Safety and Efficacy of Caffeine Citrate in Premature Infants NICHD-2014-CAF01

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NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______

Pediatric Trials Network

Funding Sponsor:

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Funding Mechanism: Task Order

Protocol Number: NICHD-2014-CAF01

Protocol Date: 03AUG2015

Protocol Version: 2.0

IND Number: N/A

Principal Investigator (IND Sponsor): P. Brian Smith, MD, MPH, MHS Professor of Pediatrics

Duke University Medical Center 2400 Pratt St. Durham, NC 27705 Redacted

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NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______

Statement of Compliance

This trial will be conducted in compliance with the protocol, International Conference on Harmonization (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]).

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 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 efficacy 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 subjects with informed consent forms, as required by government and International Conference on Harmonization 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.

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., product label), 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.

P. Brian Smith, MD, MPH, MHS

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 ...... vi Protocol Synopsis ...... …viii

1 Key Roles ...... 1 2 Background Information and Scientific Rationale...... 2 2.1 Background Information ...... 2 2.2 Apnea of Prematurity ...... 2 2.3 Caffeine ...... 2 2.3.1 Safety ...... 3 2.3.2 Pharmacokinetics/Pharmacodynamics ...... 4 2.3.3 The Caffeine for Apnea of Prematurity Trial (CAP)31 ...... 5 2.3.4 Caffeine and NEC ...... 6 2.3.5 Caffeine and BPD ...... 6 2.4 Scientific Rationale ...... 6 2.5 Potential Risks and Benefits ...... 6 2.5.1 Potential Risks ...... 6 2.5.2 Potential Benefits ...... 7 3 Study Design ...... 8 4 Study Population ...... 9 4.1 Selection of the Study Population ...... 9 4.1.1 Objective 1: Safety ...... 9 4.1.2 Objective 2: Efficacy ...... 9 4.1.3 Objective 3: Exposure-response Relationship ...... 9 4.2 Inclusion/Exclusion Criteria ...... 9 5 Study procedures ...... 11 5.1 Pediatrix Clinical Data Warehouse Database ...... 11 5.2 Electronic Health Record Data Extraction ...... 12 5.3 PROP ...... 13 5.4 Review of Published Data from the CAP Trial ...... 14 5.5 Enrollment/Baseline ...... 14 5.6 Follow-up ...... 14 5.7 Final Study Visit ...... 14 6 Study Product Description ...... 15 6.1 Concomitant Medications/Treatments ...... 15 7 Assessment of Safety ...... 16 8 Clinical Monitoring ...... 17 9 Statistical Considerations ...... 18 9.1 Sample Size ...... 18 9.1.1 Pediatrix Clinical Data Warehouse Database Review ...... 18 9.1.2 Electronic Health Record Data Extraction ...... 18 9.1.3 PROP ...... 18 9.1.4 Review of Published Data from the CAP Trial ...... 18 9.2 Planned Interim Analyses (if applicable) ...... 18 9.3 Analysis Plan ...... 19 ______iv NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______

Table of Contents - continued

page 9.3.1 Pediatrix Database Analysis, Electronic Health Record Data Extraction, and PROP - Safety Analyses ...... 19 9.3.2 Electronic Health Record Data Extraction - Exposure-response Relationship ...... 20 9.3.3 Review of the Published Data from Prospective Trial (Safety and Efficacy Review) ...... 20 10 Patient Confidentiality ...... 21 11 Informed Consent Process ...... 22 12 Source Documents and Access to Source Data/Documents ...... 23 13 Quality Control and Quality Assurance ...... 24 14 Ethics/Protection of Human Patients ...... 25 14.1 Ethical Standard ...... 25 14.2 Institutional Review Board ...... 25 14.3 Participant Confidentiality ...... 25 14.4 Study Discontinuation ...... 25 15 Data Handling and Record Keeping ...... 26 15.1 Data Capture Methods ...... 26 15.2 Types of Data ...... 26 15.3 Timing/Reports ...... 26 15.4 Study Records Retention ...... 26 15.5 Participant Privacy/Authorization ...... 27 16 Publication Policy ...... 28 17 Appendix A: Clinical Events of Interest ...... 29 18 Appendix B: Laboratory Values of Interest...... 30 19 Literature References ...... 31

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List of Abbreviations

AE Adverse Event ALT Alanine Transaminase AOP Apnea of Prematurity AST Aspartate Transaminase BPCA Best Pharmaceuticals for Children Act BPD Bronchopulmonary Dysplasia BUN Blood Urea Nitrogen CAP Caffeine for Apnea of Prematurity (Trial) CEI Clinical Event of Interest CFR Code of Federal Regulations CHOC Children’s Hospital of Orange County CL Clearance CNS Central Nervous System CL Confidence Level CSF Cerebrospinal fluid DCC Data Coordinating Center DCRI Duke Clinical Research Institute DMC Data Monitoring Committee DUMC Duke University Medical Center eCRF Electronic Case Report Form FDA Food and Drug Administration GA Gestational Age GCP Good Clinical Practice GGT Gamma-glutamyl transpeptidase HIPAA Health Insurance Portability and Accountability Act ICH International Conference on Harmonization IND Investigational New Drug Application IRB Institutional Review Board IVH Intraventricular Hemorrhage kg Kilogram mg Milligram MedDRA Medical Dictionary for Regulatory Activities N Number (typically refers to patients) NICHD National Institute of Child Health and Human Development NDI Neurodevelopmental impairment NEC Necrotizing Enterocolitis NICU Neonatal Intensive Care Unit NIH National Institutes of Health OR Odds Ratio PD Pharmacodynamics PI Principal Investigator PK Pharmacokinetics PMA Post Menstrual Age PNA Postnatal Age

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List of Abbreviations - continued

PPRU Pediatric Pharmacology Research Unit PTN Pediatric Trials Network ROP Retinopathy of Prematurity SAE Serious Adverse Event UCSD University of California San Diego UNC University of North Carolina V Volume of Distribution WBC White Blood Count WHO World Health Organization

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Protocol Title: Safety and Efficacy of Caffeine Citrate in Premature Infants Phase: N/A Product: Caffeine citrate Objectives: 1. Characterize safety of caffeine citrate 2. Characterize efficacy of caffeine citrate 3. Evaluate the caffeine exposure-response relationship Study Data 1. Pediatrix Clinical Data Warehouse review: safety Sources: 2. Electronic Health Record Data Extraction: safety and exposure-response 3. Prematurity and Respiratory Outcome Program (PROP): safety 4. Review of published data from 1 randomized controlled trial: Caffeine for Apnea of Prematurity (CAP) Trial Study Population: 1. Premature infants discharged from intensive care nurseries managed by the Pediatrix Medical Group who received caffeine citrate per standard of care 2. Electronic Health Record Data Extraction: Premature infants from up to 6 sites that received caffeine citrate administered per standard of care 3. Prematurity and Respiratory Outcome Program (PROP): Premature infants from approximately 13 sites that received caffeine citrate per standard of care 4. Caffeine for Apnea of Prematurity (CAP) Trial: Premature infants enrolled in 1 randomized controlled trial Number of 1. Pediatrix Clinical Data Warehouse analysis: N~ 75,000 infants Patients: 2. Electronic Health Record Data Extraction: N~ 400 infants 3. Prematurity and Respiratory Outcome Program (PROP): N~750 infants 4. Review of published data from randomized controlled trial (CAP Trial): N=2006 infants Number of Study 1. Pediatrix Clinical Data Warehouse analysis: ~280 sites Sites: 2. Electronic Health Record Data Extraction: up to 6 sites 3. Prematurity and Respiratory Outcome Program (PROP): ~13 sites 4. Review of published data from randomized controlled trial (CAP Trial): ~34 sites Estimated Start: August 2015

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1 KEY ROLES

For questions regarding this protocol, contact:

A) Study Principal Investigator P. Brian Smith, MD, MPH, MHS Professor of Pediatrics Duke University Medical Center 2400 Pratt St. Durham, NC 27705 Redacted

B) NICHD Contract Officer Technical Representative: Ekaterina Tsilou, MD, Medical Officer Obstetric and Pediatric Pharmacology and Therapeutics Branch Center for Research for Mothers and Children Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH 6100 Executive Boulevard, Redacted Bethesda, MD 20892-7510 Redacted

C) Best Pharmaceuticals for Children Act (BPCA), Data Coordinating Center (DCC): The Emmes Corporation 401 N. Washington St., Redacted Rockville, MD 20850 Telephone: 301-251-1161 Redacted

PI: Redacted Project Director: Redacted

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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 409I of the Public Health Service Act; as such, the results from this research may be submitted to the FDA for review and used in negotiated labeling changes. This research study is contractually supported by the NICHD. The NICHD awarded a contract to Duke University to establish a Pediatric Trials Network (PTN) through its affiliate the Duke Clinical Research Institute (DCRI), in order to facilitate trial design for studies supported by NIH. A separate contract is awarded to The Emmes Corporation to serve as the BPCA Data Coordinating Center.

2.2 Apnea of Prematurity

Apnea of prematurity (AOP) is common and if untreated, causes significant long-term sequelae in premature infants. Approximately 85% of infants born < 34 weeks and almost all infants born < 29 weeks gestational age (GA) develop AOP.1,2 Infants with AOP experience frequent episodes of apnea, resulting in hypoxemia and bradycardia and placing the infant at risk for prolonged mechanical ventilation, retinopathy of prematurity, bronchopulmonary dysplasia, and long-term neurodevelopmental impairment (NDI).3-5 Caffeine is commonly used to treat AOP.

2.3 Caffeine

Caffeine citrate is labeled for the short-term treatment of AOP in infants between 28 and < 33 weeks gestational age. However, caffeine is frequently used off-label beyond short-term use in infants as early as 22 weeks gestation.6,7 The drug label recommends single loading doses of 20 mg/kg intravenously and maintenance doses of 5 mg/kg administered intravenously or orally every 24 hours.7

Caffeine is a methylxanthine that acts as a central nervous system (CNS) stimulant, bronchial smooth muscle relaxant, cardiac muscle stimulant, and diuretic. Its mechanism of action in treating apnea of prematurity is not known, but its pharmacologic effects are thought to result from antagonism of the A1 and A2 adenosine receptors on cell surfaces.7 This is thought to result in stimulation of respiratory centers, increased minute ventilation, increased pulmonary blood flow, increased sensitivity of central medullary regions to hypercapnia, increased skeletal muscle tone, decreased diaphragmatic fatigue, increased metabolic rates, and increased oxygen consumption.7,8

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Caffeine demonstrates a wide therapeutic index and is generally regarded as safe and well tolerated.9 Adverse events (AEs) associated with caffeine use in premature infants affect several major systems including the CNS, cardiovascular, gastrointestinal, endocrine, and renal systems (Table 1).7 Toxicity related to caffeine overdoses in infants have been reported, with post-overdose serum levels ranging between 24 – 350 mg/L.7 None resulted in death and, except in 1 case, affected infants experienced complete resolution of symptoms with no known long-term sequelae (Table 2).10-14

Table 1. Adverse events associated with caffeine use in premature infants7 Organ System Adverse events CNS Irritability Restlessness Jitteriness Cardiovascular Tachycardia Gastrointestinal Increased gastric aspirates Gastrointestinal intolerance Endocrine Hypoglycemia Hyperglycemia Renal Increased urine flow rate Increased creatinine clearance Increased sodium excretion Increased calcium excretion

Table 2. Case reports of toxicities associated with caffeine overdose Case Report N GA Dose (mg/kg) Caffeine level Toxicities reported Kulkarni (1979)10 1 Term 33.8 55 mg/L Jitteriness, tremors, tachypnea, exaggerated reflexes Banner (1980)11 4 Term 94 32 mg/L Opisthotonos, tremors, irritability Term 136 Tachypnea, jitteriness, irritability, posturing, nonpurposeful mouth movements, seizure Term 84 26 mg/L Seizure, rigidity, nonpurposeful mouth movements, 32 wk 36 80 mg/L Bradycardia, hypotension, intracranial hemorrhage, severe neurological impairment van den Anker (1992)12 1 33 wk NR 346 mg/L Tachypnea, tachycardia, compromised circulation, vomiting, convulsions Anderson (1999)13 31 wk 160 218 mg/L Hypertonia, sweating, tachycardia, cardiac failure, pulmonary edema, metabolic acidosis, hyperglycemia, creatinine kinase elevation, gastric dilation Ergenekon (2001)14 1 28 wk 300 NR Agitation, irritability, tachycardia, tachypnea, diuresis, electrolyte abnormalities, hyperglycemia, metabolic acidosis GA, gestational age; NR, not reported

Caffeine citrate was well tolerated in a randomized, double-blind, placebo-controlled trial with an open-label rescue phase conducted in 9 neonatal intensive care units involving 85 premature infants 28 – < 33 weeks gestational age.15 Between the treatment and placebo groups, no significant differences in the number and frequency of AEs were seen. A total of 4 infants

______3 NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______receiving caffeine and 2 receiving placebo developed necrotizing enterocolitis (NEC). One of the infants in the placebo group had been exposed to open-label caffeine prior to development of NEC. Among the 4 infants who received caffeine, the investigators determined caffeine to be possibly related in 1 infant and unrelated in the 3 others.

2.3.2 Pharmacokinetics/Pharmacodynamics

2.3.2.1 Pharmacokinetics

The primary mode of caffeine elimination is through hepatic metabolism. In adults, the fraction of caffeine eliminated unchanged in the urine is only 2%.16 Numerous pharmacokinetic studies demonstrate prolonged caffeine systemic clearance and half-lives with significant interindividual variability in caffeine pharmacokinetic parameters among premature infants (Table 3). These findings can be attributed to postnatal age, reflecting renal and hepatic immaturity.17,18 However, infants of similar age can still have systemic clearances that differ by > 3-fold.19,20 Caffeine is rapidly distributed into the CNS with cerebrospinal fluid levels approximating plasma levels.7

Table 3. Caffeine Pharmacokinetic Studies in Premature Infants

Study N Weight GA PNA CL T1/2 Vd (g) (weeks) (days) (mL/kg/hr) (hours) (mL/kg) Aranda, 197921 12 685-1870 25-34 3-32 2.5-16.8 41-231 475-1280 Gorodischer, 198222 13 920-2060 25-34 1-42 5.8-12.2 48-87 470-1010 Pons, 198823 21 NR 31-41 20-588 0.13a 4.8a 441-1736 Pearlman, 198924 17 820-2310 26-33 15-38 NR 20-99 NR De Carolis, 199125 15 770-1980 27-32 0-15 NR 72±12b NR Thomson, 199617 60 600-2900 25-41 1-100 7.9±1.9b NR 640a Lee, 199718 119 571-2307 24-31 2-15 2.3-9.0 86-277 740-1400 Erenberg, 200015 45 695-1955 25-32 28-32.7 4.4a NR 830a Charles, 200820 110 568-1570 24-29 1-45 1.6-22.6 24-371 365-1761 Patel, 201326 67 650-2500 24-32 1-69 2.3-16.9 13-112 174-1005

CL, clearance; GA, gestational age; NR, not reported; PNA, postnatal age; T1/2, half-life; Vd, volume of distribution a Plateau values reached in oldest infants b Mean±SD reported

2.3.2.2 Pharmacodynamics, Efficacy, and Dosing

Three published Cochrane Reviews on the use of methylxanthines in premature infants concluded that methylxanthines including caffeine were effective in reducing the number of apneic episodes in the short term; reducing the use and duration of oxygen therapy and ventilator support; increasing the chances of successful extubation of preterm infants in the first week of life; and improving long-term growth and neurodevelopmental outcomes.27-29 However, the authors suggested that more evidence was needed to address whether long-term use of methylxanthines in premature infants would lead to improvement in the incidence or severity of apnea and associated symptoms such as bradycardia and hypoxemia.28

There is uncertainty in the exact dose or plasma concentration of caffeine needed to achieve therapeutic effects.9 Although the drug label recommends loading doses of 20 mg/kg and maintenance doses of 5 mg/kg/day, doses of caffeine citrate prescribed in practice include loading doses of 10-40 mg/kg and maintenance doses of 2.5-10 mg/kg/day.19 Plasma caffeine concentrations needed for therapeutic effect are generally accepted to be 5-20 mg/L.6,19

______4 NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______However, some investigators propose that higher levels (> 35 mg/L) are needed to maximize efficacy.18 A pharmacodynamics profile developed from 268 infants over a 3-year period suggested that a decline in caffeine concentrations from 20 mg/L to 10 mg/L could result in therapeutic failure in up to 35% of potential responders.30

2.3.3 The Caffeine for Apnea of Prematurity Trial (CAP)31

This randomized, placebo-controlled, multicenter trial was conducted to evaluate the short- and long-term efficacy and safety of caffeine therapy in premature infants. The study randomized 2006 infants with gestational age (mean±SD) 27±2 weeks to treatment with caffeine citrate or placebo in a 1:1 ratio. Infants in the active treatment group were given a loading dose of 20 mg/kg followed by a daily maintenance dose of 5 mg/kg. Blood levels of caffeine were not measured during this study.

Caffeine significantly reduced the frequency of bronchopulmonary dysplasia (BPD), defined as the requirement of supplemental oxygen at a postmenstrual age of 36 weeks, in the caffeine group compared to placebo (36.3% vs. 46.9%, adjusted odds ratio [OR] 0.63, p<0.001). Mortality prior to discharge (5.2% vs. 5.5%), ultrasound findings suggestive of brain injury (13.0% vs 14.3%), NEC (6.3% vs. 6.7%), and ROP (39.2% vs. 43.2%) did not differ significantly between the 2 groups.

Caffeine improved survival without neurodevelopmental disability at 18 to 21 months corrected age. Only 377/937 (40.2%) infants who received caffeine died or survived with neurodevelopmental disability compared to 431/932 (46.2%) infants who received placebo (OR 0.77, p=0.008).32 The number needed to treat with caffeine to prevent one adverse outcome was 16. When compared to placebo, caffeine also significantly reduced the incidence of cerebral palsy (4.4% vs. 7.3%, OR 0.58, p=0.009) and cognitive delay (33.8% vs. 38.3%, OR 0.81, p=0.04). Rates of death, deafness, and blindness did not differ significantly between the 2 groups.

At the 5-year follow up, children who received caffeine as an infant (n=833) no longer differed significantly compared to children given placebo (n=807) in terms of composite outcome of death or survival with motor impairment, cognitive impairment, behavior problems, poor general health, deafness, or blindness.33 The investigators remarked that motor impairment in the caffeine-treated children were less severe than the controls. Furthermore, overall rates of cognitive impairment were significantly lower in both groups compared to rates at 18 to 21 month corrected age (Table 4). Caffeine-treated children showed no significant differences in adverse effects on long-term outcomes when compared to the placebo-treated children.

Table 4. CAP Study Long-term Cognitive and Motor Impairment 18-21 months32 5 years33 Adjusted OR Adjusted OR Outcome Caffeine Placebo Caffeine Placebo (95% CI) (95% CI) no./total no. (%) no./total no. (%) Cognitive 293/867 (33.8) 329/858 (38.3) 0.81 (0.66-0.99) 38/768 (4.9) 38/750 (5.1) 0.97 (0.61-1.55) impairment Motor NR NR NR 13/803 (1.6) 21/773 (2.7) 0.59 (0.29-1.18) impairment CI, confidence interval; NR, not reported; OR, odds ratio

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2.3.4 Caffeine and NEC

The current caffeine drug label warns of an association of caffeine and NEC based on the findings from the earlier randomized, double-blind, placebo-controlled trial involving 85 premature infants.7,15 The CAP study, which included 2006 premature infants, failed to find a significant difference in rates of NEC between the caffeine and control groups.31 There is little available evidence suggesting that caffeine use in premature infants is associated with an increased risk for NEC.9

2.3.5 Caffeine and BPD

The most common serious morbidity associated with premature birth is BPD. More than 60,000 infants are born ≤ 29 weeks gestational age each year in the United States and nearly 40% develop BPD. Premature infants with BPD are challenging to treat and frequently suffer from multiple morbidities such as pulmonary hypertension, prolonged hospitalization, death, and life- long problems.34-36 Because the consequences are so catastrophic, there is an urgency to identify therapies that can prevent BPD. The CAP study found that infants who received caffeine had significantly lower rates of BPD compared to infants that received placebo (36.3% vs. 46.9%, OR 0.63, p<0.001).31 This suggests that caffeine may have clinical utility in the prevention of BPD in premature infants.

2.4 Scientific Rationale

The data evaluated through this initiative will provide valuable safety and efficacy for the use of caffeine in infants < 28 weeks gestational age and for use beyond the short-term. This study will assess the strength of association between caffeine and NEC. This study will also investigate the clinical utility of caffeine for the prevention of BPD in premature infants. This project will not involve prescribing study drug or collecting biological samples to/from infants. This will allow for a minimal risk study and maximize interpretation of available data.

2.5 Potential Risks and Benefits

2.5.1 Potential Risks

The administration of study drug or the collection of study samples from infants is not a part of this study. The only risk is potential breach of confidentiality. Data obtained from the Pediatrix Clinical Data Warehouse and Prematurity and Respiratory Outcome Program (PROP) are limited datasets and will be covered by a signed data use agreement. Information from the CAP study will be limited to aggregate data reported in the literature.31-33 The study follows the procedures specified by Duke University Hospital System IRB for maintaining confidentiality. Data collected from Electronic Health Records will be transmitted to DCRI in a secured manner and will be stored in a secured FISMA zone within the DCRI firewall. Access to this data will be limited at the DCRI. Data will be securely transmitted to the BPCA DCC (Emmes) for analysis. It will be housed by the DCC in a secure, limited access environment.

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2.5.2 Potential Benefits

Conclusions drawn from this study will benefit infants receiving treatment with caffeine through better characterization of the safety profile of caffeine when used off-label and through potential determination of caffeine as an efficacious therapy for the prevention of BPD.

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3 STUDY DESIGN

This will be an observational study using 4 data sources: 1. Pediatrix Clinical Data Warehouse - infants discharged from the NICUs managed by the Pediatrix Medical Group in the United States between 2005 and 2013. Information in this database is captured from admission notes, daily progress notes, discharge notes, and laboratory results generated during daily patient care 2. Electronic Health Record Data Extraction - infants admitted to up to 6 centers between 2005 and 2013 3. Prematurity and Respiratory Outcome Program (PROP): infants admitted to approximately 13 centers between 2011 and 2014 4. Review of published data from the CAP trial31-33

Objective 1: Characterize safety of caffeine citrate Safety will be evaluated in infants exposed to caffeine using the Pediatrix Clinical Data Warehouse, Electronic Health Record Data Extraction, PROP, and published data from the CAP trial.31

Objective 2: Characterize efficacy of caffeine citrate Clinical outcomes including mortality, postmenstrual age at last need for mechanical ventilation, and BPD will be assessed using published data from the CAP trial.31-33

Objective 3: Evaluate the caffeine exposure-response relationship Correlation of plasma concentrations when available per standard of care and safety data will be evaluated in the Electronic Health Record Data Extraction.

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4 STUDY POPULATION

4.1 Selection of the Study Population

No new patients prospectively treated with caffeine will be enrolled in this study.

4.1.1 Objective 1: Safety

The following patients will be included in the safety analysis: 1) Pediatrix Clinical Data Warehouse – Infants born < 33 weeks GA and exposed to caffeine in the Pediatrix Medical Group administrative database between 2005 and 2013 will be identified to evaluate safety while on caffeine. This will include approximately 75,000 infants at approximately 280 sites. 2) Electronic Health Record Data Extraction– Infants born < 28 weeks GA and exposed to caffeine per standard of care between 2005 and 2013 up to 6 sites. This will include approximately 400 infants. 3) Prematurity and Respiratory Outcome Program (PROP): infants born 23-28 weeks gestation admitted to approximately 13 centers between 2011 and 2014. This will include approximately 750 infants. 4) Infants enrolled in the CAP trial. This will include 2006 infants with a birth weight of 500- 1250 g and considered to be candidates for methylxanthine therapy during the first 10 days of life from 34 sites.31

4.1.2 Objective 2: Efficacy

Infants enrolled in the CAP trial that were included in the published manuscripts will be used to evaluate efficacy outcomes.

4.1.3 Objective 3: Exposure-response Relationship

The cohort from the Electronic Health Record Data will be used to relate caffeine exposures to safety.

4.2 Inclusion/Exclusion Criteria

1) Pediatrix Clinical Data Warehouse a. Inclusion criteria: 1. Discharged from an intensive care nursery managed by the Pediatrix Medical Group from 2005 to 2013 2. < 33 weeks gestational age at birth 3. ≥ 1 day of caffeine therapy 4. < 120 days of age (PNA) at earliest dose of caffeine

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b. Exclusion criteria: 1. Known major congenital anomaly

2) Electronic Health Record Data Extraction a. Inclusion criteria: 1. < 28 weeks gestational age at birth 2. < 120 days of age (PNA) at earliest dose of caffeine 3. ≥ 1 day of caffeine therapy 4. Admitted to an intensive care nursery from 2005 to 2013 b. Exclusion criteria: 1. Known major congenital anomaly

3) PROP a. Inclusion Criteria: i. Infants who are ≤7 days old ii. ≥ 1 day of caffeine therapy iii. < 120 days of age (PNA) at earliest dose of caffeine iv. Gestational Age (GA) between 23 weeks and 0/7 days and 28 weeks and 6/7 days b. Exclusion Criteria: i. The infant is not considered to be viable (decision made not to provide life-saving therapies) ii. Congenital heart disease (not including PDA and hemodynamically insignificant VSD or ASD) iii. Structural abnormalities of the upper airway, lungs or chest wall iv. Other congenital malformations or syndromes that adversely affect life expectancy or cardio-pulmonary development v. Family is unlikely to be available for long-term follow-up 4) Infants from the CAP trial: a. Inclusion criteria: 1. 500-1250 g birth weight 2. First 10 days of life 3. Considered by clinician as candidate for methylxanthine therapy b. Exclusion criteria: 1. Dysmorphic feature or congenital anomaly likely to affect neurologic outcome or life expectancy. 2. Unlikely to be available for long-term follow-up 3. Previously treated with methylxanthines

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5 STUDY PROCEDURES

5.1 Pediatrix Clinical Data Warehouse Database

The following data will be extracted (Table 5):

Table 5. Variables collected from the Pediatrix Clinical Data Warehouse

During At birth Discharge hospitalization Demographics Gestational age X Postnatal age X Infant’s day of admission to hospital X Year of discharge from hospital X Weight X Gender X Maternal race/ethnicity X Inborn/outborn X Mode of delivery X 5 minute APGAR score X Singleton/multiple birth X Antenatal steroids X Surfactant therapy X Clinical events Mortality X BPD X Medical NEC X Surgical NEC X Spontaneous intestinal perforation X Grade II IVH X Grade III or IV IVH X PDA requiring surgical treatment X Seizure X Arrhythmia X Laboratory valuesa Creatinine X Glucose X Sodium X Calcium X AST X ALT X Caffeineb Days of administration X Dose amount X Weight X Concomitant medications of interestc Days of administration X a Lab data collection details will be outlined in the MOP b Every change in caffeine dosing/frequency associated will be recorded c Per concomitant medication list (Section 6.1)

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5.2 Electronic Health Record Data Extraction

The following data will be extracted (Table 6):

Table 6. Variables collected from the medical records:

At During Discharge birth hospitalization

Demographics Birthdate X Gestational age X Infant’s date of admission to hospital X Date of discharge from hospital X Weight X Gender X Maternal race/ethnicity X Inborn/outborn X Mode of delivery X 5 minute APGAR score X Singleton/multiple birth X Antenatal steroids X Surfactant therapy X Clinical events Mortality X BPD X Medical NEC X Surgical NEC X Spontaneous intestinal perforation X Grade II IVH X Grade III or IV IVH X PDA requiring surgical treatment X Seizure X Arrhythmia X Laboratory valuesa Plasma caffeine levels X Creatinine X Glucose X Sodium X Calcium X AST X ALT X Caffeineb Days of Administration X Each Dose amount X Weight within 1 week of each X administration Concomitant medications of interestc Days of administration X a All standard of care labs will be recorded b Every change in caffeine dosing/frequency associated will be recorded c Per concomitant medication list (Section 6.1)

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5.3 PROP

The following data will be extracted if available:

Table 7. Variables collected from PROP dataset

At During Discharge birth hospitalization

Demographics Birth date X Gestational age X Infant’s date of admission to hospital X Date of discharge from hospital X Weight X Gender X Maternal race/ethnicity X Inborn/outborn X Mode of delivery X 5 minute APGAR score X Singleton/multiple birth X Antenatal steroids X Surfactant therapy X Clinical events Mortality X BPD X Medical NEC X Surgical NEC X Spontaneous intestinal perforation X Grade II IVH X Grade III or IV IVH X PDA requiring surgical treatment X Seizure X Arrhythmia X Caffeine Days of Administration X Each Dose amount X Weight within 1 week of each X administration Concomitant medications of interesta Days of administration X a Per concomitant medication list (Section 6.1)

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5.4 Review of Published Data from the CAP Trial

Published data on subject demographics, clinical characteristics, and caffeine administration will be reviewed.31-33 Clinical events of interest (CEIs) including mortality, BPD, NEC, from this trial will be included.

5.5 Enrollment/Baseline

No new patients prospectively treated with caffeine will be enrolled in this protocol.

5.6 Follow-up Data will be collected only during the hospitalization during which caffeine is administered.

5.7 Final Study Visit

No patients will be enrolled in this protocol and there will be no study-related visits.

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6 STUDY PRODUCT DESCRIPTION

Drug of interest in this protocol is caffeine. Administration of study drug/investigational product is not part of this protocol.

6.1 Concomitant Medications/Treatments

If records are available, the number of days of administration for concomitant medication of interest administered during hospitalization will be abstracted for the Pediatrix Data Warehouse, Electronic Health Record Data Extraction, and PROP. Specific concomitant medications of interest include:

1. Furosemide 23. Miconazole 2. Bumetanide 24. Nifedipine 3. Ethacrynic acid 25. Omeprazole 4. Hydrochlorothiazide 26. Propranolol 5. Chlorothiazide 27. Ranitidine 6. Spironolactone 28. Sildenafil 7. Acetazolamide 29. Carbamazepine 8. Indomethacin 30. Phenobarbital 9. Ibuprofen 31. Rifampin 10. Hydrocortisone 32. Fosphenytoin 11. Morphine 33. Lorazepam 12. Fentanyl 34. Midazolam 13. Hydromorphone 35. Pentobarbital 14. Methadone 36. Phenytoin 15. Amiodarone 37. Dopamine 16. Amlodipine 38. Dobutamine 17. Dexmedetomidine 39. Epinephrine 18. Erythromycin 40. Milrinone 19. Fluconazole 41. Norepinephrine 20. Ketoconazole 42. Phenylephrine 21. Lidocaine 43. Vasopressin 22. Methimazole 44. Acetaminophen

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7 ASSESSMENT OF SAFETY

No patients will be enrolled in this protocol. The administration of caffeine or concomitant medications and collection of samples is not part of this protocol. Thus, there will be no separate assessment of safety other than what is described under the primary outcome measures.

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8 CLINICAL MONITORING

To ensure regulatory compliance and protection of confidentiality of patients, 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 study progress (Section 12).

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9.1 Sample Size

9.1.1 Pediatrix Clinical Data Warehouse Database Review

Approximately 75,000 infants meet the inclusion criteria from 2005 to 2013. This sample size will provide for reasonable estimates and 95% CI for safety. If 1% of the infants have a CEI, then the 95% CI (exact binomial) for that event within the participant population will be 0.03 to 5.4%.

9.1.2 Electronic Health Record Data Extraction

Data will be collected on approximately 400 infants (approximately 100 infants from each center). Data will be collected in consecutive, reverse chronological order, starting with the most recent data available (infants born 12/31/2013) until the desired sample size is reached at each site. The sample size of 400 will provide for a reasonable estimate for safety. If one infant has a CEI, the 95% CI (exact binomial) for that event within the participant population is 0.04 to 8.9%.

9.1.3 PROP

Data will be collected on approximately 750 infants.

9.1.4 Review of Published Data from the CAP Trial

Of the 2006 infants that were enrolled in this study, 1006 infants received caffeine and 1000 infants received placebo.

Table 7. Sample Size Objective #1: Objective #2: Objective 3: Safety Efficacy Exposure-Response Pediatrix Clinical Data Warehouse 75,000 N/A N/A Electronic Health Record Data 400 400 N/A Extraction PROP 750 N/A N/A CAP Trial 2006 1006 N/A Total 78,156 1006 400 N/A, not applicable

9.2 Planned Interim Analyses (if applicable)

There will be no planned interim analysis in this protocol.

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9.3 Analysis Plan

9.3.1 Pediatrix Database Analysis, Electronic Health Record Data Extraction, and PROP - Safety Analyses

Severity of diagnoses and laboratory values will be assigned according to predetermined definitions (Appendix A and B).

9.3.1.1 Safety

9.3.1.1.1. Definitions

Clinical events

Clinical outcomes and events occurring after initiation of caffeine therapy through hospital discharge will be included (Appendix A)

Clinical events attributed to caffeine – A clinical event will be attributed to caffeine if it first presented on a day that the infant was exposed to caffeine.

Laboratory events attributed to caffeine – A laboratory even will be attributed to caffeine if it occurs on a day that the infant was exposed to caffeine (Appendix A).

9.3.1.1.2. Bronchopulmonary Dysplasia

The diagnosis of BPD will be made based on the NICHD definition:37 A diagnosis of BPD will be made if an infant requires supplemental oxygen (> 21% fraction of inspired oxygen, FiO2) or positive pressure ventilation or continuous positive airway pressure at 36 weeks postmenstrual age.

9.3.1.1.3. Arrhythmia

An infant will be considered to have an arrhythmia if given the following diagnoses during hospitalization: 1) Supraventricular tachycardia 2) Atrial flutter 3) Atrial fibrillation 4) Ventricular tachycardia 5) Ventricular fibrillation 6) Torsades de pointes 7) Second degree atrioventricular block (Type 1 or 2) 8) Third degree atrioventricular block (Complete)

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9.3.1.1.4. Analysis Plan

We will describe infants who received caffeine by demographic characteristics including gestational age, gender, maternal race/ethnicity, and others. Point estimates and 95% confidence intervals will be reported. Descriptive analysis will be used to examine the frequency of clinical and laboratory events. Analysis of all clinical events and events attributed to caffeine will occur at the infant level. Laboratory events attributed to caffeine will be analyzed at the infant-day level. The number and percentage of infants who experienced an event and the total number of events will be summarized via tables and graphs as needed. The data will also be summarized by demographic subgroups, when appropriate. Clinical characteristics will be summarized among the patients who had an event. The maximal daily and total doses will be summarized via tables and graphs as needed.

9.3.2 Electronic Health Record Data Extraction - Exposure-response Relationship

9.3.2.1 Exposure-response Relationship

Logistic regression models for each clinical and laboratory events attributed to caffeine will be used to relate these events with daily dose, cumulative dose, and plasma levels of caffeine adjusting for gestational age at birth, race, postnatal age, and sex. Linear regression will be used to model caffeine exposures and relate caffeine doses and levels to clinical and laboratory event attributed to caffeine.

9.3.3 Review of the Published Data from Prospective Trial (Safety and Efficacy Review)

In the CAP trial, clinical outcomes were assessed at hospital discharge and at 18-21 months corrected age. Clinical outcomes at hospital discharge (safety) and through 21 months corrected age (efficacy) will be included when appropriate.

9.3.3.1 Safety

Data published in the primary literature will be reviewed.31-33 These include the following: 1. Mortality 2. NEC 3. PDA requiring surgical treatment

9.3.3.2 Efficacy

Data on mortality, and BPD, published in the primary literature will be reviewed.31-33

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10 PATIENT CONFIDENTIALITY

No patients will be enrolled into this protocol. No samples will be collected as a part of this study. Human participant data obtained during Electronic Health Record Data Extraction will not be identifiable directly. Patient confidentiality is held strictly in trust by the participating investigators, their staff, and the sponsor(s) and their agents. 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 third party without prior written approval of the sponsor. Patient information collected in this study will comply with the standards for protection of privacy of individually identifiable health information as promulgated by HIPAA (Health Insurance Portability and Accountability Act) and as mandated in Title 45 CFR Parts 160 and 164. All data records will be kept confidential. Participant data records will not be released to anyone other than the Sponsor or its designees and responsible regulatory authorities when requested. In all cases, caution will be exercised to assure the data are treated confidentially and that the participant’s privacy is protected.

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11 INFORMED CONSENT PROCESS

The Pediatrix Clinical Data Warehouse and Electronic Health Record Data Extraction do not involve the enrollment of patients. For patients in the completed CAP trial, informed consent was obtained under the supervision of the enrolling site’s IRB during the study. Because no new patients prospectively treated with caffeine will be enrolled for this study, no informed consent is required. The Safety evaluation via a review of medical charts or past study data by the PI or their representatives cannot be practically performed if informed consent is required of each participant. Therefore, a waiver of informed consent will be requested from the reviewing Institutional Review Board (IRB).

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12 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS

During the Electronic Health Record Data Extraction process, each participating site will meet regulatory and institutional requirements for the protection of confidentiality of patients. 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 study 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, patients’ memory aid 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, and participant files and records kept at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. Data collection forms will be provided by Emmes Corp., the Data Coordinating Center (DCC), to assist data extraction.

Data from the Pediatrix Clinical Data Warehouse and the PROP network will be provided as limited datasets per a signed data use agreement.. Data from the CAP Trial will be obtained solely from the published manuscripts.31-33 Source data from these resources will not be available to research staff during this study.

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13 QUALITY CONTROL AND QUALITY ASSURANCE

The principal investigator will provide direct access to all trial-related sites participating in the Electronic Health Record Data Extraction including source data/documents 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. The DCC and the DCRI Informatics team will implement quality control procedures. Any missing data or data anomalies will be communicated for prompt clarification and resolution.

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14 ETHICS/PROTECTION OF HUMAN PATIENTS

14.1 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 federal, state, and local regulations. The investigator will ensure the study is conducted in accordance with the provisions as stated and will comply with the prevailing local laws and customs.

14.2 Institutional Review Board

The investigator will ensure that the protocol is reviewed and approved by the appropriate Institutional Review Board (IRB) prior to the start of any study activities. The IRB will be appropriately constituted and will perform its functions in accordance with FDA regulations, ICH GCP guidelines, and local requirements as applicable.

14.3 Participant Confidentiality

No patients will be enrolled in this protocol. Data obtained from the Pediatrix Clinical Data Warehouse, Electronic Health Record Data Extraction, PROP data, and CAP trial will be used for the analyses detailed in this protocol. Data obtained from the Pediatrix database is a limited dataset as defined by the HIPAA Privacy Rule (45 CFR 164.514 (a) and (b)). Data obtained from the Electronic Health Record Data Extraction and PROP dataset will be coded; patients will be identified by code numbers and not by name. All Protected Health Information except for dates will be removed prior to data transfer to DCRI. Appropriate and adequate provisions for ensuring participant privacy and data confidentiality will be maintained by the participating investigators, their staff, the sponsor(s), and their agents. The study protocol, documentation, data, and all other information generated by this study will be maintained in a secure manner and will be kept confidential as required by law. Data access will be limited to study personnel and the data will be stored on servers which have limited physical access (e.g., locked rooms) and limited electronic access (e.g., password controlled access to data, computers and, if applicable, networks). No information concerning the study or the data will be released to any third party without prior written approval of the sponsor.

Study records, including medical and pharmacy records, may be reviewed in order to meet federal or state regulations. Reviewers may include the Food and Drug Administration (FDA), IRBs, the sponsor and its representatives, and the NIH.

14.4 Study Discontinuation

Not applicable. No patients will be enrolled in this study. Prescription of study drug is not part of this protocol.

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15 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 by form FDA 1572, applicable state laws, and the International Conference on Harmonization, Good Clinical Practice, Consolidation Guideline.

During the Electronic Health Record Data Extraction, the investigator(s) at participating site(s) will ensure, to the best of their abilities, the accuracy, completeness, and legibility of the data reported.

Data Management Responsibilities All data files must be reviewed by the clinical team who will ensure that the data files are accurate and complete. 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 data records for the study.

The DCRI will be serving as the Electronic Health Record data liaison and intermediate data conversion/transformation experts. Emmes Corporation will be responsible for analysis, and reporting of the study data.

The PROP data will be analyzed at the PROP CC – Children’s Hospital of Philadelphia (CHOP). The data will be sent to DCRI from CHOP in Summary Tables for inclusion into the Clinical Study Report.

15.1 Data Capture Methods

Clinical data (including CEIs) obtained through Electronic Health Record Data Extraction will be stored in secure data files.. Clinical data will be extracted directly from the electronic health records or source documents.

15.2 Types of Data

Data for this study will include safety and efficacy.

15.3 Timing/Reports

Not applicable

15.4 Study Records Retention

Records and source documents pertaining to the conduct of this study (including EMR, laboratory test results, medication administration records and other source documents), must be retained by the Investigator for 10 years after the end of the study or per local/state regulations or until subjects reach 21 years of age, whichever is longer. No records will be destroyed without the written consent of the Sponsor.

______26 NICHD-2014-CAF01 – CAFFEINE Version 2.0 IND # N/A 03AUG2015 ______15.5 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 patients of clinical trials.

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16 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 Trials Network. 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 and 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.

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/ http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html

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17 APPENDIX A: CLINICAL EVENTS OF INTEREST

Body System Mild Event Severe Event Respiratory • BPD Gastrointestinal • Medical NEC • Surgical NEC • Spontaneous intestinal perforation Neurologic • Grade II IVH • Grade III or IV IVH • Seizure

Cardiovascular • Arrhythmia • PDA requiring surgical treatment General • Death PDA = patent ductus arteriosus

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18 APPENDIX B: LABORATORY VALUES OF INTEREST

Laboratory Values Mild Event Severe Event Serum electrolytes Hyperglycemia > 150 mg/dL > 400 mg/dL Hypoglycemia < 40 mg/dL < 20 mg/dL Hypernatremia > 150 mmol/L > 160 mmol/L Hyponatremia < 125 mmol/L < 115 mmol/L Hypercalcemia (iCa) > 12.0 mg/dL (> 1.5 mmol/L) > 14.0 mg/dL (> 1.6 mmol/L) Hypocalcemia (iCa) < 6.0 mg/dL (< 0.9 mmol/L) < 4.0 mg/dL (< 0.8 mmol/L) Renal dysfunction Elevated creatinine > 1.7 mg/dL > 3.0 mg/dL Liver dysfunction Elevated AST > 400 U/L > 1000 U/L Elevated ALT > 200 U/L > 1000 U/L

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