Prospective Observational Study of the Risk Factors for Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (HABP/VABP)
Conditions: Pneumonia, Ventilator-Associated, Pneumonia, Bacterial, Pneumonia, Hospital-Acquired
Sponsor: Duke University

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Clinical Trial Transformation Initiative (CTTI) 
 
Prospective Observational Study of the Risk Factors for Hospital-Acquired and Ventilator-Associated 
Bacterial Pneumonia (HABP/VABP) 
 
Protocol Number: CTTI_001 
 
Funding Sponsor: Clinical Trials Transformation Initiative (CTTI) and The Eunice Kennedy Shriver 
National Institute of Child Health and Human Development (NICHD) 
 
Funding Mechanism: This project is funded by a U.S. Food and Drug Administration grant R18 
FD005292 and annual fees paid by member organizations to support infrastructure expenses and 
projects. In addition, individuals from many member organizations, and some non-member organizations, 
contribute time and other resources. Co-funded by IDIQ Contract HHSN275201000003I-Task Order 
HHSN27500042 
 
 
 
 
Protocol Date: 
April 15, 2016 
Protocol Version: 
2.1 (Amendment 1) 
Principal Investigator: 
 
 
Vance Fowler, MD, MHS 
Duke University Medical Center 
 
 
 
Apr 18, 2016

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Signature Page 
 
 
The signature below documents the review and approval of this protocol and provides the necessary 
assurances that this study will be conducted according to the protocol (per undersigned participating 
study Arm), including all statements regarding confidentiality, and according to national, regional, and 
local legal and regulatory requirements. 
The CTTI/PTN Risk Factors for HABP/VABP Study includes two arms -  an Adult (Arm 1) and a Pediatric 
(Arm 2). An institution may participate either in Arm 1 only, Arm 2 only, or both Arm 1 and 2. Each arm will 
have a separate Principal Investigator. The signature below indicates in which arm of the protocol the 
principal investigator is participating.  
 
 
 
 
 
 
 
 
   
 
 
 
Site Principal Investigator Name (Print)  
 
 
Adult (Arm 1)  
 
 
 
Signature 
 
Date 
   
 
 
 
Site Principal Investigator Name (Print)  
 
 
Pediatric (Arm 2)  
 
 
 
Signature 
 
Date 

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RISK FACTORS FOR HABP/VABP STUDY CONTACT INFORMATION 
 
Protocol Chair 
Name Vance Fowler 
Address: Room 153 Hanes House, Trent Drive, Durham, NC 27710 
Phone: 919-668-2549 
Email: vance.fowler@duke.edu 
 
PTN Chair 
Danny Benjamin, MD, PhD, MPH 
Address: 2400 Pratt Street Durham, NC 27715 
Phone: 919-668-7081 
Email: danny.benjamin@duke.edu 
 
 
Project Leader 
Name: Peidi Gu 
Address: 2400 Pratt St. Rm 0311 Terrace Level, Durham, NC 27705 
Phone: 919-668-8232 
Email: peidi.gu@duke.edu 
 
CTTI Project Manager 
Name: Sara Calvert 
Address: 300 West Morgan St. Durham, NC 27701 
Phone: 919-668-7540 
Email: sara.calvert@duke.edu 
 
 
 

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Protocol change history /summary: 
 
 
 
 
Version 1.0 (12/17/2015) 
Version 2.1 (4/15/2016) 
Protocol version 
N/A. Original version 
Amendment #1 
Study population 
Adult (>= 18 years old) only 
Adult and Pediatric 
# Patients 
6850 Adults 
6850 Adults (Arm 1) and 1000 
Pediatric (Arm 2) 
# study sites 
45 
Added 10 Pediatric sites 
Funding Sponsor 
FDA 
FDA and  NICHD 
Protocol Chair 
Dr. Vance Fowler 
Added Dr. Danny Benjamin as 
PTN Chair 
Appendix B (Pediatric supplement) 
N/A 
Included 
Interim Analysis 
The interim analysis will 
occur after 500 high-risk 
CRFs are completed or 3 
months after all U.S. sites 
are activated, whichever 
occurs first. 
The interim analysis will occur 
three months after 50% of US 
sites have begun enrolling 
patients. 

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Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................................................. 6 
PROTOCOL SYNOPSIS .................................................................................................................................. 7 
RISK FACTORS FOR HABP/VABP STUDY FLOWCHART (ARM 1: AGE ≥18 YEARS OLD) ................................ 8 
1.0 
BACKGROUND AND SCIENTIFIC RATIONALE ...................................................................................... 9 
1.1 
BACKGROUND INFORMATION .................................................................................................................... 9 
1.2 
SCIENTIFIC RATIONALE ............................................................................................................................ 9 
2.0 
HYPOTHESES .................................................................................................................................... 10 
2.1 
PRIMARY HYPOTHESIS .......................................................................................................................... 10 
3.0 
OBJECTIVES ...................................................................................................................................... 10 
3.1 
PRIMARY OBJECTIVES (ARM 1: AGE ≥18 YEARS OLD): .............................................................................. 10 
3.2 
KEY SECONDARY OBJECTIVE ................................................................................................................. 11 
3.3 
SECONDARY OBJECTIVES ...................................................................................................................... 11 
4.0 
STUDY DESIGN .................................................................................................................................. 12 
4.1 
INCLUSION CRITERIA (ARM 1: AGE ≥18 YEARS OLD) ................................................................................. 13 
4.2 
EXCLUSION CRITERIA (ARM 1) ............................................................................................................... 14 
4.3 
CO-ENROLLMENT GUIDELINES ................................................................................................................ 14 
4.4 
STUDY DISCONTINUATION ...................................................................................................................... 14 
5.0 
STUDY PROCEDURES ....................................................................................................................... 14 
5.1 
RECRUITMENT PLAN .............................................................................................................................. 14 
5.2 
ENROLLMENT (ARM 1) ........................................................................................................................... 14 
5.3 
HIGH-RISK PROTOCOL (ARM 1) ............................................................................................................. 15 
5.4 
OTHER-ICU PROTOCOL (ARM 1) ............................................................................................................ 15 
5.5 
STUDY COMPLETION (ARM 1) ................................................................................................................. 15 
6.0 
STATISTICAL ANALYSIS PLAN (ARM 1) ............................................................................................. 15 
6.1 
GENERAL CONSIDERATIONS ................................................................................................................... 16 
6.2 
ENDPOINTS .......................................................................................................................................... 16 
6.3 
SAMPLE SIZE ........................................................................................................................................ 16 
6.4 
FINAL ANALYSIS .................................................................................................................................. 16 
6.5 
BASELINE SUMMARIES ........................................................................................................................... 18 
6.6 
INTERIM ANALYSIS ................................................................................................................................ 19 
7.0 
ETHICS AND REGULATORY ............................................................................................................... 19 
7.1 
ETHICAL STANDARDS ............................................................................................................................ 19 
7.2 
DATA CONFIDENTIALITY ......................................................................................................................... 20 
7.3 
DATA HANDLING AND RECORD KEEPING ................................................................................................. 20 
8.0 
PUBLICATION POLICY ....................................................................................................................... 21 
9.0 
REFERENCES .................................................................................................................................... 21 
APPENDIX A: DATA COLLECTION SCHEDULE (ARM 1) ............................................................................... 22 
APPENDIX B: SUPPLEMENT FOR PEDIATRIC SUBJECTS (ARM 2: <18 YEARS OLD) ................................... 23 
RISK FACTORS FOR HABP/VABP STUDY FLOWCHART (ARM 2: ................................................................. 26 

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List of Abbreviations 
 
BiPAP 
Bilevel Positive Airway Pressure 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
CTTI 
Clinical Trials Transformation Initiative 
DCRI 
Duke Clinical Research Institute 
EDC 
Electronic Data Capture 
FDA 
U.S. Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
HABP 
Hospital-Acquired Bacterial Pneumonia 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
LPM 
Liters Per Minute 
LRTI 
Lower Respiratory Tract Infection 
MRSA 
Methicillin-Resistant Staphylococcus aureus 
NICHD 
National Institute of Child Health and Human Development 
PTN 
Pediatric Trials Network 
VABP 
Ventilator-Associated Bacterial Pneumonia 
 

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Protocol Synopsis 
Protocol Title 
Prospective Observational Study of the Risk Factors for Hospital-Acquired and 
Ventilator-Associated Bacterial Pneumonia (HABP/VABP) 
Study Design 
Prospective, multi-center, observational study 
Primary Study 
Objectives 
• 
Estimate the rates of hospital-acquired or ventilator-associated bacterial 
pneumonia (HABP/VABP) developing in intensive care unit (ICU) patients 
considered high risk for pneumonia, as defined by treatment with one or 
more of the following respiratory modalities for at least 12 hours, either 
currently or within the prior 7 days in patients age ≥18 year old (Arm 1)*: 
− 
Invasive mechanical ventilation  
− 
Noninvasive ventilation (bilevel positive airway pressure [BiPAP] or 
continuous positive airway pressure [CPAP] for any indication other 
than obstructive sleep apnea) 
− 
High-flow, supplemental oxygen therapy via nasal cannula. Only 
include systems using an air/oxygen blender capable of delivering a 
precise fraction of inspired oxygen [FiO2] level, not just a flow in 
liters per minute (LPM) 
− 
High flow supplemental oxygen therapy delivering at least 50% FiO2 
via aerosol facemask or tracheostomy collar (mask).  Only include 
systems using an air/oxygen blender capable of delivering a precise 
FiO2 level, not just a flow in LPM. 
− 
Supplemental oxygen therapy delivered via either partial or non-
rebreather face mask. 
* For patients age <18 year old (Arm 2), see Appendix B 
• 
Estimate the proportion of patients diagnosed with HABP/VABP who would 
be eligible for enrollment in a clinical trial of antibacterial therapy for 
HABP/VABP per U.S. Food and Drug Administration (FDA) draft guidance 
document criteria. 
Study Population 
Arm 1: Adult (≥18 years) patients admitted to ICUs 
Arm 2: Pediatric (<18 years) patients admitted to ICUs or intermediate care unit 
Number of 
Subjects 
Arm 1: 6850 ICU patients meeting high-risk criteria 
Arm 2: ~1000 pediatric (<18 years) patients 
Number of Sites 
Arm 1: 45 total: 30 in the United States, 15 outside the United States  
Arm 2: ~ 10 sites in the United States 
Clinical Samples 
None 
Estimated Start 
of Enrollment 
January 30, 2016 
Estimated Time 
to Completion 
Up to 12 months of enrollment 

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Risk Factors for HABP/VABP Study Flowchart (Arm 1: age ≥18 years old) 
 

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1.0 
Background and Scientific Rationale  
1.1 
Background Information  
Clinical trials to evaluate the efficacy and safety of new antibacterial drugs for hospital-acquired 
bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are 
challenging to conduct and expensive, and there are a very limited number of clinical trials of new 
drugs for this indication in progress or planned.  Evaluating new antibacterial drugs for efficacy in 
HABP/VABP is important, as a number of antibacterial drugs with demonstrated efficacy in the 
treatment of other serious bacterial infections have demonstrated limitations when studied in 
HABP/VABP.  In addition, patients with infections caused by multi-drug resistant Gram-negative 
bacteria often present with HABP/VABP.1 
 
The Clinical Trial Transformation Initiative (CTTI) is a collaborative organization that seeks to 
improve the quality and efficiency of clinical trials. The CTTI Streamlining HABP/VABP Trials 
Project includes a number of collaborative efforts to better understand the challenges of 
conducting HABP/VABP trials and address these challenges through streamlining the operational 
processes and building efficiencies for data collection in HABP/VABP trials.2 A data gathering and 
mapping project conducted in collaboration with the Tufts Center for the Study of Drug 
Development found that the cost of screen failures, as well as screen failure rates, are the main 
drivers of cost for a Phase 3 HABP/VABP trial.3 HABP/VABP Phase 3 trials are generally non-
inferiority trials. To address the concern of bias toward non-inferiority, FDA Draft Guidance4 
recommends that patients who have received effective antibacterial drug therapy for HABP/VABP 
for a continuous duration of more than 24 hours during the previous 72 hours be excluded from 
HABP/VABP clinical trials.  In a guided discussion with experienced research coordinators 
conducted by CTTI, this recommended exclusion criteria was noted as a significant challenge to 
enrollment as care standards in the intensive care unit often lead to antibacterial drugs being 
administered as soon as pneumonia is suspected.  In addition, patients are often quite ill and 
unable to provide informed consent themselves, so legally authorized representatives must be 
identified and contacted.  Other necessary enrollment procedures such as laboratory tests and 
other procedures to meet inclusion/exclusion criteria, randomization, and obtaining study drug 
from the pharmacy can add to the time between administration of antibacterial drugs and study 
enrollment.  Strategies to address these feasibility concerns while ensuring that trial 
interpretability will not be limited by a bias toward non-inferiority are needed. 
A HABP/VABP pilot study, incorporating many of the recommendations from the CTTI 
Streamlining HABP/VABP Trials Project, is planned. The primary objective is to conduct a study 
that will lead to improved HABP/VABP clinical trial feasibility. The proposed design of the future 
pilot study is a randomized trial comparing early enrollment and traditional enrollment strategies. 
The early enrollment strategy (treatment arm) will include approaching AND consenting patients 
at high risk for developing pneumonia, many before pneumonia symptoms develop. The rationale 
of this early enrollment strategy is to identify and enroll high-risk patients at the time they meet 
criteria for a diagnosis of HABP/VABP and before they have received more than 24 hours of 
effective antibacterial therapy. 
1.2 
Scientific Rationale  
One of the challenges in planning the HABP/VABP pilot study is determining which patients to 
approach for early enrollment. A group of patients at risk for pneumonia is required, but selecting 
criteria based on existing literature will involve a tradeoff between sensitivity and 
specificity. Approaching only the highest risk patients (e.g., those on a ventilator for a pre-
specified length of time) would likely yield a relatively high percentage of patients who go on to 
develop pneumonia.5 The drawbacks of this approach include 1) not including a mix of VABP and 
non-VABP HABP; 2) exclusion of a large group of other patients who go on to develop 

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pneumonia in the hospital in absence of the highest risk factors; and 3) increased likelihood of 
exclusion due to current use of antibiotics. Using a more inclusive approach, such as enrolling 
patients with a history of aspiration or with chronic lung disease, would increase the total number 
of patients who ultimately develop pneumonia, but would decrease the proportion of enrolled 
patients that develop pneumonia. If the proportion of patients developing pneumonia is too low, it 
is possible that the time, effort, and money required to conduct a study using an early enrollment 
strategy would not result in a meaningful increase in number of patients enrolled who ultimately 
meet study criteria for antibacterial therapy for HABP/VABP. Therefore, this risk factor study will 
be conducted to better define the population at highest risk for developing HABP/VABP. 
2.0 
Hypotheses 
2.1 
Primary Hypothesis 
• 
At least 5% of patients considered high risk for developing nosocomial pneumonia 
will ultimately be diagnosed with HABP/VABP during an intensive care unit (ICU) 
stay. High-risk patients are those admitted to an ICU who are treated with one or 
more of the following respiratory modalities for at least 12 hours (Arm 1) or 24 hours 
(Arm 2), either currently or within the prior 7 days: invasive mechanical ventilation; 
noninvasive mechanical ventilation for any indication other than obstructive sleep 
apnea; or supplemental oxygen therapy with a partial or non-rebreather mask, high-
flow nasal cannula (a system that uses an air/oxygen blender and delivers a precise 
fraction of inspired oxygen [FiO2] level, not just a flow in liters per minute [LPM]), or 
high flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask).  
• 
At least 75% of patients diagnosed with HABP/VABP during an ICU admission would 
meet the inclusion and exclusion criteria outlined in the FDA draft guidance document 
for HABP/VABP drug development for a clinical trial of antibacterial therapy for 
HABP/VABP. 
 
3.0 
Objectives 
3.1 
Primary Objectives (Arm 1: age ≥18 years old): 
a. Estimate the rates of HABP/VABP diagnosis in ICU patients considered high risk for 
pneumonia. High risk is defined by treatment with one or more of the following 
respiratory modalities for at least 12 hours, currently or within the prior 7 days: 
i. 
Invasive mechanical ventilation  
ii. 
Noninvasive ventilation (bilevel positive airway pressure [BiPAP] or continuous 
positive airway pressure [CPAP] for any indication other than obstructive sleep 
apnea) 
iii. High-flow, supplemental oxygen therapy via nasal cannula. Only include systems 
using an air/oxygen blender capable of delivering a precise FiO2 level, not just a 
flow in LPM. 
iv. High flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask). Only include systems using an 
air/oxygen blender capable of delivering a precise FiO2 level, not just a flow in 
LPM. 
v. Supplemental oxygen therapy delivered via either partial or non-rebreather face 
mask  

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b. Estimate the proportion of patients diagnosed with HABP/VABP who would be 
eligible for enrollment in a clinical trial of antibacterial therapy for HABP/VABP per 
FDA draft guidance document criteria.  
i. 
Diagnosed is defined as fulfilling study HABP/VABP diagnostic criteria.  
ii. 
Eligible for enrollment will be defined as: Subject fulfills study HABP/VABP 
diagnostic criteria, and the time at which these diagnostic criteria were met is 
less than 24 hours after the first dose of antibiotics for HABP/VABP.  
Please see Appendix B for Arm 2 (age <18 years old) information 
 
3.2 
Key Secondary Objective 
a. In patients treated with respiratory modalities classified as high risk, identify 
demographic factors, comorbid medical illnesses, and treatment exposures that are 
associated with an increased risk of HABP/VABP development during ICU 
admission. 
3.3 
Secondary Objectives 
a. Estimate the proportion of patients treated for HABP/VABP who would be eligible for 
enrollment in a clinical trial of antibacterial therapy for HABP/VABP per FDA draft 
guidance document criteria.  
i. 
Treated is defined as received antibiotics for suspected HABP/VABP. 
ii. 
Eligible for enrollment will be defined as: Subject fulfills study HABP/VABP 
diagnostic criteria, and the time at which these diagnostic criteria were met is 
less than 24 hours after the first dose of antibiotics for HABP/VABP. 
b. Estimate the proportion of patients diagnosed with HABP/VABP who would otherwise 
meet FDA phase 3 clinical trial inclusion criteria but would be excluded from 
enrollment due to treatment with >24 hours, >36 hours, or >48 hours of effective 
antibiotics prior to pneumonia diagnosis. 
i. 
Determine the most common reasons for administration of antibacterial therapy 
prior to patients meeting the diagnosis of HABP/VABP per FDA draft guidance 
document criteria. 
c. Estimate the proportion of patients treated for HABP/VABP who have lower 
respiratory tract cultures collected either on the day antibiotics are started for 
pneumonia treatment or within the prior 48 hours. 
i. 
Determine the proportion of lower respiratory tract cultures for which gram stain 
results are reported prior to the initiation of antibacterial therapy for HABP/VABP. 
ii. 
Determine the proportion of patients with HABP/VABP for which gram stain 
results are available within 24 hours of initiation of antibacterial therapy for 
HABP/VABP. 
d. Estimate the proportion of patients treated for HABP/VABP for which a causative 
bacterial pathogen is identified. 
e. Determine the most common bacterial causes of HABP/VABP among patients with 
positive lower respiratory tract culture. 

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f. 
Determine the incidence of the following types of antibacterial resistance among 
relevant pathogens: 
i. 
Methicillin resistance among S. aureus HABP/VABP lower respiratory tract 
isolates 
ii. 
Extended-spectrum beta-lactamase production among gram-negative organisms  
iii. Carbapenem resistance among gram-negative organisms 
iv. Fluoroquinolone resistance among gram-negative organisms 
g. Determine the most common initial antibiotics prescribed for the treatment of 
HABP/VABP. 
i. 
Determine the proportion of patients treated with an initial antibacterial active 
against methicillin-resistant Staphylococcus aureus (MRSA). 
ii. 
Determine the proportion of patients with HABP/VABP treated with at least 1 
initial anti-pseudomonal antibiotic (within 24 hours of HABP/VABP antibiotic 
initiation). 
iii. Determine the proportion of patients with HABP/VABP treated with 2 or more 
initial anti-pseudomonal antibiotics (within 24 hours of HABP/VABP antibiotic 
initiation). 
h. Determine the proportion of patients with HABP/VABP for whom antibiotic therapy 
was changed because the initial regimen was either inactive or ineffective against the 
pathogen isolated on lower respiratory tract culture. 
i. 
Determine the proportion of patients with HABP/VABP for whom antibiotic therapy 
was changed because of clinical deterioration or lack of clinical improvement. 
j. 
Determine the frequency with which all antibacterials prescribed for HABP/VABP 
treatment are discontinued within 24 hours after final negative lower respiratory tract 
culture. 
k. Determine the frequency with which antibacterials prescribed for HABP/VABP 
treatment are changed to narrow the antibacterial spectrum within 24 hours of 
positive (and negative) lower respiratory tract culture results. 
l. 
Determine the average and median number of days a subject is followed in the risk 
factor study. 
m. Estimate the proportion of subjects for which a causative viral pathogen is identified. 
(Arm 2 only) 
n. Estimate the proportion of subjects for which normal respiratory flora is identified on 
lower respiratory tract cultures (Arm 2 only) 
 
4.0 
Study Design 
This is a prospective, multi-center, observational study of patients - admitted to ICUs. Patients will 
be enrolled into 2 Arms based on their age – Arm 1: ≥18 years old, Arm 2: <18 years old.  
Generally, all patients admitted to the ICU for any indication will be considered at risk for 
developing HABP/VABP. A subset of the at-risk patients treated with select respiratory modalities 

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for at least 12 hours (Arm 1) or 24 hours (Arm 2) will be considered high risk for the development 
of HABP/VABP, will have baseline data collected, and will be screened daily for antibiotic 
treatment for suspected pneumonia. Patients <120 days old will be considered high risk if treated 
with a select respiratory modality for at least 5 days. Patients not meeting high-risk criteria, “other-
ICU patients”, will be screened twice weekly for antibiotic treatment for suspected pneumonia.  
Once a high-risk subject or other-ICU patient is treated with antibiotics for either a lower 
respiratory tract infection (LRTI) or undifferentiated sepsis, additional clinical information will be 
recorded from the subject’s medical record. All subjects treated with antibiotics for either 
indication will subsequently be screened for the development of pneumonia, as defined by the 
FDA draft guidance document for drug development in HABP/VABP. Subjects who meet the FDA 
draft guidance definition of pneumonia will have vitals and physiologic data collected and will be 
followed for 4 days after pneumonia is diagnosed to capture the results of any microbiologic 
testing and changes to initial antibiotic therapy. 
All observational data will be collected from the subject’s electronic health record and recorded in 
a secure electronic case report form. No information on outcomes, such as vital status, discharge 
destination, or length of stay will be collected. The data collected in this risk factor study will be 
used to better define the ICU population at highest risk for developing HABP/VABP.  
4.1 
Inclusion Criteria (Arm 1: age ≥18 years old) 
• 
Admission to participating ICU 
• 
Hospitalized for >48 hours or admitted <7 days after discharge from an inpatient 
acute or chronic care facility 
 
Please see Appendix B for Arm 2 (age <18 years old) information 
 
4.1.1 
High-Risk Inclusion (Arm 1) 
Treated with one or more of the following respiratory modalities for at least 12 hours, 
either currently or within the prior 7 days:  
• 
Invasive mechanical ventilation 
• 
Noninvasive ventilation (BiPAP or CPAP for any indication other than obstructive 
sleep apnea) 
• 
High-flow, supplemental oxygen therapy via nasal cannula. Only include systems that 
using an air/oxygen blender capable of delivering a precise FiO2 level, not just a flow 
in LPM. 
• 
High flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask).  Only include systems using an air/oxygen 
blender capable of delivering a precise FiO2 level, not just a flow in LPM. 
• 
Supplemental oxygen therapy delivered via either partial or non-rebreather face mask 
 
Please see Appendix B for Arm 2 information 
 
 
 
4.1.2 
Other-ICU Inclusion (Arm 1) 
All patients who meet eligibility criteria in 4.1, but do not fulfill high-risk criteria in 4.1.1, 
and are receiving an antibiotic for treatment of LRTI or undifferentiated sepsis. 
 
Please see Appendix B for Arm 2 information 
 

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4.2 
Exclusion Criteria (Arm 1) 
• 
Age <18 years old 
• 
Pregnancy (current) or breastfeeding 
• 
Lung cancer or another malignancy metastatic to the lungs (currently receiving 
treatment)  
• 
Patient previously enrolled and treated for suspected HABP or VABP (More than 
CRF Part 1 was previously completed) 
• 
Patient is on comfort measures (e.g. would not receive antibiotics) 
 
Please see Appendix B for Arm 2 information 
4.3 
Co-enrollment Guidelines 
Co-enrollment in other clinical trials or studies is permitted except for protocols that would violate 
the exclusion criteria.  
4.4 
Study Discontinuation 
This study may be terminated at any time by the principal investigator in consultation with CTTI 
and/or the FDA. 
5.0 
Study Procedures 
5.1 
Recruitment Plan 
This study will collect data on subjects who meet protocol-specified high-risk criteria. In addition, 
data will be collected on subjects not meeting high-risk criteria but who are treated with antibiotics 
for LRTI or undifferentiated sepsis for which HABP/VABP is considered in the differential 
diagnosis. 
• 
Arm 1: approximately 6850 patients ≥18 years old 
• 
Arm 2: approximately 1000 patients < 18 years old 
Sections 5.2 through 5.5 below apply to Arm 1. Please see Appendix B for Arm 2 information 
5.2 
Enrollment (Arm 1) 
All patients admitted to a study site ICU who have been hospitalized for at least 48 hours or 
discharged from an inpatient acute or chronic care facility within the prior 7 days will be screened 
for study inclusion. If any exclusion criterion is present, the patient will be recorded as a 
“screening failure” in the screening log and no further data will be collected. 
If the patient satisfies the study enrollment criteria, he/she will be enrolled in the study. The 
subject will be counted as an inclusion in the screening log, and he/she will also be registered in 
the electronic data capture (EDC) system. For each enrolled subject, the types of respiratory 
support received at the time of enrollment and within the previous 7 days will be recorded. Those 
subjects receiving one or more of the modalities of respiratory support described in section 4.1.1. 
for at least 12 hours will be followed per the “High-Risk” protocol. 
All other ICU patients, meeting eligibility criteria in 4.1, but not receiving respiratory support via 
one of the modalities in 4.1.1 or receiving for less than 12 hours will be followed according to the 
“Other-ICU” protocol. Other-ICU patients are enrolled only if they receive antibiotic therapy for 
LRTI or undifferentiated sepsis. 

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5.3 
High-Risk Protocol (Arm 1) 
Demographic, admission, and medical problems will be recorded for subjects meeting criteria for 
“high-risk” on the day of enrollment. High-risk subjects will be followed daily for the initiation of 
antibiotic therapy for either the treatment of LRTI or undifferentiated sepsis for which HABP/VABP 
is considered in the differential diagnosis. Antibiotics prescribed and evaluation for the study 
definition of pneumonia will be completed for subjects treated with antibiotics for either of these 
indications. If the study criteria for HABP/VABP are present, treatment exposures and 
microbiology will then be completed, and the subject will be followed for an additional 4 days as 
described in Section 5.5. Subjects treated with antibiotics for either LRTI or undifferentiated 
sepsis but not meeting criteria for HABP/VABP will be reevaluated daily for the fulfillment of 
HABP/VABP study criteria. If antibiotics for LRTI or undifferentiated sepsis are discontinued, 
screening per the High-Risk protocol will resume. 
Subjects who have not met the study criteria for HABP/VABP will be followed daily per the High-
Risk protocol until they have not received support from at least one respiratory modality listed in 
the high-risk criteria within the past 7 days. If a subject remains in the ICU beyond this time 
period, they will then be followed per the Other-ICU protocol until discharged from the ICU or 
transitioned to comfort measures and are no longer being treated with antibiotics. If support with a 
respiratory modality included in the “high-risk” criteria is later required, the subject will then be 
followed per the High-Risk protocol again. 
5.4 
Other-ICU Protocol (Arm 1) 
Patients not meeting the “high-risk” criteria will be screened at least twice weekly for treatment 
with an antibiotic for either LRTI or undifferentiated sepsis for which HABP/VABP is considered in 
the differential diagnosis. Demographic, admission, medical problems, and antibiotics prescribed 
will be completed for subjects treated with antibiotics for either of these indications. Evaluation of 
the study definition of pneumonia will occur. If the study criteria for HABP/VABP are present, 
treatment exposures and microbiology will then be completed, and the subject will be followed for 
an additional 4 days as described in Section 5.5. Subjects treated with antibiotics for either LRTI 
or undifferentiated sepsis but not meeting criteria for HABP/VABP will be reevaluated daily for the 
fulfillment of HABP/VABP study criteria until antibiotics for LRTI or undifferentiated sepsis are 
discontinued. For those other-ICU patients who never receive antibiotic treatment for LRTI or 
undifferentiated sepsis during their ICU stay, no information will be collected. 
Subjects who have not met the study criteria for HABP/VABP will be followed per the Other-ICU 
protocol until discharged from the ICU or transitioned to comfort measures and are no longer 
being treated with antibiotics. Subjects originally assigned to the Other-ICU protocol who later 
require support with a respiratory modality described in section 4.1.1. for at least 12 hours will be 
subsequently followed per the High-Risk protocol.  
5.5 
Study Completion (Arm 1) 
Subjects developing HABP/VABP will be followed for 4 days beyond the initial fulfillment of 
HABP/VABP study criteria to collect microbiologic and antibacterial treatment data. After 4 days, 
the patient will no longer be followed in the risk factor study.  
Subjects who do not develop HABP/VABP will be followed until discharge from the ICU. Or, 
follow-up will end if the subject is transitioned to comfort measures and are no longer being 
treated with antibiotics. At the end of follow up, treatment exposures will be collected using the 
most abnormal values/events from the ICU stay.  
6.0 
Statistical Analysis Plan (Arm 1) 
Please see Arm 2 (< 18 years old) information in Appendix B. 

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6.1 
General Considerations 
All continuous variables will be summarized using descriptive statistics, including number of 
observations, number of missing observations, mean, standard deviation, minimum, 25th 
percentile, median, 75th percentile, and maximum. All categorical variables will be summarized 
using frequency counts and percentages.  
No missing data imputation will be performed. All statistical tests will be two-sided and interpreted 
at the 5% level of significance without correction for multiple comparisons. 
All analyses will be performed in SAS 9.2 or higher.  
6.2 
Endpoints 
The primary endpoint is the development of FDA-defined HABP/VABP.  
6.3 
Sample Size  
Due to the exploratory nature of this study, no power calculations are performed.  
A sample size of 6850 high-risk patents was chosen based on an estimate of the number of 
patients that can feasibly be enrolled at 45 sites over 12 months, and it is believed that this 
number will provide a meaningful number of patients who develop HABP/VABP. This number 
assumes enrollment of one new high-risk patient per business day per site and the months of 
participation per site will range from 3-12 months. 
The sample size will provide reasonable estimates and exact 95% confidence intervals for the 
rate of HABP/VABP development (see Table 1 above). If the estimated rate of HABP/VABP is 
5%, then the margin of error will be less than 1%. 
 
Table 1: Exact confidence intervals for estimated rates of HABP/VABP development for 
100%, 90%, and 80% of planned sample size. 
 
Exact 95% Confidence Intervals 
Estimated 
Rate of 
HABP/VABP 
N=6850 
N=6165 
N=5480 
1% 
(0.78% - 1.27%) 
(0.77% - 1.29%) 
(0.76% - 1.30%) 
3% 
(2.62% - 3.44%) 
(2.59% - 3.46%) 
(2.57% - 3.50%) 
5% 
(4.50% - 5.55%) 
(4.48% - 5.59%) 
(4.44% - 5.61%) 
7% 
(6.41% - 7.64%) 
(6.38% - 7.67%) 
(6.35% - 7.72%) 
9% 
(8.34% - 9.71%) 
(8.30% - 9.74%) 
(8.27% - 9.80%) 
 
6.4 
FINAL Analysis 
6.4.1 
Analysis Populations 
The following analysis populations will be defined: 
• 
The high-risk population (ICU subjects who meet the predefined high-risk criteria) 
• 
The treated population (subjects given antibiotics to treat possible HABP/VABP) 

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6.4.2 
The HABP/VABP population (subjects meeting diagnostic criteria for HABP/VABP) 
Primary Analyses 
• 
Estimate the rate of HABP/VABP diagnosis in ICU subjects who meet the predetermined 
high-risk criteria.   
• 
Estimate the proportion of ICU subjects diagnosed with HABP/VABP who would be 
eligible for enrollment in a clinical trial of antibacterial therapy for HABP/VABP per FDA 
draft guidance on HABP/VABP. 
The estimated rates will be presented as well as its exact 95% confidence interval. 
6.4.3 
Key Secondary Analysis 
The key secondary analysis will be: 
• 
Assess the risk factors, comorbid medical illnesses, and treatment exposures associated with 
the development of HABP/VABP in ICU subjects at high-risk for developing pneumonia using 
a logistic regression model with age, sex, height (cm), weight (kg), ICU type, admission 
source, hospital length of stay at the time of screening (calendar days), ICU length of stay at 
the time of screening, ICU admission diagnosis, aspiration risk, medical history, type and 
duration of ventilation, enteral nutrition, medications, and other therapies of interest as 
factors. 
Estimated proportions will be presented as well as their 95% confidence intervals. 
Odds ratios, 95% confidence intervals and p-values will be reported for each factor in the 
regression model.  
Summary statistics will also be presented for all factors included in the regression model.  
6.4.4 
Secondary Analysis 
The following summaries will be conducted in the treated population: 
• 
Estimate the proportion of ICU subjects who would be eligible for enrollment in a clinical 
trial of antibacterial therapy for HABP/VABP per FDA draft guidance document criteria. 
• 
Estimate the proportion of subjects who develop HABP/VABP. 
• 
Estimate the proportion of subjects who have lower respiratory tract cultures collected 
within 48 hours preceding treatment of pneumonia with antibiotics.  
• 
Estimate the proportion of subjects for which a causative bacterial pathogen is identified 
on lower respiratory tract cultures. 
• 
Summarize prescribed initial antibiotics. 
• 
Estimate the proportion of subjects treated within 24 hours of HABP/VABP antibiotic 
initiation with an initial antibacterial agent active against MRSA, the proportion treated 
with at least 1 initial antibacterial agent active against Pseudomonas aeruginosa, and the 
proportion treated with at least 2 initial antibacterials active against Pseudomonas 
aeruginosa. 
The following summaries will be conducted for subjects in the HABP/VABP population: 

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• 
Estimate the proportion of subjects who meet clinical trial inclusion criteria but would be 
excluded from enrollment due to effectively being treated for pneumonia within 24 hours, 
36 hours, or 48 hours preceding pneumonia diagnosis. 
• 
Estimate the proportion of subjects for which gram stain results are available within 
24 hours preceding initiation of antibacterial therapy for HABP/VABP. 
• 
Estimate the proportion of subjects treated with at least 1 initial anti-pseudomonal 
antibiotic within 24 hours of initial HABP/VABP antibiotic treatment. 
• 
Estimate the proportion of subjects treated with at least 2 initial anti-pseudomonal 
antibiotics within 24 hours of initial HABP/VABP antibiotic treatment. 
• 
Estimate the proportion of subjects for whom antibiotic therapy was changed because the 
initial regimen was either inactive or ineffective against the pathogen isolated on lower 
respiratory tract culture.  
• 
Estimate the proportion of subjects for whom antibiotic therapy was changed because of 
clinical deterioration or lack of clinical improvement. 
The following summaries will be conducted for subjects in the HABP/VABP population who have 
lower respiratory cultures collected: 
• 
Estimate the proportion of gram stain results reported prior to the start of antibacterial 
therapy. 
• 
Estimate the rate of HABP/VABP antibacterial discontinuation within 24 hours after final 
negative lower respiratory tract culture.  
• 
Estimate the rate at which HABP/VABP antibacterials are changed within 24 hours of 
lower respiratory tract culture results to narrow the antibacterial spectrum.  
The following summaries will be conducted for subjects in the HABP/VABP population who have 
positive lower respiratory cultures: 
• 
Summarize the bacterial pathogens of HABP/VABP. 
• 
Summarize the types of antibacterial resistance by pathogen.  
All estimated proportions and rates will be presented with their exact 95% confidence intervals. 
All summaries will be presented as frequency counts and percentages. 
6.5 
Baseline Summaries 
The high-risk population will be summarized according to the following factors measured at the 
time of high-risk determination: 
• 
Invasive mechanical ventilation 
• 
Noninvasive ventilation 
• 
High-flow, supplemental oxygen therapy via nasal cannula. 
• 
High flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask)   
• 
Supplemental oxygen therapy delivered via either partial or non-rebreather face mask 

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• 
Demographics: age, sex, height (cm), weight (kg), ICU type, admission source, hospital 
length of stay at the time of screening (calendar days), ICU length of stay at the time of 
screening, identification of legally authorized representative or medical proxy 
• 
Medical problems: reason for hospital and ICU admission, aspiration risk, medical history, 
and drug allergies 
• 
Treatment exposures: type and duration of ventilation, enteral nutrition, medications, and 
other therapies of interest 
6.6 
Interim Analysis 
One interim analysis will be conducted during the study. The primary purpose of the interim 
analysis is to assess futility by investigating the primary objectives and the first two secondary 
objectives (3.1a-b, 3.2a, and 3.3a). The interim analysis will occur three months after 50% of US 
sites have begun enrolling patients. 
 
The following analyses will be conducted on the high-risk population: 
 
1. Estimate the rate of HABP/VABP development as well as its exact 95% confidence interval. If 
the exact 95% confidence interval for the pneumonia rate in high-risk subjects does not 
include 5%, the feasibility of continuing the risk factor study and/or an amendment to expand 
the high-risk definition will be discussed.  
 
2. Assess the risk factors, comorbid medical illnesses, and treatment exposures associated with 
the development of HABP/VABP in ICU subjects at high-risk for developing pneumonia using 
a logistic regression model with age, sex, height (cm), weight (kg), ICU type, admission 
source, hospital length of stay at the time of screening (calendar days), ICU length of stay at 
the time of screening, ICU admission diagnosis, aspiration risk, medical history, type and 
duration of ventilation, enteral nutrition, medications, and other therapies of interest as 
factors. 
 
The following analysis will be conducted on the HABP/VABP population: estimate the proportion 
of subjects, as well as its exact 95% confidence interval, who would be eligible for enrollment in a 
clinical trial of antibacterial therapy for HABP/VABP per FDA guidance document criteria. 
 
The following analysis will be conducted on the treated population: estimate the proportion of 
subjects, as well as its exact 95% confidence interval, who would be eligible for enrollment in a 
clinical trial of antibacterial therapy for HABP/VABP per FDA guidance document criteria  
 
7.0 
Ethics and Regulatory 
7.1 
Ethical Standards 
The investigator will ensure that the study will be conducted in accordance with all applicable 
national, regional, and local regulations. This study will request a waiver of informed consent, 
consistent with CFR Title 45 part 46.116(d). The study does not involve direct interaction with 
human subjects. The medical records of patients admitted to the ICU will be screened and data 
collected from those records according this protocol. The patients will not be approached to 
obtain information, no intervention is being tested, and no samples or specimens are being 
collected. Therefore, the study should be considered no more than minimal risk, and the waiver 
will not adversely affect the rights and welfare of the patients observed.  
This research could not practicably be carried out without the waiver of consent since the most 
critically ill patients, like the ICU patients, are very problematic to consent. This risk factor study 
requires screening of the medical records of all ICU patients, and data collection on a large 

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number of patients meeting high-risk characteristics and/or receiving antibiotics to obtain a 
complete picture of HABP/VABP development in ICUs. Studies in a different critically ill 
population, one with MRSA bloodstream infections, showed that the mortality risk of patients with 
MRSA is considerably lower in studies that required informed consent6 relative to those that do 
not.7 Hence, requiring informed consent would systematically bias the study towards less 
severely infected patients. Less severely ill high-risk patients are also less likely develop 
pneumonia. If the number of high-risk patients identified is too low, the proportion developing 
pneumonia will be too small to provide meaningful information. 
 
7.2 
Data Confidentiality 
The study 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.  
Duke Clinical Research Institute’s (DCRI) configured the EDC database (eClinical OS data) that 
will be hosted by Merge, which uses a Peak 10 datacenter located in Morrisville, NC. Database 
access will be limited to study personnel who are issued a unique user identification and 
password. Data will be entered via a web-based interface at each site by study personnel. No 
information concerning the study or the data will be released to any third party without prior 
written approval of the sponsor. Study records may be reviewed in order to meet federal or state 
regulations. Reviewers may include the IRBs or the the DCRI. 
7.2.1 
Quality Control and Quality Assurance  
The local site principal investigator will ensure that study personnel are appropriately trained and 
applicable documentations are maintained.  
The DCRI will implement a Quality Plan to ensure that protocol training and data quality and data 
security measures are being undertaken. 
7.2.2 
Source Documents and Access to Source Data 
All study monitoring will be performed centrally via the electronic study database. If necessary, a 
site monitoring visit will be arranged by the DCRI. 
7.3 
Data Handling and Record Keeping 
7.3.1 
Data Capture Methods 
This study will use a web-based e-CRF database configured by the DCRI. The investigator's site 
staff, who will be entering data, will receive training on the system, after which each person will be 
given access to the study database.  
7.3.2 
Data Editing and Audit Trail 
eClinical OS maintains an audit trail that consists of creation and/or modification date and time, 
identification of the user that created/changed the record, the device where the data were added 
or changed, and the reason for the change if applicable. Data changes do not obscure previously 
recorded data. 
If incomplete or inaccurate data are found, a data clarification request will be generated and 
distributed to clinical centers for a response. Clinical centers will resolve data inconsistencies and 
errors and enter all corrections and changes into the study EDC database. 
 

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8.0 
Publication Policy  
Following completion of the study, the results of this research will be written up in a manuscript to be 
submitted to a scientific journal.  As part of the publication of results, CTTI will make the de-identified data 
from this study, and the underlying code and research provenance available not only in summary form but 
also via a web platform—with appropriate data governance and security—for other researchers to review. 
Prior to submission, it will undergo review by CTTI’s Publication Committee, a subcommittee of the 
Executive Committee.  The Executive Committee includes distinguished U.S. and international thought 
leaders in government, academia, industry, and patient advocacy who are experienced at envisioning and 
facilitating improvements in health care and medical research systems (http://www.ctti-
clinicaltrials.org/who-we-are/organizational-structure/executive-committee). The purpose of the 
Publication Committee review is to foster the quality of CTTI products. The Publication Committee 
reviews papers to be submitted to peer-reviewed journals and posters to be presented at professional 
meetings. The primary decision on content stays with the author, unless the paper or poster represents 
an official CTTI position, which can only be established by the Executive Committee. 
 
9.0 
References 
1. Jones R. Microbial Etiologies of Hospital-Acquired Bacterial Pneumonia and Ventilator-
Associated Bacterial Pneumonia. Clinical Infectious Diseases 2010; 51(S1):S81–S87. 
2. Streamlining HABP/VABP Trials. (n.d.). Retrieved October 20, 2015, from http://www.ctti-
clinicaltrials.org/what-we-do/ctti-projects/habpvabp-trials.  
3. Stergiopoulos S, Tenaerts P, Getz KA. Cost Drivers of a Hospital Acquired Bacterial Pneumonia 
and Ventilator Acquired Bacterial Pneumonia (HABP/VABP) Phase Three Clinical Trials. Poster 
session presented at: ID Week; 2015 October 9; San Diego, CA. 
https://idsa.confex.com/idsa/2015/webprogram/Paper52187.html 
4. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research, Guidance for Industry: Hospital-Acquired Bacterial Pneumonia and 
Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment (Draft Guidance, 
Revision 2), 2014: Rockville, MD, USA. p. 19. 
5. Ego A, Preiser J, Vincent J. Impact of diagnostic criteria on the incidence of ventilator-associated 
pneumonia. Chest. 2015;147:347-355.  
6. Fowler VG Jr, Olsen MK, Corey GR, et al. Clinical identifiers of complicated Staphylococcus 
aureus bacteremia. Arch Intern Med. 2003;163:2066-2072.  
7. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia 
and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665. 
 
 

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APPENDIX A: DATA COLLECTION SCHEDULE (Arm 1) 
Event 
Screen
-ing 
High-Risk 
Criteria 
Met 
Other-ICU 
(Not 
Meeting 
High-Risk 
Criteria) 
High-Risk Protocol 
with Pneumonia 
Symptoms or 
Antibiotics Started 
for any LRTI or 
Undifferentiated 
Sepsis 
Other-ICU 
Protocol 
with 
Antibiotics 
Started for 
LRTI or 
Undifferen
tiated 
Sepsis 
Meets 
HABP or 
VABP 
Definition 
(in Either 
High-Risk 
or Other-
ICU Group) 
Lower 
Respira-
tory 
Tract 
Cultures 
Obtained 
Full CRF 
Complete 
or 
Condition 
Met to 
Stop Data 
Collection 
Review 
eligibility 
criteria 
X 
 
 
 
 
 
 
 
Daily status 
worksheet 
 
X 
 
 
 
 
 
 
Twice weekly 
status 
worksheet 
 
 
X 
 
 
 
 
 
Collect: 
demographic
s, admission, 
medical 
problems 
 
X 
 
 
X 
 
 
 
Evaluate 
clinical 
signs/sympto
ms of 
pneumonia 
(HABP/VABP 
definition) 
 
 
 
X 
X 
 
 
 
Collect 
Treatment 
Exposures 
 
 
 
 
 
X 
 
X (In those 
not 
meeting 
HABP or 
VABP 
definition)  
Collect 
Antibiotics 
 
 
 
X 
X 
X 
 
 
Collect: 
microbiology 
 
 
 
 
 
 
X 
 
Collect Study 
Outcomes 
Page  
 
 
 
 
 
 
 
 
X 
CRF, case report form; HABP, hospital-acquired bacterial pneumonia; LRTI, lower respiratory tract infection; ICU, 
intensive care unit; VABP, ventilator-associated bacterial pneumonia. 
 

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Appendix B: Supplement for pediatric subjects (Arm 2: <18 years old) 
 
1. Study Objectives: 
1.1. Primary Objectives: 
a. 
Estimate the rates of HABP/VABP diagnosis in pediatric patients considered high risk for 
pneumonia. High risk is defined in section 2.1 of this Appendix.  
1.2. Secondary Objectives (In addition to Arm 1 items): 
a. Estimate the proportion of subjects for which a causative viral pathogen is identified 
b. Estimate the proportion of subjects for which normal respiratory flora is identified on lower 
respiratory tract cultures 
 
2. Inclusion Criteria 
• 
< 18 years old 
• 
Admission to participating ICU or intermediate care unit 
• 
Hospitalized for >48 hours or admitted <7 days after discharge from an inpatient acute or 
chronic care facility 
Note: Children and infants with pulmonary and cardiac anomalies are eligible to participate. 
 
2.1. High-Risk Inclusion  
Subjects ≥120 days old and <18 years old:  
Currently treated with one or more of the following respiratory modalities for at least 24 hours:  
a. Invasive mechanical ventilation via endotracheal intubation 
b. New initiation of mechanical ventilation, BiPAP or CPAP via tracheostomy 
c. Noninvasive ventilation (BiPAP or CPAP for any indication other than obstructive sleep 
apnea) 
d. High-flow, supplemental oxygen therapy delivering at least 1.5LMP with 100% FiO2 via 
nasal cannula when delivered using an air/oxygen blender capable of delivering a precise 
FiO2 level, not just a flow in LPM 
e. High flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask)  when delivered using an air/oxygen blender 
capable of delivering a precise FiO2 level, not just a flow in LPM 
f. 
Supplemental oxygen therapy delivered via either partial or non-rebreather face mask 
 
Subjects <120 days old:  
Currently treated with mechanical ventilation via endotracheal intubation for at least 5 days  
 
2.2. Standard-Risk Inclusion 
All patients who meet eligibility criteria in Appendix B Section 2, but do not fulfill high-risk criteria 
in Appendix B Section 2.1, and are receiving an antibiotic for treatment of LRTI or 
undifferentiated sepsis. 
 
 
3. Exclusion Criteria 
• 
Known pregnancy (current) or breastfeeding 
• 
Lung cancer or another malignancy metastatic to the lungs (currently receiving treatment)  
• 
Patient previously enrolled and treated for suspected HABP or VABP (More than Pediatric 
CRF Part 1 was previously completed) 
• 
Patient is on comfort measures (e.g. would not receive antibiotics) 
 
4. Co-enrollment Guidelines 

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Co-enrollment in other clinical trials or studies is permitted except for protocols that would violate 
the exclusion criteria.  
5. Study Discontinuation 
This study may be terminated at any time by the principal investigator in consultation with CTTI 
and/or the FDA. 
6. Study Procedures 
6.1. Recruitment Plan 
This study will collect data on pediatric subjects who meet protocol-specified high-risk criteria. In 
addition, data will be collected on subjects not meeting high-risk criteria but who are treated with 
antibiotics for LRTI or undifferentiated sepsis for which HABP/VABP is considered in the 
differential diagnosis. Approximately 1000 subjects will be recruited. 
6.2. Enrollment 
All patients admitted to a study site ICU or intermediate care unit who have been hospitalized for 
at least 48 hours or discharged from an inpatient acute or chronic care facility within the prior 7 
days will be screened for study inclusion. If any exclusion criterion is present, the patient will be 
recorded as a “screening failure” in the screening log and no further data will be collected. 
If the patient satisfies the study enrollment criteria, he/she will be enrolled in the study. The 
subject will be counted as an inclusion in the screening log, and he/she will also be registered in 
the electronic data capture (EDC) system. For each enrolled subject, the types of respiratory 
support received at the time of enrollment and within the previous 7 days will be recorded. Those 
subjects receiving one or more of the modalities of respiratory support described in section 
Appendix B Section 2.1. for at least 24 hours will be followed per the “High-Risk” protocol. 
All other patients, meeting eligibility criteria in Appendix B Section 2, but not receiving respiratory 
support via one of the modalities in Appendix B Section 2.1 or receiving for less than 24 hours will 
be followed according to the “Standard-risk ” protocol. Standard-risk patients are enrolled only if 
they receive antibiotic therapy for LRTI or undifferentiated sepsis. 
6.3. High-Risk Protocol 
Demographic, admission, and medical problems will be recorded for subjects meeting criteria for 
“high-risk” on the day of enrollment. High-risk subjects will be followed or be flagged by the 
electronic medical record daily for the initiation of antibiotic therapy for either the treatment of 
LRTI or undifferentiated sepsis for which HABP/VABP is considered in the differential diagnosis. 
Antibiotics prescribed and evaluation for the study definition of pneumonia will be completed for 
subjects treated with antibiotics for either of these indications. If the study criteria for HABP/VABP 
are present, treatment exposures and microbiology will then be completed, and the subject will be 
followed for an additional 4 days as described in Appendix B Section 6.5. Subjects treated with 
antibiotics for either LRTI or undifferentiated sepsis but not meeting criteria for HABP/VABP will 
be reevaluated daily for the fulfillment of HABP/VABP study criteria. If antibiotics for LRTI or 
undifferentiated sepsis are discontinued, screening per the High-Risk protocol will resume. 
Subjects who have not met the study criteria for HABP/VABP will be followed daily per the High-
Risk protocol until they have not received support from at least one respiratory modality listed in 
the high-risk criteria within the past 7 days. If a subject remains in the ICU  or intermediate care 
unit beyond this time period, they will then be followed per the standard-risk  protocol until 
discharged from the ICU or intermediate care unit or transitioned to comfort measures and are no 
longer being treated with antibiotics. If support with a respiratory modality included in the “high-
risk” criteria is later required, the subject will then be followed per the High-Risk protocol again. 
 
 

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6.4.  Standard-risk Protocol 
Patients not meeting the “high-risk” criteria will be screened at least twice weekly or be flagged by 
the electronic medical record for the initiation of treatment with an antibiotic for either LRTI or 
undifferentiated sepsis for which HABP/VABP is considered in the differential diagnosis. 
Demographic, admission, medical problems, and antibiotics prescribed will be completed for 
subjects treated with antibiotics for either of these indications. Evaluation of the study definition of 
pneumonia will occur. If the study criteria for HABP/VABP are present, treatment exposures and 
microbiology will then be completed, and the subject will be followed for an additional 4 days as 
described in Appendix B Section 6.5. Subjects treated with antibiotics for either LRTI or 
undifferentiated sepsis but not meeting criteria for HABP/VABP will be reevaluated daily for the 
fulfillment of HABP/VABP study criteria until antibiotics for LRTI or undifferentiated sepsis are 
discontinued. For those  standard-risk patients who never receive antibiotic treatment for LRTI or 
undifferentiated sepsis during their ICU or intermediate care unit stay, no information will be 
collected. 
Subjects who have not met the study criteria for HABP/VABP will be followed per the  standard-
risk protocol until discharged from the ICU or intermediate care unit or transitioned to comfort 
measures and are no longer being treated with antibiotics. Subjects originally assigned to the 
standard-risk protocol who later require support with a respiratory modality described in Appendix 
B Section 2.1 for at least 24 hours if ≥120 days old or for at least 5 days if <120 days old will be 
subsequently followed per the High-Risk protocol.  
6.5. Study Completion 
Subjects developing HABP/VABP will be followed for 4 days beyond the initial fulfillment of 
HABP/VABP study criteria to collect microbiologic and antibacterial treatment data. After 4 days, 
the patient will no longer be followed in the risk factor study.  
Subjects who do not develop HABP/VABP will be followed until discharge from the ICU or 
intermediate care unit. Or, follow-up will end if the subject is transitioned to comfort measures and 
are no longer being treated with antibiotics. At the end of follow up, treatment exposures will be 
collected using the most abnormal values/events from the ICU or intermediate care unit stay.  
 
 
 
 
 
 

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Risk Factors for HABP/VABP Study Flowchart (Arm 2: age <18 years old) 

CTTI_PTN Risk Factors for HABP/VABP Study 
 
 
 
 
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7. Statistical Analysis Plan 
 
7.1. General Considerations 
All continuous variables will be summarized using descriptive statistics, including number of 
observations, number of missing observations, mean, standard deviation, minimum, 25th 
percentile, median, 75th percentile, and maximum. All categorical variables will be summarized 
using frequency counts and percentages.  
No missing data imputation will be performed. All statistical tests will be two-sided and interpreted 
at the 5% level of significance without correction for multiple comparisons. 
All analyses will be performed in SAS 9.2 or higher.  
7.2. Endpoints 
The primary endpoint is the development of FDA-defined HABP/VABP. HABP/VABP is defined as 
all below criteria are met: 
a. Chest radiograph showing the presence of new or progressive infiltrate(s) suggestive of 
bacterial pneumonia within 48 hours of all other diagnostic criteria being present 
b. New onset or worsening cough, dyspnea, tachypnea (respiratory rate >60 breaths per minute 
for children <1 year old, >40 breaths per minute for children ages 1-3 years, >30 breaths per 
minute for children ages 4-12 years, >20 breaths per minute for children >12 years), OR 
expectorated sputum production OR new requirement for invasive mechanical ventilation OR 
hypoxemia (partial pressure of oxygen <60 millimeters of mercury measure by arterial blood 
gas or worsening (decrease >10%) of the ratio of arterial partial pressure of oxygen to 
fraction of inspired oxygen (PaO2/FiO2) or pulse oximetry reading of <90% or new 
supplemental oxygen requirement or greater than 50% increase in supplemental oxygen 
requirement for patients on chronic supplemental oxygen therapy) OR need for acute 
changes (≥20% increase in FiO2 or ≥3cmH20 increase in PEEP over the “baseline daily 
minimum), after 2 days of stability in ventilator support OR new onset of suctioned respiratory 
secretions. 
c. Systemic inflammation: body temperature ≥38 degrees Celsius or ≤35 degrees Celsius OR 
leukocytosis (total peripheral white blood cell count ≥10,000 cells/cubic millimeter) OR 
leukopenia, ( total peripheral white blood cell count ≤4,500 cells/cubic millimeter) OR greater 
than 15% immature neutrophils (bands) noted on peripheral blood film OR a C-reactive 
protein ≥5 times the upper limit of normal.  
d. Timing: Signs/symptoms of pneumonia first noted >48 hours after hospital admission OR 
signs/symptoms of pneumonia first noted >48 hours after initiation of mechanical ventilation  
7.3. Sample Size 
Due to the exploratory nature of this study, no power calculations are performed.  
A sample size of 1000 - pediatric patents was chosen based on an estimate of the number of 
patients that can feasibly be enrolled at 10 sites over 12 months, and it is believed that this 
number will provide a meaningful number of patients who develop HABP/VABP. 
 
 
 

CTTI_PTN Risk Factors for HABP/VABP Study 
 
 
 
 
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7.4. Final Analysis 
 
7.4.1. Analysis Populations 
The following analysis populations will be defined: 
• 
The high-risk pediatric population ≥120 days old but <18 years old ( subjects who meet 
the predefined high-risk criteria) 
• 
The high-risk pediatric population <120 days old (subjects who meet the predefined high-
risk criteria) 
• 
The treated pediatric population ≥120 days old but <18 years old (subjects given 
antibiotics to treat possible HABP/VABP) 
• 
The treated pediatric population <120 days old (subjects given antibiotics to treat 
possible HABP/VABP) 
• 
The HABP/VABP pediatric population ≥120 days old but <18 years old (subjects meeting 
diagnostic criteria for HABP/VABP)  
• 
The HABP/VABP pediatric population <120 days old (subjects meeting diagnostic criteria 
for HABP/VABP)  
7.4.2. Primary Analyses 
• 
Estimate the rate of HABP/VABP diagnosis in pediatric subjects who meet the 
predetermined high-risk criteria.   
• 
Estimate the proportion of pediatric subjects diagnosed with HABP/VABP who would be 
eligible for enrollment in a clinical trial of antibacterial therapy for HABP/VABP per FDA 
draft guidance on HABP/VABP. 
The estimated rates will be presented as well as its exact 95% confidence interval. 
7.4.3. Key Secondary Analysis 
The key secondary analysis will be: 
• 
Assess the risk factors, comorbid medical illnesses, and treatment exposures associated 
with the development of HABP/VABP in pediatric subjects at high-risk for developing 
pneumonia using a logistic regression model with age, sex, height (cm), weight (kg), 
hospital admission type, admission source, hospital length of stay at the time of 
screening (calendar days),hospital length of stay at the time of screening, hospital 
admission diagnosis, aspiration risk, medical history, type and duration of ventilation, 
enteral nutrition, medications, and other therapies of interest as factors. 
Estimated proportions will be presented as well as their 95% confidence intervals. 
Odds ratios, 95% confidence intervals and p-values will be reported for each factor in the 
regression model.  
Summary statistics will also be presented for all factors included in the regression model.  
7.4.4. Secondary Analysis 
The following summaries will be conducted in the treated population: 

CTTI_PTN Risk Factors for HABP/VABP Study 
 
 
 
 
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• 
Estimate the proportion of  subjects who would be eligible for enrollment in a clinical trial 
of antibacterial therapy for HABP/VABP per FDA draft guidance document criteria. 
• 
Estimate the proportion of subjects who develop HABP/VABP. 
• 
Estimate the proportion of subjects who have lower respiratory tract cultures collected 
within 48 hours preceding treatment of pneumonia with antibiotics.  
• 
Estimate the proportion of subjects for which a causative bacterial pathogen is identified 
on lower respiratory tract cultures. 
• 
Estimate the proportion of subjects for which a causative viral pathogen is identified. 
• 
Estimate the proportion of subjects for which normal respiratory flora is identified on lower 
respiratory tract cultures  
• 
Summarize prescribed initial antibiotics. 
• 
Estimate the proportion of subjects treated within 24 hours of HABP/VABP antibiotic 
initiation with an initial antibacterial agent active against MRSA, the proportion treated 
with at least 1 initial antibacterial agent active against Pseudomonas aeruginosa, and the 
proportion treated with at least 2 initial antibacterials active against Pseudomonas 
aeruginosa. 
• 
Estimate the sensitivity, specificity and positive and negative predictive values of C-
reactive protein, procalcitonin and leukocytosis in the diagnosis of HABP/VABP. 
 
The following summaries will be conducted for subjects in the HABP/VABP population: 
• 
Estimate the proportion of subjects who meet clinical trial inclusion criteria but would be 
excluded from enrollment in an FDA phase 3 trial due to effectively being treated for 
pneumonia within 24 hours, 36 hours, or 48 hours preceding pneumonia diagnosis. 
• 
Estimate the proportion of subjects for which gram stain results are available within 
24 hours preceding initiation of antibacterial therapy for HABP/VABP. 
• 
Estimate the proportion of subjects treated with at least 1 initial anti-pseudomonal 
antibiotic within 24 hours of initial HABP/VABP antibiotic treatment. 
• 
Estimate the proportion of subjects treated with at least 2 initial anti-pseudomonal 
antibiotics within 24 hours of initial HABP/VABP antibiotic treatment. 
• 
Estimate the proportion of subjects for whom antibiotic therapy was changed because the 
initial regimen was either inactive or ineffective against the pathogen isolated on lower 
respiratory tract culture.  
• 
Estimate the proportion of subjects for whom antibiotic therapy was changed because of 
clinical deterioration or lack of clinical improvement. 
The following summaries will be conducted for subjects in the HABP/VABP population who 
have lower respiratory cultures collected: 
• 
Estimate the proportion of gram stain results reported prior to the start of antibacterial 
therapy. 

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• 
Estimate the rate of HABP/VABP antibacterial discontinuation within 24 hours after final 
negative lower respiratory tract culture.  
• 
Estimate the rate at which HABP/VABP antibacterials are changed within 24 hours of 
lower respiratory tract culture results to narrow the antibacterial spectrum.  
• 
Estimate the rate at which HABP/VABP antibacterials are changed within 24 hours of 
lower respiratory tract culture results to broaden the antibacterial spectrum.  
The following summaries will be conducted for subjects in the HABP/VABP population who 
have positive lower respiratory cultures: 
• 
Summarize the bacterial pathogens of HABP/VABP. 
• 
Summarize the types of antibacterial resistance by pathogen.  
• 
Estimate the proportion of study sites in which MRSA was identified on ≥1 lower 
respiratory tract culture. 
• 
Estimate the proportion of study sites in which an ESBL-producing Gram negative 
bacillus was identified on ≥1 lower respiratory tract culture. 
• 
Estimate the proportion of study sites in which an carbapenemase-producing Gram 
negative bacillus was identified on ≥1 lower respiratory tract culture. 
All estimated proportions and rates will be presented with their exact 95% confidence intervals. 
All summaries will be presented as frequency counts and percentages. 
7.5. Baseline Summaries 
The high-risk population will be summarized according to the following factors measured at the 
time of high-risk determination: 
• 
Invasive mechanical ventilation 
• 
Noninvasive ventilation 
• 
High-flow, supplemental oxygen therapy via nasal cannula. 
• 
High flow supplemental oxygen therapy delivering at least 50% FiO2 via aerosol 
facemask or tracheostomy collar (mask)   
• 
Supplemental oxygen therapy delivered via either partial or non-rebreather face mask 
• 
Demographics: age, sex, height (cm), weight (kg), hospital admission type, admission 
source, hospital length of stay at the time of screening (calendar days), hospital length of 
stay at the time of screening, identification of legally authorized representative or medical 
proxy 
• 
Medical problems: reason for hospital and ICU admission, aspiration risk, medical history, 
and drug allergies 
• 
Treatment exposures: type and duration of ventilation, enteral nutrition, medications, and 
other therapies of interest 
 

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7.6. Interim Analysis 
One interim analysis will be conducted during the study. The primary purpose of the interim 
analysis is to assess futility by investigating the primary objectives and the first two secondary 
objectives (1.1a-b, 1.2a, and 1.2b). The interim analysis will occur after 50 pediatric high-risk 
CRFs are completed or 3 months after all pediatric sites are activated, whichever occurs first.  
The following analyses will be conducted on the high-risk population: 
a. Estimate the rate of HABP/VABP development as well as its exact 95% confidence interval. If 
the exact 95% confidence interval for the pneumonia rate in high-risk subjects does not 
include 5%, the feasibility of continuing the risk factor study and/or an amendment to expand 
the high-risk definition will be discussed.  
 
b. Assess the risk factors, comorbid medical illnesses, and treatment exposures associated with 
the development of HABP/VABP in subjects at high-risk for developing pneumonia using a 
logistic regression model with age, sex, height (cm), weight (kg), hospital admission type, 
admission source, hospital length of stay at the time of screening (calendar days), hospital 
length of stay at the time of screening, hospital admission diagnosis, aspiration risk, medical 
history, type and duration of ventilation, enteral nutrition, medications, and other therapies of 
interest as factors. 
 
The following analysis will be conducted on the HABP/VABP population: estimate the proportion 
of subjects, as well as its exact 95% confidence interval, who would be eligible for enrollment in a 
clinical trial of antibacterial therapy for HABP/VABP per FDA guidance document criteria. 
 
The following analysis will be conducted on the treated population: estimate the proportion of 
subjects, as well as its exact 95% confidence interval, who would be eligible for enrollment in a 
clinical trial of antibacterial therapy for HABP/VABP per FDA guidance document criteria.  

CTTI_PTN Risk Factors for HABP/VABP Study 
 
 
 
 
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KEY ROLES / STUDY CONTACT 
 
 
Principal Investigators: 
Danny Benjamin, MD, PhD, MPH  
Duke Clinical Research Institute 
2400 Pratt Street, Durham, NC 27715 
Email: danny.benjamin@duke.edu 
 
Brian Smith, MD, MPH, MHS 
Duke Clinical Research Institute 
2400 Pratt Street, Durham, NC 27715 
Email: brian.smith@duke.edu 
 
 
Co-Investigators: 
Co-investigators are included in the signature log at 
each clinical site 
 
Thought Leaders: 
Jessica Ericson, MD 
Penn State College of Medicine 
500 University Dr., P.O. Box 850 
Hershey, PA 17033 
Email: jericson@hmc.psu.edu   
 
John Bradley, MD 
University of California San Diego, School of Medicine 
Rady Children's Hospital San Diego 
3020 Children’s Way MC 5041 
San Diego, CA 92123 
Email: jbradley@rchsd.org 
 
NICHD Contract Officer   
 
David Siegel, MD 
Technical Representative: 
The Eunice Kennedy Shriver National Institute of Child Health 
and Human Development (NICHD) 
6100 Executive Boulevard 
Bethesda, MD 20892-7510 
Email: siegelda@mail.nih.gov 
 
Project Leader:   
 
 
Jamie Gao, MS, PMP 
Duke Clinical Research Institute 
2400 Pratt Street, Durham, NC 27715 
Phone: 919-668-8942 
Email: jamie.gao@duke.edu