterson 198050 
0.239 +/-0.027 
10.6+/-2.1 
19.9+/-3 
Vert 198251 
0.204+/-0.075 
6.9+/-5.1 
26.8+/-12.2 
Mirochnick 198852 
0.23 +/- 0.04 
1.62-73.8 (range) 
1.8-67.3 (range) 
 
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The use of furosemide varies widely among infants (Table 2-6) and among centers 
(Figure 2-1): Exposure of premature infants to diuretics varied widely across infants and sites. 
In some centers, the exposure is very high, suggesting that diuretics are used prophylactically, 
presumably to prevent BPD. Conversely, in other centers exposure is rare. These observations 
suggest that there is no universally accepted standard of care for when to expose infants to 
diuretics, and that no exposure is an option exercised in some centers. 
 
Table 2-6. Respiratory support on 1st day of each new diuretic course in infants <32 weeks and <1500 g44 
 
No 
support 
Nasal 
cannula 
HFNC/ 
NCPAP 
Mechanical 
ventilation 
High frequency 
ventilation 
FiO2 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
median, IQR 
furosemide 
4886 (6) 
12,935 (15) 
21,324 (25) 
32,811 (39) 
12,053 (14) 
35 (25, 50) 
spironolactone 
626 (5) 
3336 (29) 
4073 (35) 
3122 (27) 
460 (4) 
35 (27, 50) 
chlorothiazide 
463 (4) 
2867 (27) 
3151 (30) 
3418 (33) 
613 (6) 
36 (28, 50) 
hydrochlorothiazide 
147 (5) 
732 (27) 
984 (36) 
751 (27) 
130 (5) 
35 (26, 49) 
bumetanide 
18 (1) 
43 (2) 
98 (5) 
853 (47) 
813 (45) 
45 (30, 75) 
acetazolamide 
40 (2) 
178 (9) 
636 (33) 
917 (48) 
153 (8) 
35 (27, 48) 
HFNC: high flow nasal cannula 
NCPAP: nasal continuous positive airway pressure 
 
Figure 2-1. Percentage of infants <32 weeks and <1500g exposed to furosemide in 222 
sites of the Pediatrix Medical Group44  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
We reviewed the safety and outcomes of infants < 28 weeks born at UNC and Duke from 
2006-2012: We reviewed infants < 28 weeks gestation and survived > 7 postnatal days at UNC 
and Duke. Traditionally, UNC is a low furosemide exposure site with a high rate of BPD and 
Duke is a high furosemide exposure site with a low rate of BPD. We found that the data 
confirmed this supposition (Table 2-7 and Figure 2-2) — UNC had a 58% furosemide exposure 
with a 60% incidence of death or BPD while Duke had a 95% furosemide exposure with a 
35%% incidence of death or BPD.  UNC infants were most often exposed to 0-2 mg/kg/day of 
furosemide (Figure 2-2) while Duke infants were most often exposed to 4-6 mg/kg/day of 
furosemide, with 25% exposed to >8 mg/kg/day. 
 
 
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Table 2-7. Premature infants <28 weeks from 2006-2012 at Duke or UNC NICU 
Characteristics 
DUKE 
UNC 
N 
350 
329 
Gestational Age(weeks): Median (IQR) 
25 (24, 27)
26 (24, 27)
Birth Weight(grams): Median (IQR) 
760 (640, 870)
760 (640, 880)
Antenatal Steroids: % 
92.8%
86.8%
Surfactant: % 
87.1%
81.7%
Furosemide: % 
94.6%
57.8%
Maximum Daily Dose(mg/kg/day): Median (IQR) 
6.3 (4.2, 8.3)
2.0 (1.9, 2.9)
Cumulative Dose(mg/kg): Median (IQR) 
100.9 (40.3, 191.7)
12.5 (4.3, 39.6)
 Duration(days): Median (IQR) 
33 (14, 54)
7 (3, 26)
Bronchopulmonary Dysplasia or Death at 36 Weeks: % 
35.4%
59.6%
Failed Hearing: % 
9.1% 
3% 
Hypernatremia: % 
1.1% 
7.3% 
Hyponatremia: % 
5.4% 
3.3% 
Hyperchloremia: % 
19.7%
36.8%
Hyperkalemia: % 
13.1%
15.8%
Hypokalemia: % 
21.4%
11.2%
High Bicarbonate: % 
9.4% 
0% 
Low Bicarbonate: % 
70.3%
40.7%
Elevated BUN: % 
23.4%
4.60%
Elevated Creatinine: % 
12.9%
1.5%
Elevated Alkaline Phosphate: % 
6.3%
3.6%
Figure 2-2. Maximum daily dose of furosemide at UNC and Duke 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
cBecause the bioavailability of enteral furosemide is approximately 0.5 times that of the intravenous formulation, the enteral + 
intravenous furosemide dose was calculated as:0.5 * enteral dose (mg/kg) + intravenous dose (mg/kg) 
0
10
20
30
40
50
60
Percent of premature infants exposed
Maximum daily dose of furosemide (mg/kg/day)
UNC
Duke
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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
2.3.1.1 Risks of Blood Drawing 
There are small risks to blood sampling, usually some pain/discomfort with the blood stick and 
blood loss. We will make every effort to avoid additional (to standard of care) sticks for this 
study and will time clinical blood draws to coincide with timed samples, using existing 
intravenous lines when possible.  
2.3.1.2 Furosemide 
Furosemide is associated with water loss and electrolyte depletion. Literature reports indicate 
that premature infants with postmenstrual age < 31 weeks receiving doses exceeding 
1 mg/kg/24 hours may develop plasma levels associated with potential toxic effects including 
ototoxicity. In premature infants, furosemide may precipitate nephrocalcinosis/nephrolithiasis.  If 
furosemide is administered to premature infants during the first weeks of life, it may increase the 
risk of persistence of patent ductus arteriosus. 
2.3.2 Potential Benefits 
Furosemide is used to reduce pulmonary edema, improve pulmonary mechanics, reduce 
exposure to mechanical ventilation, and prevent BPD. Although these improvements are not 
proven, increase in pulmonary function42 and decrease risk of BPD are potential benefits for 
participants enrolled in the study who receive furosemide. Conclusions drawn from this study 
will benefit infants receiving furosemide in the future through better understanding of dose 
response and characterization of the safety profile of these drugs. 
 
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3 
OBJECTIVES 
 
Primary: Describe the safety of furosemide in premature infants at risk of BPD  
 
Secondary: Preliminary effectiveness and pharmacokinetics (PK) of furosemide. 
3.1 
Study Outcome Measures 
3.1.1 Primary Outcome Measures 
Safety as determined by adverse events experienced by the participants. 
3.1.2 Secondary Outcome Measures 
3.1.2.1 Preliminary effectiveness: Risk of BPD 
The outcome measure is change in moderate-severe BPD or death risk from baseline. 
Moderate-severe BPD or death risk will be defined by the NICHD Neonatal Research Network 
BPD outcome estimator. (https://neonatal.rti.org/index.cfm?fuseaction=BPDCalculator.start).  
 
The BPD outcome estimator uses the following information to provide individual risk of BPD: 
1. Gestational age (weeks) 
2. Birth weight (g) 
3. Sex 
4. Maternal Race/Ethnicity 
5. Postnatal day 
6. Ventilation type (on the postnatal day of interest) 
7. FiO2 (%) (on the postnatal day of interest) 
 
Note: The BPD estimator provides an estimate of the risk of BPD (as defined by NIH: none, 
mild, moderate, severe) or death by postnatal day. The risk of BPD is presented as a %. For this 
protocol, we will dichotomize the outcome as above (none-mild vs. moderate-severe-death).  
For example, a 25 week Hispanic female with birth weight of 689 g on postnatal day 14 on 
mechanical ventilation with a FiO2 of 0.45 has risk of no BPD of 1.6%, mild 27.9%, moderate 
28.9%, severe 30.5%, and death 11%. Thus, none-mild risk is 29.5% and moderate-severe-
death risk is 70.5%.  
 
We will collect risk of BPD or death as defined by NICHD NRN BPD estimator on days 7, 14, 21 
and 28 of study drug. We will use the day closest to the day used to calculate the BPD 
estimator. The BPD estimator includes infants up to 28 postnatal days; for infants in this 
protocol older than that, we will use the 28 day estimates. 
3.1.2.2 Pharmacokinetics 
A population PK analysis will be performed. Using the final population PK model, empirical 
Bayesian estimates of clearance (CL), volume of distribution (V), half life, and exposure metrics 
(e.g. AUC, maximum concentration) will be generated for each patient.  
 
3.1.3 Other safety and efficacy outcomes 
1. Death: All infants who died at or before 36 weeks PMA will be included. 
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2. BPD: We will define BPD as it was defined for the NICHD BPD estimator.  We will 
define BPD as a dichotomous (none-mild vs. moderate-severe) variable and as a 
categorical variable (none, mild, moderate, or severe) among survivors by modifying 
the NIH consensus definition of BPD20,21 to include infants transferred prior to 36 
weeks and the need for oxygen at 36 weeks PMA (or discharge, if sooner than 36 
weeks PMA).29 We will define BPD as follows:  
1. No BPD: receiving > 21% supplemental oxygen (O2) for ≤28 days) and not at 36 
weeks PMA 
2. Mild BPD: receiving > 21% O2 for ≥28 days  but not at 36 weeks PMA 
3. Moderate BPD: receiving > 21% O2 for ≥28 days  plus treatment with <30% O2 
at 36 weeks PMA 
4. Severe BPD: receiving > 21% O2 for ≥28 days plus ≥30% O2 and/or positive 
pressure at 36 weeks PMA 
5. Death or BPD: either 1 or 2 
6. Hearing loss: Hearing loss will be identified by hearing test (e.g. BAER) prior to 
 
discharge. 
7. Nephrocalcinosis/nephrolithiasis: Nephrocalcinosis/nephrolithiasis will be 
determined by renal ultrasounds performed locally and interpreted by the local 
radiologist.  Renal ultrasounds that are positive for nephrocalcinosis or 
nephrolithiasis will be reviewed by an independent study radiology specialist to 
verify the positive findings.  
 
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4 
STUDY DESIGN 
See Protocol Synopsis. 
 
This study will be conducted in accordance with current U.S. Food and Drug Administration 
regulations and guidelines, (or, as applicable, international regulations and associated 
guidelines), the International Conference on Harmonisation Guidelines on Good Clinical 
Practice (which incorporate the principles of the Declaration of Helsinki), as well as all other 
applicable national and local laws and regulations. 
 
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5 
STUDY POPULATION 
5.1 
Selection of the Study Population 
Premature infants (inpatient in neonatal intensive care units) will be randomized in a dose 
escalating approach 3:1 (furosemide:placebo) into 3 Cohorts with escalating doses of 
furosemide.  There will be 40 randomized and dosed participants in each Cohort for a total of up 
to 120 participants. 
5.2 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. Documented informed consent from legal guardian, prior to study procedures  
2. Receiving positive airway pressure (nasal continuous airway pressure, nasal intermittent 
positive pressure ventilation, or nasal cannula flow > 1LPM) or mechanical ventilation 
(high frequency or conventional) at time of randomization 
3. < 29 weeks gestational age at birth 
4. 7-28 days postnatal age at time of randomization 
 
Exclusion Criteria 
1. Exposure to any diuretic ≤ 72 hours prior to randomization  
2. Previous enrollment and dosing in current study, “Safety of Furosemide in Premature 
Infants at Risk of Bronchopulmonary Dysplasia” 
3. Hemodynamically significant patent ductus arteriosus, as determined by the investigator 
4. Major congenital anomaly (e.g. congenital diaphragmatic hernia, congenital pulmonary 
adenomatoid malformation) 
5. Meconium aspiration syndrome 
6. Known allergy to any diuretic 
7. Serum creatinine >1.7 mg/dl < 24 hours prior to randomization 
8. BUN >50 mg/dl < 24 hours prior to randomization  
9. Na <125 mmol/L < 24 hours prior to randomization  
10. K ≤2.5 mmol/L < 24 hours prior to randomization  
11. Ca ≤ 6 mg/dL (or ionized calcium ≤3.2 mg/dl) < 24 hours prior to randomization  
12. Indirect bilirubin >10 mg/dl < 24 hours prior to randomization* 
13. Any condition which would make the participant, in the opinion of the investigator, 
unsuitable for the study 
 
*If total bilirubin is measured without the differentiated (conjugated (direct) and 
unconjugated (indirect)) fractions and is ≤10mg/dl, this value can be accepted for 
determination of indirect bilirubin ≤10mg/dl.   
5.3 
Treatment Assignment Procedures  
5.3.1 Additional Participants 
If a participant is randomized (see 5.3.2) and receives < 7 days of study drug, then additional 
participants may be enrolled. 
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5.3.2 Randomization Procedures 
Participants who satisfy all eligibility criteria will be randomized 3:1 (furosemide: placebo). All 
three Cohorts will use the same randomization scheme. The first 40 subjects will be enrolled in 
Cohort 1, and dose escalation via enrollment in other Cohorts will occur only after safety criteria 
are satisfied (see section 8.5). Participants randomized to placebo will receive the standard of 
care with regards to fluid imbalance; use of similar strategies for fluid and ventilator 
management will be part of the site selection criteria. 
 
The participant’s randomized treatment assignment will be obtained through the AdvantageEDC 
enrollment module. In the event that AdvantageEDC is not available at the time of 
randomization, a back-up system specified in the MOP will be used. 
 
Randomization will be stratified by center. If a participant is randomized but does not receive 
study drug, that participant will not count towards total sample size and will be replaced by a 
new participant who, in turn, will be assigned a new identification number and receive treatment 
corresponding to the new identification number. The reason for not dosing the participant will be 
noted on the CRF.  
 
 
5.3.3 Masking Procedures 
Infants randomized to the placebo treatment group will receive the equivalent volume of 
dextrose 5% appropriate for IV use or enteral use (if receiving enteral study drug). The 
Pharmacy at each site will prepare and dispense the study drug into appropriate sized syringes 
in a masked manner, staff assessing participant outcomes will be blinded to treatment. 
 
 
5.3.4 Reasons for Participant Withdrawal 
The clinician may choose to suspend study drug dosing for up to 48 hours for any reason.    
 
 
The investigator will withdraw a participant from receiving further study interventions if: 
1. Any clinically significant adverse event (AE) is deemed by the principal investigator to 
require discontinuation of investigational product.  The participant will continue to be 
followed for safety for 7 days after the last dose and complete all remaining follow up 
assessments unless consent has been withdrawn. 
2. Suspension of the study drug for >48 hours. If study product is suspended for >48 hours, 
this is not a protocol deviation.  The participant will proceed directly into the follow-up 
period and be followed for safety for 7 days after the last dose and complete all 
remaining follow up assessments unless consent has been withdrawn. 
3. Intentional unmasking of the subject. All intentional unmasking events should be 
recorded on a protocol deviation form in EDC within 24 hours of the unmasking. The 
decision to unmask will be made in consultation with the Medical Monitor if at all 
possible.  The unmasked participant will be followed for safety for 7 days after the last 
dose and complete all remaining follow up assessments unless consent has been 
withdrawn. 
4. Requested by the NIH, FDA, PTN, or DMC. 
5. Participants’ parent or legal guardian may withdraw voluntarily from participation in the 
study at any time. Participants’ parent or legal guardian is not obligated to state the 
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reason for withdrawal. The reasons for withdrawal, or failure to provide a reason, must 
be documented by the investigator on the completion/ withdrawal section of the 
electronic case report form (CRF).  
 
6. Before discontinuing a participant from the investigational product, the local investigator 
must contact the medical monitor and/or protocol PI/Chair except in emergency 
situations. If the site cannot wait until the next business day, it will be considered an 
emergency situation. Participants who are prematurely discontinued from receiving study 
product for any reason will be followed for 7 days for adverse event monitoring and 
complete all remaining study assessments unless consent has been withdrawn.  
5.3.5 Termination of Study  
This study may be terminated at any time by FDA, NIH, the Investigational New Drug 
Application (IND) sponsor, or the Data Monitoring Committee (DMC). 
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6 
STUDY PROCEDURES 
6.1 
Summary of Procedures 
 
Table 6-1: Schedule of study procedures 
 
Screen/ 
Baseline 
Treatment 
Follow-up 
 36 weeks 
PMA 
assessment 
Final study 
assessment 
Time (Day) 
01 
1-282 
Day 1-7 post last 
study dose 
36 weeks PMA Discharge/ET/ 
or Transfer 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Physical examination 
X 
 
X 
X 
 
Medical history 
X 
 
 
 
 
Actual Weight 
X 
 
X 
X 
 
Respiratory assessment 
X 
X (Q WEEK) 
X 
X 
X 
Laboratory evaluations 
X 
X6 (2X WEEK) 
X 
X 
 
Study drug administration 
 
X 
 
 
 
Concomitant medications 
 
X 
 
 
 
Adverse events 
X4 
X 
X 
 
 
Blood sampling 
 
X (AFTER DAY 
7) 
 
 
 
Hearing screen 
 
 
 
 
X 
Renal ultrasound  
 
X5 
X5 
X5 
X 
Discharge information3 
 
 
 
 
X 
1 Refers to time point prior to start of study drug and may be the same calendar date as day 1   
2 While on study drug 
3 Transfer, discharge, or death 
4 AEs will be collected following initial study-specific procedure (e.g., screening blood draws, dosing) 
5 Record results of renal ultrasound if collected as standard of care 
6.2 
Screening  
Infants < 29 weeks GA at birth will be screened for eligibility.  
6.3 
Enrollment/Baseline 
Research staff will document informed consent from the parent/guardian for all participants who 
satisfy eligibility criteria.  
 
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The following information will be recorded in the CRF from the clinical medical record: 
 
1. Participant demographics, including birth weight and gestational age at birth 
2. Medical history 
3. Physical examination, including weight 
4. Respiratory assessment (see 6.8) 
5. Laboratory evaluations (see 6.9) 
6. Adverse events following initial study-specific procedure (see 6.11) 
6.4 
Treatment Period 
The treatment period will include days 1 to 28 or last day of study drug if early withdrawal of 
study therapy. 
 
The following information will be collected while the participant is on study: 
1. Weight, assessed every 7 (+/- 1) days throughout the treatment period 
2. Date, time, and route of each study drug dose will be recorded 
3. All concomitant medications 
4. Respiratory assessment, weekly (see 6.8) 
5. Laboratory evaluations, at least 2x/week minimum (see 6.9). 
6. PK sampling (see 6.10) 
7. Results of renal ultrasound if performed per SOC; specifically 
nephrocalcinosis/nephrolithiasis 
8. Adverse events (see 6.11) 
6.5 
Follow-up Period 
Follow-up period will include days 1-7 after last study dose, including in cases of early 
withdrawal of study therapy.  
 
The following information will be reported at Day 7 (or day closest to Day 7, if > 1 assessment is 
available):  
1. Physical examination, including weight 
2. Respiratory assessment (see 6.8) 
3. Laboratory evaluations (see 6.9) 
4. Results of renal ultrasound, if performed per SOC 
5. Adverse events (all during the follow-up period) (see 6.11) 
6.6 
36-week PMA Assessment 
The following information will be reported at 36 weeks PMA if available. If the participant is 
discharged before 36 weeks, record assessment closest to discharge date.  (Record latest 
results within week 36 if > 1 assessment is available): 
1. Physical examination, including weight 
2. Respiratory assessment (see 6.8) 
3. Laboratory evaluations (see 6.9) 
4. Results of renal ultrasound (if obtained per SOC) 
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6.7 
Final Study Assessment 
Final study assessment will occur at the time of discharge, early termination or transfer and the 
following information will be collected:  
1. Respiratory assessment (see 6.7) 
2. Results of hearing test (e.g. BAER; must be performed if not done per SOC after the 
treatment period). If multiple tests are performed per SOC throughout the study period, 
all results should be recorded in AdvantageEDC.  
3. Results of renal ultrasound (must be performed if not done per SOC after the treatment 
period).  If multiple tests are performed per SOC throughout the study period, all results 
should be recorded in AdvantageEDC. 
4. Discharge information 
a. Home or transfer 
b. Died or alive 
c. Duration of hospitalization 
6.8 
Respiratory Assessment 
The following information will be collected at baseline, on day 7, 14, 21, and 28 (+/- 1 day) of 
study drug administration, once during the follow-up period, once at 36 weeks PMA, and once at 
discharge: 
1. Maximum FiO2 (defined as the maximum FiO2 on day of assessment, unless it is known 
to be a temporary (<2 hour) increase in FiO2) 
2. Ventilation type: 
a. High frequency ventilator 
b. Conventional mechanical ventilator 
c. NCPAP (or equivalent, see inclusion criteria in protocol synopsis table) 
d. Cannula/Hood 
e. None (room air with no support) 
6.9 
Laboratory Evaluations 
The following laboratory evaluations must be conducted (if not obtained per SOC) prior to 
randomization (within 24 hours of randomization), and at least 2 times per week (at least 42 
hours apart).  For cohort 2 and 3, laboratory values must be obtained in the 48 hours prior to 
increasing the study drug dose. All laboratory values below will be collected from the 1st dose of 
study drug through 7 days following the last dose of study drug.  The values will also be 
captured at 36 weeks PMA. 
1. Indirect bilirubin*  
2. Sodium 
3. Potassium 
4. Bicarbonate 
5. BUN 
6. Creatinine 
7. Calcium and/or ionized calcium 
*If a total bilirubin value is measured without the differentiated (conjugated (direct) and unconjugated 
(indirect)) fractions and is ≤ 10mg/dl, this value can be reported instead of indirect bilirubin 
 
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If the above laboratory evaluations are obtained more frequently than required by protocol, all 
test results must be entered into the EDC system. 
SOC laboratory evaluations: We will also record values for platelets, phosphorus, chloride, 
alkaline phosphatase, and caffeine levels from 24 hours prior to randomization through 7 days 
following the last dose of study drug if reported per SOC.  The values will also be captured at 36 
weeks PMA if reported per SOC. 
6.10 
PK Sampling 
Table 6-2 below provides the optimal sampling collection windows. Blood samples will be 
collected after any dose following completion of 7 days (168 hours) of study drug administration. 
Every effort should be made to collect plasma samples within the below windows; however, 
samples obtained outside of the sampling windows will not be considered protocol deviations. 
Sample collection windows are relative to the end of the infusion; all samples should be 
collected after the flush. Blood samples should not be drawn during infusions or during the flush. 
Elimination samples will only be obtained around the last dose of study drug. 
 
Table 6-2: Optimal sampling collection windows (time in relation to end of infusion) 
Dosing interval (hours) 
Sample # 
6 Hour 
24 Hour 
1 
within 30 min 
within 30 min 
2 
2-4 hours 
2-4 hours 
3 
Within 30 min prior to next dose 
6-8 hours 
4 
12-18 hours (elimination) 
12-16 hours 
5 
N/A 
20-22 hours 
6 
N/A 
Within 30 min prior to next dose 
7 
N/A 
48-72 hours (elimination) 
 
6.10.1 Minimizing Blood Loss 
Plasma samples will be collected in 200 μL blood aliquots. To minimize the amount of blood 
sampling, a limited sampling scheme will be employed such that no more than 7 timed PK 
samples (1.4 mL of blood) are obtained from each participant for analysis.  Participants in all 
treatment groups (including placebo) will have samples collected. Infants assigned to the 
placebo treatment group will have biomarkers of bronchopulmonary dysplasia measured in a 
central laboratory (details in MOP; biomarkers may include: IL-1, IL-6, IL-8, TNF-α, and 
RANTES) instead of PK levels. 
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6.10.2 Specimen Preparation, Handling, and Shipping  
Detailed information will be in the MOP.  
6.11 
Adverse Event 
AEs will be collected following initial study-specific procedure (e.g., screening blood draws, drug 
administration), through 7 days post last study dose. See section 8 for safety information. 
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STUDY PRODUCT DESCRIPTION 
7.1 
Dosage and Study Drug Information  
Table 7-1: Dosing  
Table. N and dosing scheme 
 
 
N 
Furosemide 
(IV) 
or 
Furosemide  
(enteral) 
N 
Cohort N 
Cohort 1 
Placebo 
10 
1 mg/kg q 24 
hours 
or 
2 mg/kg q 24 
hours 
30 
40 
Cohort 2* 
Placebo 
10 
1 mg/kg q 6 
hours 
or 
2 mg/kg q 6 
hours 
30 
40 
Cohort 3* 
Placebo 
10 
2 mg/kg q 6 
hours 
or 
4 mg/kg q 6 
hours 
30 
40 
* See dose escalation, below, for Cohorts 2 and 3 
 
Dosing escalation for participants in Cohort 2 and Cohort 3: Participants enrolled in Cohort 
2 and Cohort 3 will initially start at 1 mg/kg q 24 hours of study drug and will increase to the 
assigned target in “every other day” increments.  For example, infants assigned to Cohort 3 who 
are receiving IV dosing will start at 1 mg/kg q 24, then 1 mg/kg q 12, then 1 mg/kg q 6, and then 
2 mg/kg q 6, in this example the assigned target dose would be achieved on treatment day 7.  
NOTE: Dosing will increase as long as the BUN ≤ 50 mg/dL, the creatinine is ≤ 1.7 mg/dL, the 
Na is > 125 mmol/L, and the K is > 2.5 mmol/L, Ca >6 mg/dL (or ionized Ca > .8 mmol/L)  on 
surveillance chemistries obtained within 48 hours prior to dose escalation. An infant will meet 
respiratory criteria for escalation only if the infant is receiving exogenous oxygen or respiratory 
support (nasal cannula or positive pressure from any device) for at least 12 hours. Infants who 
do not initially qualify for escalation should be reevaluated daily for whether they meet these 
criteria, and escalation must occur within 24 hours of an infant meeting all criteria (respiratory 
and laboratory).  If escalation does not occur within this timeframe, then a protocol deviation 
must be recorded.  
 
Weight:  
• 
Actual weight will be recorded at baseline, once during safety follow-up, and at 36 weeks 
PMA.  
• 
Dosing weight is the weight utilized to determine dosing (which may be different from 
actual weight), and will be recorded for each study dose. Dosing should be reassessed 
for adjustment according to any dosing weight changes determined every 7 (+/- 1) days 
throughout the treatment period. There is no protocol requirement to modify dose based 
solely on actual weight. Dose may or may not be adjusted based on the weight.  
 
Open label diuretics: Administration of other diuretics during the study period (day 1-28) will be 
considered a protocol deviation because administration of no diuretics is considered part of 
standard of care at some centers. Clinicians may choose to administer diuretics after day 28 at 
their discretion. 
 
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Na/K supplementation Na and K supplementation is permitted at the discretion of the clinical 
team. 
 
Intravenous (IV) versus enteral dosing: If the participant does not have an IV or if the clinical 
team elects to use enteral dosing, then the dose of study drug will be twice that of the IV dosing 
(from the product label). Placebo will be administered either enterally or IV as well.  
 
7.2 
Formulation, Packaging, and Labeling  
All study drugs will be standard intravenous or enteral formulations. Only marketed IV 
formulation for IV administration and marketed oral solution for the enteral route will be used. 
Sites must only use the alcohol free enteral formulation. This protocol will not specify the brand 
of product. Each product will be “off the shelf” as provided by the site’s pharmacy. Detailed 
information will be part of the MOP.  
 
7.3 
Preparation and Administration of Study Intervention/Investigational Product 
The pharmacy at each site will prepare and distribute the study drug in a masked manner to the 
NICU/PICU and drug will be administered by bedside nurse. Intravenous doses of study drug 
will be administered within15 minutes.  Enteral doses will be administered with feedings.  The 
enteral formulation, if used, will be administered enterally either by mouth, orogastric, 
nasogastric, gastrostomy tube, or other enteral tubes. For enteral administration in infants 
receiving bolus feedings, mixing and timing of administration should follow the institutional 
policy.  If there is no specific institutional policy, study drug will be mixed in 10 mL of feedings to 
be given at the end of the feed, and if not followed, it will be considered a protocol deviation. If 
feeds are administered on pump, timing of administration should follow the institutional policy.  If 
there is no specific institutional policy, study drug will be mixed in the last 30 minutes of feeding 
volume, and if not followed, it will be considered a protocol deviation.  The investigational 
pharmacist will be unmasked, and will prepare masked study drug.  
 
Administration of the study drug must occur within: 
• 
+/- 3 hours of the scheduled time of q24h dosing, 
• 
+/- 2 hours of the scheduled time for q12h dosing, 
• 
+/- 1 hour of the scheduled time for q6h dosing. 
 
Further guidance will be included in the MOP. 
 
7.4 
Product Storage and Stability  
Detailed information will be part of the MOP. 
7.5 
Concomitant Medications/Treatments 
All drugs and/or treatments, other than additional diuretics, are permitted while on study. Use of 
other or additional diuretics is considered a protocol deviation. All concomitant medications, 
including intravenous potassium boluses or enteral electrolyte supplements, and treatments 
(including other diuretics) will be reported during the study drug administration period. We will 
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collect the dose amount, start time and date for all caffeine doses administered during study 
drug administration period.  Any instances in which additional diuretics, including standard of 
care furosemide, are administered during the study drug administration period will be 
considered a protocol deviation. 
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8 
ASSESSMENT OF SAFETY 
8.1 
Methods and Timing for Assessing, Recording and Analyzing Safety Parameters 
Safety will be assessed following initial study-specific procedure e.g., screening blood draws, 
dosing through 7 days post last study dose and it will be assessed by frequency and incidence 
of AEs and SAEs. A safety monitoring committee (DMC) will be convened by NIH to review data 
and safety information from study participants throughout the study and prior to dose escalation 
into Cohorts 2 and 3. 
8.1.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in humans, whether or not 
considered drug-related, which occurs during the conduct of a clinical trial. (Any change in 
clinical status, routine labs, x-rays, physical examinations, etc.), that is considered clinically 
significant by the study investigator is considered an AE. 
 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. A reasonable possibility implies that there is evidence 
that the drug caused the event.  
 
Adverse reaction is any adverse event caused by the drug.  
 
Serious adverse event or serious suspected adverse reaction or serious adverse reaction 
as determined by the investigator or the sponsor is any event that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening AE (“life-threatening” means that the study participant was, in the 
opinion of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention)  
3. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event  
8.1.2 Unexpected Adverse Event  
This is defined as any adverse event, the specificity or severity of which is not consistent with 
the package insert or investigational plan. 
8.1.3 Identification of Events and Timeframe for Reporting  
As all participants in this study will have pre-existing medical conditions and may be currently 
hospitalized, those pre-existing conditions will not be considered as adverse events. New 
events that occur or pre-existing conditions that worsen in terms of frequency or intensity will be 
reported as adverse events.  
 
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All reportable events as defined above, determined to be an AE based on physical examination, 
laboratory findings, or other means, will be reported in the electronic case report form (e-CRF). 
The investigator will provide the date of onset and resolution, intensity, frequency, action(s) 
taken, changes in study drug dosing, relationship to study drug, and outcome. 
8.1.4 Follow-up of Adverse Events 
All events (study-related or not) must be followed until resolution, or if ongoing at the time of last 
safety contact, will be followed up to adequately evaluate the participant’s safety or until the 
event stabilizes. All serious suspected adverse reactions and serious adverse reactions will be 
followed until resolution or until the patient is medically stable. All other events that cannot be 
resolved by 30 days after the safety monitoring period will be considered resolved by 
convention and entered in the electronic data capture (EDC) system as such. Any event 
beginning more than 7 days after the last dose of study drug will not be captured.  
8.1.5 Guidelines for Assessing Intensity of an Adverse Event 
The investigator should use the following definitions when assessing intensity of an adverse 
event: 
1. MILD: Participant is aware of symptoms or has minor findings but tolerates them well, 
and no or minimal intervention required 
2. MODERATE: Participant experiences enough symptoms or findings to require 
intervention  
3. SEVERE: Participant experiences symptoms or findings that require significant 
intervention 
8.1.6 Guidelines for Determining Causality 
The investigator will use the following question when assessing causality of an adverse event to 
study drug, where an affirmative answer designates the event as a suspected adverse reaction: 
Is there a reasonable possibility that the drug caused the event? ‘‘Reasonable possibility’’ 
means that there is evidence to suggest a causal relationship between the drug and the adverse 
event. 
8.1.7 Discontinuation of a Participant Due to Adverse Events 
Participants may be withdrawn from the study at any time. Participants withdrawn from the study 
product due to an AE, whether serious or non-serious, must be followed by the investigator until 
the clinical outcome from the AE is determined. Any participant who experiences an AE may be 
withdrawn at any time from the study at the discretion of the investigator. The AE(s) should be 
noted on the appropriate CRFs, and the participant’s progress should be followed until the AE is 
resolved or considered stable. The medical monitor or project manager must be notified. If the 
AE may relate to overdose of study treatment, the package insert should be consulted for 
details of any specific actions to be taken. 
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8.1.8 Reporting Procedures 
All adverse events will be entered into the safety data system within 7 days of identification. 
Serious events will be entered into the data system within 24 hours of identification. If there are 
any technical difficulties, the SAE will be reported by direct communication with the medical 
monitor. Results of hearing tests (hearing loss / impairment) and renal ultrasound 
(nephrocalcinosis / nephrolithiasis) are considered adverse events of interest and will be 
captured on the SPE (Special Testing) form and will not be captured on the AE (Adverse 
Events) form in the EDC system.  
8.2 
Serious Adverse Events 
Any serious adverse event entered in the safety database will generate an automatic email 
notification to the IND sponsor or the in-country designee and funding sponsor. The DCC 
medical monitor will review all SAEs at the time that they are reported. Investigators must also 
submit safety reports locally as required by their IRB. 
8.3 
Regulatory Reporting  
Any event that requires expedited reporting based on federal regulations will be forwarded to 
the IND sponsor. The IND sponsor or its in-country representative will submit expedited safety 
reports (e.g. IND safety reports) to the regulatory agencies as necessary, and will inform the 
investigators of such regulatory reports. Site investigators must submit safety reports as 
required by their IRB. Documentation of the submission and receipt by the IRB must be retained 
for each expedited safety report. 
 
All serious events irrespective of their designation as “related” or “not related” to study 
product(s) will be reported to the FDA at least annually in a summary format. 
 
8.4 
Safety Oversight  
The DMC will review serious adverse events on a monthly basis. In addition, a qualified and 
experienced clinician not otherwise associated with this protocol will serve as the medical 
monitor. The medical monitor will review all SAEs at the time they are reported. If safety 
concerns are identified, the medical monitor may request a meeting of the DMC to review safety 
data. At a minimum, the medical monitor will comment on the outcomes of the SAE and causal 
relationship of the SAE to the study product. The medical monitor will also indicate whether 
he/she concurs with the details of the report provided by the study investigator. If no SAEs 
prompt review at an earlier time point, the DMC will review AEs and SAEs at the regularly 
scheduled meeting.  Additionally, DMC will periodically review interim safety analyses (see 
Section 10.3). The DMC will convene and make recommendations on termination of the study 
based on review of safety reports and halting rules. The safety data will be compiled by DCC. 
Based on the recommendations of the DMC, and NIH, the IND sponsor will make a decision to 
terminate or continue the study. 
 
8.5 
Dose Escalation and Halting Criteria: Safety Concerns 
The trial will be halted (paused) for a safety review by the DMC if there are 4 or more Serious 
Adverse Reactions within a given cohort (1, 2, or 3). If there are <4 Serious Adverse Reactions 
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total, the DMC will receive a summary of masked safety data and enrollment will continue in the 
next highest dose cohort.  Enrollment in the next highest dose cohort will begin immediately 
after the 40th (or 80th) subject is enrolled and the following criteria have been met: 
 
Table 8-5 – Rules for advancing to next highest dose cohort 
Number of Serious Adverse 
Reactions 
% total evaluable safety days (days of drug dosing + 7 days of safety 
follow-up for all 40 participants) completed from lower dose cohort 
3 
100% 
2 
95% 
1 
80% 
 
0 
 
70% 
If a 4th Serious Adverse Reaction occurs in the lower dose cohort after enrollment begins in 
higher dose cohort, enrollment will be halted for safety review but current subject dosing will 
continue pending DMC review. If there are 4 or more Serious Adverse Reactions, then the DMC 
may choose to be unmasked to treatment assignment. 
 
 
 
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9 
CLINICAL MONITORING 
Site monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and DCRI sponsor standard operating procedures. 
The IND sponsor, or as detailed in the Transfer of Regulatory Obligations (TORO),  NIH, FDA, 
or its designee will conduct site-monitoring visits as detailed in the monitoring plan or in the 
manual of procedures.  
 
Site visits will be made at standard intervals as defined by the site monitoring plans and may be 
made more frequently as directed by the IND sponsor. Monitoring visits will include, but are not 
limited to, review of regulatory files, accountability records, CRFs, informed consent forms, 
medical and laboratory reports, and protocol compliance. Study monitors will meet with 
investigators to discuss any problems and actions to be taken and document visit findings and 
discussions. 
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10 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
Primary safety endpoints are the incidence of AEs and SAEs. Secondary endpoints include 
BPD risk, BPD incidence, death rate, rate of death or BPD, incidence of 
nephrocalcinosis/nephrolithiasis, incidence of hearing loss, and PK parameters. 
10.2 
Sample Size Considerations 
The sample size of 30 in each dose group is sufficient to estimate AE or SAE incidence with 
sufficient precision. Table 9-1 provides widths for 95% Wilson confidence intervals in the dose 
groups of size 30 and the total furosemide treatment cohort of 90 with different incidence rates. 
An event with an incidence rate of 0.05 has a 79% chance of being observed at least once in a 
dose group and a 99% chance of being observed at least once in the total furosemide cohort. 
 
Table 9-1. Widths for 95% Wilson confidence intervals. 
 
N=30 
N=90 
Rate 
Width 
Rate 
Width 
0.1 
0.22 
0.1 
0.13 
0.2 
0.28 
0.2 
0.16 
0.3 
0.31 
0.3 
0.19 
 
Population for Analysis 
All participants enrolled, randomized, and dosed will be included in safety population and the 
safety analyses. All participants who had at least one interpretable PK sample will be included in 
the PK analysis.  
10.3 
Interim Safety Analysis 
A masked interim safety analysis will be performed after completion of the safety follow up 
period of Cohort 1 participants, and again after completion of the safety follow up period of 
Cohort 2 participants to include data entered up to the cutoff time point. Enrollment will not be 
halted during the analyses.  Halting may occur if analysis shows a positive finding. The number 
and percent of AEs and SAEs within each dose group will be summarized overall as well as by 
each Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred 
term. Laboratory data will be tabulated by dose groups. Summary statistics for changes from 
baseline will be presented. 
10.4 
Analysis Plan 
Descriptive statistics 
Descriptive statistics such as number of observations, mean, median, standard deviation, 
standard error, minimum and maximum will be presented by groups for continuous variables 
(such as age, weight, etc.). Other descriptive statistics such as counts, proportions, and/or 
percentages will be presented by group to summarize discrete variables (such as race, sex, 
etc.) 
 
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Demographic and baseline characteristics 
The number of participants completed and discontinued early from study and the reasons for 
the discontinuation will be summarized. Demographic and baseline characteristics will also be 
summarized. Variables include race, age, sex, and selected clinical variables recorded prior to 
initiation of study drug. Study drug administration will be summarized in terms of number of days 
of dosing and reasons for final discontinuation of study drug.  
 
 
Effectiveness analysis 
We will use multivariable analyses (multinomial, logistic or linear regression, with interactions, 
as appropriate) to explore the relationship between the maximum and total dose of furosemide 
and change in risk of BPD (none-mild vs. moderate-severe-death), death, death or BPD, 
hearing loss, and nephrolithiasis/nephrocalcinosis.  
 
PK analysis plan 
PK parameters will be estimated by population PK approach using non-linear mixed effects 
modeling in NONMEM. The influence of covariates on PK parameters will be explored.  
 
Biomarkers 
We will relate the concentration of biomarkers (see 6.10) to the development of and severity of 
BPD. 
 
Safety  
The number and percent of AEs and SAEs within each dose group will be summarized overall 
and by each Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term. Severity of laboratory values will be assigned according to predetermined 
definitions (Appendix A). Prior and concomitant medications will be summarized by World 
Health Organization (WHO) drug class. Laboratory data will be tabulated by dose groups. 
Summary statistics for changes from baseline will be presented. Incidences of hearing loss and 
nephrolithiasis/nephrocalcinosis will be compared between dose groups using appropriate 
statistical hypothesis tests. 
 
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PARTICIPANT CONFIDENTIALITY  
Participant confidentiality is held strictly in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests, in addition to the clinical information relating to participating 
participants. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator. This documentation includes, but is 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. Clinical study sites will permit access to such records.  
 
Copies of ultrasound images assessed by the site investigator as positive for calcium deposits 
in the kidneys (nephrocalcinosis) or kidney stones (nephrolithiasis) will be submitted in a secure 
manner to the Data Coordinating Center. The Data Coordinating Center will remove any PHI 
that identifies the participant from the images before they are sent to a study radiology specialist 
for independent review. The study radiologist’s assessment of the ultrasounds are for study 
purposes only, and individual results will not be reported back to investigators. 
 
The principal investigator will ensure that the use and disclosure of protected health information 
(PHI) obtained during this research study complies with the Federal Privacy Regulation. In the 
U.S., the Health Insurance and Portability and Accountability (HIPAA) Privacy Rule applies. The 
rule provides U.S. federal protection for the privacy of protected health information sent to or 
collected in the U.S. for the purposes of this research by implementing standards to protect and 
guard against the misuse of individually identifiable health information of participants 
participating in clinical trials. “Authorization” is required from each research participant (i.e., 
specific permission granted by an individual to a covered entity for the use or disclosure of an 
individual’s protected health information). A valid authorization must meet the implementation 
specifications under the applicable Federal Privacy Regulations. The relevant privacy 
authorization will be combined in the informed consent document (approved by the IRB).   
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INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation in this study will be provided to the participants and 
their families. Consent forms describing in detail the study procedures and risks are given to the 
participant’s legal guardian, and written documentation of informed consent is required prior to 
enrolling in the study. Consent forms will be IRB-approved, and the participant’s legal guardian 
will be asked to read and review the document. Upon reviewing the document, the investigator 
will explain the research study to the participant’s legal guardian and answer any questions that 
may arise. The participant/participant’s legal guardian will sign the informed consent document 
prior to the conduct of any study procedures. The participant’s legal guardian should have the 
opportunity to think about the study prior to agreeing to participate. The participant’s legal 
guardian may withdraw consent at any time throughout the course of the study. A copy of the 
informed consent document will be given to the participants for their records. The rights and 
welfare of the participants will be protected by emphasizing to their legal guardian that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. For non-English speakers, a fully translated consent or an oral presentation accompanied 
by a short form may be used to obtain informed consent. The fully translated consent and the 
short form must be approved by the IRB and executed according to local requirements. 
 
The IND sponsor, or designee will provide the investigator, in writing, any new information that 
bears significantly on the participants' risk to receive the investigational product. This new 
information will be communicated by the investigator to participants' legal guardians who 
consent to participate in the trial in accordance with IRB requirements. The informed consent 
document will be updated, and participants’ legal guardians will be re-consented, if necessary. 
 
Site staff may employ IRB-approved recruitment efforts prior to the participant’s legal guardian 
consenting; however, before any protocol-specific procedures are performed to determine 
protocol eligibility, informed consent must be obtained and properly executed.  
 
By signing the informed consent form, the participant’s legal guardian agrees that the participant 
will complete all evaluations required by the trial, unless the participant’s legal guardian 
withdraws the participant voluntarily or the participant is withdrawn from the trial for any reason. 
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SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
An electronic case report form (eCRF) will be used to record participation data. The eCRF will 
be used for the recording of all historical participant information and study data as specified by 
this protocol. The eCRF must be completed by designated and trained study personnel. 
 
According to ICH E6, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). Source documents are defined as original 
documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, participants’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, participant files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial).  
 
It will be the responsibility of the investigator(s) to ensure that the regulatory binder at the site is 
maintained. The study file will contain, but will not be limited to: 
• 
Current package inserts, and all previous versions 
• 
Final study protocol 
• 
Protocol amendments (if applicable) 
• 
Manual of Procedures  
• 
Informed consent form (blank) 
• 
Signed informed consent form 
• 
Revised informed consent forms and/or all addenda (blank) 
• 
IRB registration or other documentation of IRB compliance with FDA regulations 
• 
Documentation of IRB approval of protocol, consent form, any protocol amendments, 
and any consent form revisions 
• 
Annual IRB updates and approvals 
• 
All correspondence between the investigator and IRB 
 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9, and regulatory and institutional requirements for the 
protection of confidentiality of participants. Each site will permit authorized representatives of 
the sponsor, its designees, and appropriate regulatory agencies to examine (and, when required 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress. These representatives will be permitted access 
to all source data, which include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
participant files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. Case report forms will be derived from the eCRFs and 
provided by the Data Coordinating Center (DCC). 
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QUALITY CONTROL AND QUALITY ASSURANCE  
The principal investigator will provide direct access to all trial-related sites, source 
data/documents, case report forms, and reports for the purpose of monitoring and auditing by 
the sponsor, and inspection by local and regulatory authorities. The principal investigator will 
ensure that all study personnel are appropriately trained and applicable documentations are 
maintained on site. 
 
DCC-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, Good Clinical 
Practice, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to the PI, PTN, and NIH/NICHD.  
 
The DCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for prompt clarification and resolution. 
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ETHICS/PROTECTION OF HUMAN PARTICIPANTS  
15.1 
Ethical Standard 
The investigator will ensure that the study will be conducted in accordance with the protocol, the 
ethical principles of Good Clinical Practice (ICH E6) that have their origin in the Declaration of 
Helsinki, and all applicable national and local regulations. The investigator will ensure that the 
study is conducted in accordance with the provisions as stated and will comply with the 
prevailing local laws and customs. 
15.2 
Institutional Review Board 
Prior to enrollment of participants into this trial, the protocol, the informed consent form, and any 
materials or advertisements presented to participants will be reviewed and approved by the 
appropriate IRB.  
 
The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial, and a copy will be provided to the DCC. Notification of the IRB's composition 
and the institution’s federal-wide assurance number (if applicable) will be provided to the DCC. 
 
If amendments to the protocol were required, the amendments will be written by the sponsor 
and provided to the investigator for submission and approval to the IRB. 
15.3 
Informed Consent  
The investigator will choose participants in accordance with the eligibility criteria detailed 
previously. The investigator will not exercise selectivity so that bias is prevented. In this study, 
participant’s parent/legal guardian will sign an informed consent for study participation.  
All legal guardians must sign an informed consent form that complies with the federal regulatory 
and privacy requirements before entering the trial. A consent form that complies with the federal 
requirements and a separate authorization form that complies with federal privacy regulations 
for the use and disclosure of the participant’s protected health information may be used instead, 
per institutional standard operating procedures. 
 
For details regarding the informed consent process, see Section 12. 
 
15.4 
Participant Confidentiality 
Participant confidentiality is held strictly in trust by the participating investigators, their staff, the 
sponsor(s), and their agents. This confidentiality extends to genetic and biological sample tests, 
in addition to the clinical information relating to participating participants. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator. This documentation includes, but is 
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not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. Clinical study sites will permit access to such records. 
15.5 
Study Discontinuation 
If the study is discontinued, enrolled participants will continue to be followed for safety 
assessments for 7 days. All adverse events must be followed through resolution. 
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DATA HANDLING AND RECORD KEEPING 
The investigator is obligated to conduct this study in accordance with U.S. Federal Regulation 
21 CFR 312.60-69 as specified on the signed form FDA 1572, applicable local laws, and the 
International Conference on Harmonisation: Good Clinical Practice: Consolidation Guideline. 
The investigator is responsible for informing the IRB of any safety issues related to the study 
and the study drug, including reports of serious adverse events, if required, and all expedited 
safety reports.  
 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.  
 
Case report forms will be derived from the eCRFs and provided by the DCC to the sites to 
record and maintain data for each participant enrolled in the study. All source documents should 
be completed in a neat, legible manner to ensure accurate interpretation of data. Permanent ink 
is required to ensure clarity of reproduced copies. When making a change or correction, the 
original entry should be crossed out with a single line, and the change should be initialed and 
dated. Do not erase, overwrite, or use correction fluid or tape on the original.  
 
Data reported in the eCRF should be consistent with the case report form/source documents, or 
the discrepancies should be documented. The sponsor and/or its designee will provide 
guidance to investigators on making corrections to the case report forms and eCRFs. 
16.1 
Data Management Responsibilities 
All case report forms and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete. Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site principal investigator or 
designee. Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site principal investigator. During the study, the investigator must maintain 
complete and accurate documentation for the study. 
 
The DCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
16.2 
Data Capture Methods 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 
11-compliant internet data entry system provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly 
from the case report forms/source documents. 
16.3 
Timing/Reports 
The DMC will convene and make recommendations on study continuation based on the safety 
data collected periodically.  
 
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16.4 
Study Records Retention 
Records and documents pertaining to the conduct of this study, including case report forms, 
source documents, consent forms, laboratory test results, and medication inventory records, 
must be retained by the investigator for at least 10 years after the end of the study or per 
local/state regulations or until participants reach 21 years, or applicable Federal laws, whichever 
is longer. No study records will be destroyed without prior authorization from the sponsor. 
16.5 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or manual of 
procedures requirements. The noncompliance may be on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with Good Clinical Practice: 
4.5. Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1. Quality Assurance and Quality Control, section 5.1.1 
5.2. Noncompliance, sections 5.20.1, and 5.20.2 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation or within 5 working days of the 
scheduled protocol-required activity. All deviations must be promptly reported to the sponsor, 
via the DCC’s Internet Data Entry System (IDES). 
 
All deviations from the protocol must be addressed in study case report forms. A completed 
copy of the protocol deviation form must be maintained in the regulatory file. Protocol deviations 
must be submitted to the local IRB/IEC per their guidelines. The site PI/study staff is responsible 
for knowing and adhering to their IRB requirements. 
16.6 
Participant Privacy/Authorization 
The principal investigator will ensure that the use and disclosure of protected health information 
obtained during a research study complies with the HIPAA Privacy Rule. The rule provides U.S. 
federal protection for the privacy of protected health information by implementing standards to 
protect and guard against the misuse of individually identifiable health information of participants 
participating in clinical trials. Authorization is required from each research participant (i.e., 
specific permission granted by an individual to a covered entity for the use or disclosure of an 
individual’s protected health information). A valid authorization must meet the implementation 
specifications under the HIPAA Privacy Rule. Authorization will be combined in the informed 
consent document (approved by the IRB). 
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PUBLICATION POLICY  
Following completion of the study, the investigator may publish the results of this research in a 
scientific journal under the oversight of the Publication Committee of the Pediatric Trails 
Network (PTN).  . The PTN Publication Committee comprises representatives of the network 
cores, thought-leaders, DCC, and PTN and is responsible for generation and coordination of the 
publications that report scientific findings of the network. All public presentations (abstracts, 
manuscripts, slides and text of oral or other presentations, and text of any transmission through 
any electronic media) by participating investigators, participating institutions, DCC, and PTN that 
use PTN data, are intended to represent the PTN, or are supported by the PTN will be reviewed 
by the Publication Committee per the Publication Committee charter.  
 
The Publication Committee guarantees that the study results are presented by experts in the 
field that have working knowledge of the study design, implementation, data synthesis/analysis, 
and interpretation. The committee goals are to ensure that any confidential or proprietary 
information is protected, and that all appropriate statistical analyses have been included.  
 
The PTN Publication Committee will adhere to the trials registration policy adopted by the 
International Committee of Medical Journal Editors (ICMJE) member journal. This policy 
requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. It is the responsibility of the IND holder to register this trial 
in an acceptable registry.  
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., phase I trials), would be exempt from 
this policy. 
 
All investigators funded by the NIH must submit or have submitted for them to the National 
Library of Medicine’s PubMed Central an electronic version of their final, peer-reviewed 
manuscripts upon acceptance for publication, to be made publicly available no later than 12 
months after the official date of publication. The NIH Public Access Policy ensures the public 
has access to the published results of NIH-funded research. It requires investigators to submit 
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. Further, the policy stipulates that these papers must be 
accessible to the public on PubMed Central no later than 12 months after publication.  
 
Refer to: 
http://publicaccess.nih.gov/ and http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-
033.html 
 
 
 
 
 
 
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APPENDIX A: LABORATORY VALUES 
Laboratory values 
Adverse event 
Serious adverse event 
Serum electrolytes 
Hypernatremia(Sodium) 
150–159 mmol/L 
> 159 mmol/L 
Hyponatremia(Sodium) 
120–124 mmol/L 
<120 mmol/L 
Hyperchloremia(Chloride) 
110-120 mmol/L 
> 120 mmol/L 
Hypochloremia(Chloride) 
80-90 mmol/L 
< 80 mmol/L 
Hyperkalemia(Potassium) 
7.0–7.9 mmol/L 
>7.9 mmol/L 
Hypokalemia(Potassium) 
2.0–2.5 mmol/L 
<2.0 mmol/L 
High Bicarbonate levels 
(Bicarbonate) 
30–45 mmol/L 
> 45 mmol/L 
Low Bicarbonate 
levels(Bicarbonate) 
12–14 mmol/L 
< 14 mmol/L 
Hypercalcemia (iCa) 
1.3–1.6 mmol/L 
>1.6 mmol/L 
Hypocalcemia (iCa) 
0.7–1.05 mmol/L 
< 0.7 mmol/L 
Hypermagnesemia (Magnesium) 
3.0-6.0 mg/dL 
> 6.0 mg/dL 
Hypomagnesemia (Magnesium) 
1.0-1.5 mg/dL 
< 1.0 mg/dL 
Hypophosphatemia(Phosphorus) 
Hyperphosphatemia(Phosphorus) 
1.0-3.0 mg/dL 
10.5-12.5 mg/dL 
<1.0 mg/dL 
>12.5 mg/dL 
Hyperbilirubinemia (Bilirubin) 
20-30 mg/dL 
>30 mg/dL 
Renal dysfunction (i.e. azotemia) 
Elevated BUN 
60–100mg/dL 
> 100 mg/dL 
Elevated creatinine 
1.5–2.5 mg/dL 
> 2.5 mg/dL 
Gastrointestinal 
Elevated alkaline phosphatase 
1000–1400 U/L 
>1400 U/L 
Hematology 
Thrombocytosis(Platelets) 
450–1000 × 10⁹/L 
>100010 × 10⁹/L 
Thrombocytopenia(Platelets) 
50–100 × 10⁹/L 
<50 × 10⁹/L 
 
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