Clinical trial NCT04963764
Conditions: Pneumonia Pediatric Respiratory Diseases Antibiotic Use Community-acquired Pneumonia
Keywords: Pediatrics Pediatric CAP Pediatric Pneumonia Antibiotic Use
Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago
Start date: 2021-10-18; Completion date: 2022-05-27
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study will evaluate study processes and feasibility of a future large-scale clinical trial that proposes to test whether low-risk children managed as outpatients with community-acquired pneumonia (CAP) and procalcitonin (PCT) levels \<0.25 ng/mL treated with placebo have a similar clinical response to those treated with antibiotics and fewer adverse effects.

Detailed description:
This pilot clinical trial is a 3-site, randomized, placebo-controlled, double-blinded trial assessing the feasibility of comparing amoxicillin to placebo in children 12 months to \<6 years of age who present to the ED with Community Acquired Pneumonia (CAP), a procalcitonin (PCT) concentration of \<0.25 ng/mL, and who will be treated as outpatients.

Screening and Enrollment This pilot feasibility trial will enroll over a 6-month period and take place at three sites (Ann and Robert H. Lurie Children's Hospital of Chicago, Cincinnati Children's Hospital Medical Center and The Children's Hospital of Philadelphia) that are or were members of the Pediatric Emergency Care Applied Research Network (PECARN). This study aims to enroll 36 patients in total (2 patients per month, per site). Clinical research coordinators (CRCs) at participating EDs will screen potentially eligible patients with respiratory tract symptoms and discuss eligibility with the treating attending physician. If thought to be eligible and a diagnosis of CAP is presumed by the treating physician, the CRC will approach the patient to complete screening procedures. The study will proceed in 2 stages, each with its own informed consent process. During Stage 1, baseline characteristics and serum PCT levels will be ascertained. Stage 2 will consist of a randomized trial of amoxicillin vs. placebo in the subset of patients from Stage 1 that have PCT \<0.25 ng/mL.

Randomization After enrollment and confirmation of a PCT \<0.25 ng/mL, patients will be randomized to a 10-day course of either amoxicillin (80-100 mg/kg divided BID up to 4,000 mg/day) or placebo. Randomization to amoxicillin or placebo will be at a 1:1 ratio with block sizes of 2 and 4. Patients will be stratified by the clinical site and randomization will be performed through an online system. As a double-blind clinical trial, the study patients and their parents/guardians, investigators and study staff will be blinded to study treatment assignment for the duration of the study.

Study Drug Administration Local investigational drug pharmacies will be provided with active study medication (i.e., amoxicillin) and matching placebo. Site pharmacies at each institution will store study drug and dispense as needed. Study medications will both be liquid reconstituted from powder, and will resemble each other with regards to appearance, favor, consistency and packaging. Study products will be labeled with numerical codes that will maintain allocation concealment. Site investigational pharmacies will be provided with amoxicillin and placebo, in addition to the randomization scheme. The pharmacy will aliquot amoxicillin and placebo into blinded bottles based on randomization scheme.

Follow-up The guardians of participants will be asked to complete a daily symptom diary, using an online data collection form in REDCap, during the first 7 days after the initial Emergency Department study visit. The follow-up will assess patient condition, clinical response, signs or symptoms of clinical deterioration and other adverse effects. The primary outcome will be assessed at day 7 (+/- 2 days), using video chat technology that is standard on most smart phones, tablets, and computers. Video follow-up will be performed by site clinician investigators. In the rare case that a mobile device or computer with video chat technology is not available to the family, the day 7 follow-up will occur by telephone or text through an online system. A final follow-up, performed by site research staff, by telephone call, will occur at Day 21 (+/- 2 days) to assess overall disease course and secondary outcomes.

Data Collection At baseline, demographics, medical history, and history of current illness will be obtained from all participants during stage 1 (pre-randomization). Vital signs will be obtained and a brief physical examination will be performed. After the initial ED visit, patients will record symptoms on daily basis for 6 days via an online data collection form. Follow-up assessments will be completed via telehealth visit or telephone for days 7 and 21. Follow-up visits will collect data regarding symptoms, adverse events and return to medical care, in addition to assessing adherence to study procedures (i.e., medication adherence and daily symptom diary completion). If there is concern for adverse events or deterioration that may warrant medical care, the participant's caregiver will be instructed to contact their primary care physician, emergency department, or call 911, as indicated.

Arms: arm 1: Randomization to receive either oral placebo or amoxicillin for a standard course (10 days) arm 2: Randomization to receive either oral amoxicillin or placebo for a standard course (10 days)
Interventions: intervention 1: Amoxicillin intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be randomized to receive oral amoxicillin for a standard course (10 days) intervention 2: Participants will be randomized to receive oral placebo for a standard course (10 days)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Procalcitonin to Reduce Antibiotic Use in Pediatric Pneumonia 
(P-RAPP) 
PECARN Protocol Number 047 
 
 
Pediatric Emergency Care Applied Research Network 
National Heart, Lung and Blood Institute 
 
 
 
 
 
Protocol Version 1.05 
Version Date: November 30, 2021 
Printing Date: November 30, 2021 


Copyright © 2019-2020. University of Utah School of Medicine on behalf of the Principal Investi- 
gator, Todd Florin, M.D., M.S.C.E. and the Pediatric Emergency Care Applied Research Network 
(PECARN). All rights reserved. 
 
This protocol is PECARN Protocol Number 047, and has been authored by Todd Florin, M.D., 
M.S.C.E., Ann and Robert H. Lurie Children’s Hospital of Chicago, for implementation with the 
PECARN investigators. This study is supported by R34-HL153474 awarded to Ann and Robert 
H. Lurie Children’s Hospital of Chicago (PI:Todd Florin, M.D., M.S.C.E.) by the National Heart, 
Lung and Blood Institute. 
 
The PECARN Research Node Centers are the University of Michigan at Ann Arbor, Cincinnati 
Children’s Hospital Medical Center, Columbia University, University of California at Davis Medical 
Center, Children’s Hospital of Pittsburgh, and Children’s National Medical Center are supported 
by Cooperative Agreements U03-MC00003, U03-MC22684, U03-MC00007, U03-MC00001, 
U03MC22685, and U03-MC00006 from the Emergency Medical Services for Children (EMSC) 
Program, Maternal and Child Health Bureau, Health Resources and Services Administration. 
 
This document was prepared by the PECARN Data Coordinating Center (DCC) located at the 
University of Utah School of Medicine, Salt Lake City, Utah. The document was written and 
typeset using LATEX 2ε. The DCC at the University of Utah is supported by Cooperative Agreement 
U03-MC00008 from the Emergency Medical Services for Children (EMSC) Program, Maternal 
and Child Health Bureau, Health Resources and Services Administration. 


Protocol 047 (Florin) 
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P-RAPP Protocol Version 1.05 
Protocol Version Date: November 30, 2021 
The EMSC Pediatric Emergency Care Applied Research Network 
 
 
PROTOCOL TITLE: 
Procalcitonin to Reduce Antibiotic Use in Pediatric Pneumonia 
Short Title: P-RAPP 
PECARN Protocol Number: 047 
 
 
Lead Investigator and Author: 
Todd Florin, M.D., M.S.C.E. 
Ann and Robert H. Lurie Children’s Hospital of Chicago 
 
 
Protocol Version: 1.05 
Version Date: November 30, 2021 
 
 
I confirm that I have read this protocol, I understand it, and I will conduct the study according to 
the protocol. I will also work consistently with the ethical principles that have their origin in the 
Declaration of Helsinki and will adhere to the Ethical and Regulatory Considerations as stated. I 
confirm that if I or any of my staff are members of the Institutional Review Board, we will abstain 
from voting on this protocol, its future renewals, and its future amendments. 
 
Principal Investigator Name:  
 
 
Principal Investigator Signature:  
 
 
Date:  
 


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Protocol 047 (Florin) 
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THIS PAGE IS INTENTIONALLY BLANK. 


5 
 
 
Contents 
Contents 
5 
List of Tables 
7 
List of Figures 
7 
1 Study Summary 
9 
1.1 Hypotheses ........................................................................................................................ 9 
 
 
 
3 Participant Eligibility, Accrual and Study Duration 
12 
3.1 Eligibility criteria. ............................................................................................................ 12 
3.2 Participant Accrual and Study Duration .......................................................................... 13 
4 Study Design 
13 
5 Study Procedures 
13 
5.1 Screening and Enrollment ................................................................................................ 13 
5.1.1 
Procalcitonin ....................................................................................................... 14 
5.2 Randomization ................................................................................................................. 16 
5.2.1 
Blinding............................................................................................................... 16 
5.3 Study Drug Administration .............................................................................................. 16 
5.3.1 
Central Pharmacy and Distribution ..................................................................... 16 
5.3.2 
Preparation, Storage & Labeling ......................................................................... 16 
5.3.3 
Unblinding Procedures ........................................................................................ 16 
5.3.4 
Discontinuation of Study Drug ........................................................................... 17 
5.4 Follow-up ......................................................................................................................... 17 
5.4.1 
Daily Follow-up .................................................................................................. 17 
5.4.2 
Day 7 Follow-up ................................................................................................. 17 
5.4.3 
Day 21 Follow-up................................................................................................ 17 
5.5 Data Collection ................................................................................................................ 18 
5.5.1 
Baseline Data ...................................................................................................... 18 
5.5.2 
Follow-up Assessment(s) .................................................................................... 18 
5.5.3 
Schedule of Evaluations ...................................................................................... 18 
5.6 Withdrawal from Study ................................................................................................... 18 
5.7 Participant Compensation ................................................................................................. 20 
6 Data Analysis 
20 
 
6.2 Feasibility Outcome Analysis .......................................................................................... 21 
 


6 
 
 
7 Data Management 
24 
7.1 Clinical Site Data Management ....................................................................................... 24 
7.2 Data Coordinating Center ................................................................................................ 24 
7.2.1 
Data Center Description ...................................................................................... 24 
7.3 Electronic Data Capture System ...................................................................................... 25 
7.4 Study Monitoring ............................................................................................................. 26 
7.4.1 
Site Monitoring Plan ........................................................................................... 26 
7.4.2 
Remote Monitoring ............................................................................................. 26 
7.4.3 
Pharmacy Monitoring .......................................................................................... 27 
7.5 Record Access ................................................................................................................. 27 
8 Protection of Human Participants 
27 
8.1 Institutional Review Board (IRB) Approval .................................................................... 27 
8.2 Informed Consent ............................................................................................................ 28 
8.3 Potential Risks ................................................................................................................. 28 
8.4 Protections Against Potential Risks ................................................................................. 29 
8.5 Potential Benefits ............................................................................................................. 30 
8.6 Risk Benefit Assessment.................................................................................................. 31 
9 Data and Safety Monitoring Plan 
31 
9.1 Data Safety Monitoring Board (DSMB) .......................................................................... 31 
9.2 Safety Monitoring ............................................................................................................ 31 
9.3 Adverse Event Reporting ................................................................................................. 32 
9.3.1 
Definition of Adverse Event and Serious Adverse Event .................................... 32 
9.3.2 
Classification of an Adverse Event (Relatedness, Severity, and Expectedness 33 
9.3.3 
Time Period for Adverse Events ......................................................................... 34 
9.3.4 
Data Collection Procedures for Adverse Events ................................................. 34 
9.3.5 
Unanticipated Problems (UP) .............................................................................. 35 
9.3.6 
Monitoring Serious Adverse Events .................................................................... 35 
9.3.7 
Follow-up of Serious, Unexpected and Related Adverse Events ........................ 36 
10 Study Training 
36 
10.1 Study Training ................................................................................................................. 36 
11 Regulatory Considerations 
37 
11.1 Food and Drug Administration ........................................................................................ 37 
11.2 Health Insurance Portability and Accountability Act ....................................................... 37 
11.3 Inclusion of Women and Minorities................................................................................. 37 
11.4 ClinicalTrials.gov Requirements ..................................................................................... 37 
11.5 Retention of Records ....................................................................................................... 37 
 
 


7 
 
 
List of Tables 
1 
Schedule of Evaluations ..................................................................................................19 
 
 
 
List of Figures 
1 
Trial Flow Diagram .........................................................................................................15 
 
 


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Abstract 
 
Although viruses are the leading cause of community-acquired pneumonia (CAP) in young 
children, antibiotics are prescribed for most children with CAP. Antibiotic overuse has sub- 
stantial societal and individual consequences, including promotion of antimicrobial resistance, 
antibiotic-associated side effects and severe complications. Procalcitonin (PCT) is a biomarker 
that is elevated in the serum of patients with bacterial infections but is not typically elevated 
in patients with viral infections. A low PCT level has been shown to have a high negative 
predictive value for detection of children with CAP caused by typical bacteria. Similarly, 
PCT algorithms have decreased antibiotic use without increasing adverse events in adults and 
children; however, clinicians may be hesitant to use PCT, as the clinical efficacy and safety of 
avoiding antibiotics in outpatient children with low-risk clinical characteristics and low PCT 
levels has not been evaluated. The overall objective of this work is to test the hypothesis that 
low-risk children 12-71 months of age managed as outpatients with CAP and PCT levels <0.25 
ng/mL treated with placebo have similar clinical response to those treated with antibiotics, with 
fewer adverse effects, through a large-scale, multi-institutional randomized trial (RCT). Given 
the complexities of conducting an RCT of this nature, the overall objective of this R34 protocol 
is to evaluate the feasibility and finalize the methods of a future large-scale trial through a 3-site 
pilot feasibility trial. We will implement and establish feasibility of all study procedures by 
conducting a 3-site pilot trial of amoxicillin vs placebo in low-risk children with CAP and 
PCT levels <0.25 ng/mL. We will enroll and randomize 36 children at 3 participating sites. 
This pilot trial will provide necessary data to plan the large-scale definitive trial, including 
assessment of facilitators and barriers of study participation, estimating enrollment and attrition 
rates, evaluating study procedures and interventions in a real-world setting, and determining 
adherence rates. In addition, we will demonstrate the ability to collect outcomes important to 
the future RCT, including clinical response, symptom resolution, adverse events and quality 
of life. The subsequent large RCT will be significant, as it will definitively address whether 
antibiotics are beneficial in low-risk children with CAP, representing an innovative departure 
from the status quo by shifting from empirical antibiotic use for all children with CAP to a 
targeted approach. 








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3 Participant Eligibility, Accrual and Study Duration 
 
3.1 Eligibility criteria. 
 
Eligible participants will be identified by study staff. Inclusion criteria are: 
1. Age 12–71 months; and 
2. Diagnosis of CAP, defined using established criteria: 
(a) Signs and symptoms of lower respiratory tract infection (LRTI), defined as one or more 
of the following: 
• new or different cough; or 
• new or different sputum production; or 
• chest pain; or 
• dyspnea/shortness of breath; or 
• documented tachypnea; or 
• abnormal findings consistent with LRTI on physical examination (e.g., crack- 
les/rales, rhonchi, wheezing) and 
(b) Fever, defined as temperature ≥38◦C, and 
(c) ED clinician diagnosis of CAP, including intention to treat with antibiotics, and 
(d) Chest radiography suspicious for CAP.4 
3. Intention to treat as an outpatient after ED visit. 
Exclusion criteria are: 
1. Hospitalization within one month preceding study visit; or 
2. Sustained oxygen saturations <90% with appropriate waveform on oximeter; or 
3. Incomplete immunization status (<2 doses of Hib and pneumococcal vaccines); or 
4. Chronic complex medical conditions (chronic heart disease, chronic lung disease (not in- 
cluding asthma), congenital airway or lung malformations, cystic fibrosis, chronic renal 
disease, protein-losing enteropathy, genetic syndromes, neurocognitive deficits, or metabolic 
disorders); or 
5. Conditions that compromise the immune system (HIV, primary immunodeficiency, asplenia, 
sickle cell disease, receipt of hematopoietic stem cell or solid organ transplant, immunosup- 
pressive agents, daily corticosteroids for more than 7 consecutive days in past 14 days) ; 
or 
6. Systemic antibiotic receipt within the previous two weeks of CAP diagnosis; or 
7. Radiographic findings of complicated pneumonia (moderate-to-large pleural effusion, empyema, 
abscess, necrotic lung disease); or 
8. Pneumonia known to be due to bacterial source at the time of enrollment, as documented 
by blood culture or PCR if available, or another clear source of bacterial infection requiring 
immediate antibiotics; or 


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9. Toxic clinical appearance, sepsis, or critical illness as determined by clinical team at ED 
presentation; or 
10. Diagnosed with pneumonia in the previous three months; or 
11. Provider diagnosis of bronchitis, or aspiration pneumonia; or 
12. Severe drug allergy to amoxicillin; or 
13. Any other condition that in the judgement of investigators or the clinical team could affect 
safety of the subject; or 
14. No access to a telephone or video technology for follow-up; or 
15. Current enrollment in another clinical trial of an investigational agent; or 
16. Previous enrollment in this trial; or 
17. Parent/guardian non-English or non-Spanish speaking; or 
18. Known allergy to milk and/or red dye. 
Note: To be eligible for stage 2 randomization, the subject must have a PCT level<0.25ng/mL. 
 
 
3.2 Participant Accrual and Study Duration 
 
This trial will enroll over a 6-month period and take place at 3 sites that are or were sites in the 
Pediatric Emergency Care Applied Research Network (PECARN), a federally funded network of 
18 pediatric EDs that have an established and successful history of completing large-scale clinical 
trials in the ED. The randomized trial (stage 2) will enroll 36 patients in total (2 patients per month, 
per site). 
 
 
4 Study Design 
 
This pilot clinical trial is a 3-site, randomized, placebo-controlled, double-blinded trial assessing 
the feasibility of comparing amoxicillin to placebo in children 12 months to <6 years of age who 
present to the ED with CAP, a PCT<0.25 ng/mL, and who will be treated as outpatients. 
 
 
5 Study Procedures 
 
5.1 Screening and Enrollment 
 
Clinical research coordinators (CRCs) at participating EDs will screen potentially eligible patients 
with respiratory tract symptoms and discuss eligibility with the treating attending physician. If 
thought to be eligible and a diagnosis of CAP is presumed by the treating physician, the CRC will 
approach the patient to complete screening procedures. As outlined in the Trial Flow Diagram 
figure 1 on page 15. The informed consent process will consist of two stages. 




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Figure 1: Trial Flow Diagram 




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situation does occur, unblinding will occur within 12 hours after presentation with anaphylaxis in 
order to guide further decision regarding the study agent or other antibiotics. If a patient presents 
to primary care or the ED and has concerns for non-fatal allergic reaction or for other concerns 
that require decisions around antibiotics, the treating clinicians will be told to assume the patient 
received amoxicillin and treat accordingly. Thirty days after randomization, the patients will have 
the option of a delayed unblinding at the requests of the clinical teams (e.g., primary care physician) 
or the parents because knowledge of the study drug could be important to future patient care. 
 
 
5.3.4 Discontinuation of Study Drug 
 
Discontinuation of study drug may occur at the discretion of the clinical team. The participant’s 
parent/guardian may opt to discontinue the study drug, but remain in the study, therefore this will 
NOT be considered a study withdrawal. See Section 5.6 on the next page 
 
 
5.4 Follow-up 
 
5.4.1 Daily Follow-up 
 
The guardians of participants will be asked to complete a daily symptom diary, using an online data 
collection form, during the first 7 days after the initial ED study visit. The follow-up will assess 
patient condition, clinical response, signs or symptoms of clinical deterioration and other adverse 
effects. 
 
 
5.4.2 Day 7 Follow-up 
 
The primary outcome will be assessed at day 7 (±2 days), using video chat technology that is 
standard on most smart phones, tablets, and computers. Video follow-up will be performed by site 
clinician investigators. In the rare case that a mobile device or computer with video chat technology 
is not available to the family, the day 7 follow-up will occur by telephone or text through an online 
system. 
 
 
5.4.3 Day 21 Follow-up 
 
A final follow-up,performed by site research staff, by telephone call, will occur at Day 21 (±2 days) 
to assess overall disease course and secondary outcomes. 


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5.5 Data Collection 
 
5.5.1 Baseline Data 
 
At baseline, demographics, medical history and history of current illness will be obtained from all 
participants during stage 1 (pre-randomization). Vital signs will be obtained and a brief physical 
examination will be performed. 
 
5.5.2 Follow-up Assessment(s) 
 
After the initial ED visit, patients will be sent a data collection form to record symptoms on daily 
basis for 6 days via an online data collection form. Follow-up assessments will be completed 
via telehealth visit or telephone for days 7 and 21. Follow-up visits will collect data regarding 
symptoms, adverse events and return to medical care, in addition to assessing adherence to study 
procedures (i.e., medication adherence and daily symptom diary completion). If there is concern for 
adverse events or deterioration that may warrant medical care, the participant’s caregiver have been 
instructed to contact their primary care physician, emergency department, or call 911 as indicated. 
 
5.5.3 Schedule of Evaluations 
 
Day 7: We will use video chat technology to assess the primary outcome (clinical response, adverse 
effects), as described above. 
Day 21: A final telephone call or text will assess secondary outcomes, overall disease course, 
in addition to surveying the parents/guardians of the participants about their attitudes and beliefs 
regarding antibiotic use after participating in the trial. 
For a detailed schedule of evaluations, please refer to table 1 on page 19. 
 
5.6 Withdrawal from Study 
 
Parents may withdraw their child from participation in this study at any time without prejudice to 
their care. If the parent/guardian expresses interest in withdrawing from participation, the study staff 
will discuss the process with them, confirm their specific wishes, and review safety information. 
If complete withdrawal of consent is received in writing from the parent, the study team will not 
collect new information about their child, and they will be withdrawn from the research study. The 
study team will preserve and use any information that has already been collected, as needed to 
maintain the integrity of the research. There are no penalties nor benefits lost to the patient if the 
parent/guardian decides to withdraw. 
The participant may also be withdrawn from the study at the discretion of the investigator. The 
investigator or the sponsor may also withdraw participants who violate the study plan, to protect the 


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Evaluation 
Baseline 
Days +1 to 
+6 
Day 
+7 
Day 
+21 
Screening and Eligibility 
X 
Consent: Stage 1 
X 
Demographics/Baseline Information 
X 
Medical History 
X 
Physical Examination 
X 
Procalcitonin 
X 
Consent: Stage 2 
X 
Randomization 
X 
Nasal Swab 
X 
Adverse Events 
X 
X 
X 
Daily Symptom Diary 
X 
Primary Outcome(DOOR) 
X 
Telehealth Evaluation 
X 
Secondary Outcomes 
X 
X 
Home Nasal Swab 
X 
X 
Parental Survey (Attitudes/Beliefs/Feasibility) 
X 
End of Study 
X 
 
Table 1: Schedule of Evaluations 








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7 Data Management 
 
7.1 Clinical Site Data Management 
 
Each clinical site will maintain study records in secure locations that may include password protected 
electronic files or locked filing cabinets. The site will maintain an Essential Documents Binder, 
which may be in paper or electronic form. Copies of all informed consent documents will be kept 
on file and be available for site monitoring inspection (on site or remote). 
 
 
7.2 Data Coordinating Center 
 
7.2.1 Data Center Description 
 
Overview The Data Coordinating Center (DCC) in the Department of Pediatrics at the University 
of Utah School of Medicine provides data coordination and management services for a variety of 
national research networks. Anchoring these services is a state-of-the-art, energy efficient data 
center. The data center facility supports more than 3500 users around the country and provides 
a secure, reliable, enterprise-wide infrastructure for delivering mission critical DCC systems and 
services. 
 
 
Facility, Hardware, Storage, Data Backup and System Availability The data center was built 
using industry standards and energy efficient cooling solutions. The data center is cooled by Liquid 
Cooling Package (LCP) inline cooling technology, providing the desired efficiency, redundancy 
and the modularity. The LCP utilizes a hot/cold aisle design that allows for even air distribution to 
minimize hot spots. The data center’s electrical power system contains an uninterruptible power 
supply (UPS) with a diesel backup generator. The data center is protected with an FM-200 backed 
fire suppression system, which provides waterless fire suppression without leaving behind residue 
or particulate. Enhanced security measures are implemented to safeguard the equipment and the 
data within in it. Security measures are enforced 24 hours a day, 7 days a week, 365 days a year by 
a combination of on-premise security guards, University police officers and video surveillance. 
The data center has a virtualized environment. This environment consists of more than 415 virtual 
servers across 25 host servers. Virtualization provides key advantages: High availability (HA) – in 
the event of hardware failure, virtual machines (VM) automatically restart on healthy resources, 
minimizing impact to end-users; Flexible infrastructure – compute and storage is seamlessly scaled 
as current needs change; Rapid deployment – new resources are provisioned on-demand. 
Production servers running mission critical applications are clustered and configured for failover 
events across multiple clusters. Entire servers are backed-up to a dedicated infrastructure. The 
backup repositories are encrypted-at-rest using AES-256. The storage area networking (SAN) 
applications, clusters, and switch-to-switch links are highly redundant. Incremental backups of data 


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occur Monday through Friday. A full data backup occurs weekly. Full backups are sent off-site on a 
weekly basis to a secure secondary location. The data center currently manages over 125 terabytes 
(TB) of data. 
Information systems are available 24/7/365 unless a scheduled maintenance period or mitigation of 
an unexpected event is required. Critical systems availability has exceeded 99.9% for the past 5 
years. 
 
 
Security, Support, Encryption and Confidentiality The data center coordinates the network 
infrastructure and security with University Information Technology (UIT) at the University of Utah. 
This provides us with robust firewall hardware, automatic network intrusion detection, and the 
expertise of dedicated security experts working at the University. Centralized authentication and 
communication over public networks are encrypted using transport layer security (TLS) and/or 
virtual private network (VPN) technologies. Direct access to data center machines is only available 
while physically on premise or via a VPN client. 
All network traffic is monitored for intrusion attempts. Security scans are regularly run against data 
center servers and IT staff are notified of intrusion alerts. Security is maintained with Windows 
user/group domain-level security. Users are required to change their passwords every 90 days. All 
files are protected at user/group levels and database security is handled in a similar manner with 
group-level access to databases, tables, and views. Finally, all laptops used by faculty and staff in 
the DCC are whole-disk encrypted. 
The data center uses monitoring tools to continuously monitor applications and servers. Environ- 
mental and network systems are also monitored to ensure up-time. System Administrators are 
on-call 24/7/365 to respond to urgent events. 
All personnel involved with the DCC have signed confidentiality agreements concerning data 
encountered in the course of their daily work. All personnel (including administrative staff) 
have received Human Subjects Protection and Health Information Portability and Accountability 
Act (HIPAA) education. We require all users to sign specific agreements concerning security, 
confidentiality, and use our information systems before access is provided. 
 
 
7.3 Electronic Data Capture System 
 
The Data Coordinating Center (DCC) will develop an electronic data capture system for this trial. 
Currently the DCC uses multiple applications, such as OpenClinica or REDCap, and will elect to 
use the most appropriate application at the time of implementation of the study. Data will be entered 
by each clinical site. 
The DCC will use an electronic discrepancy management system to notify sites of inconsistent or 
erroneous data entry, which will be corrected by the clinical site. The discrepancy management 
system maintains an audit trail of all discrepancy resolution. 


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7.4 Study Monitoring 
 
The investigators recognize the importance of ensuring data of excellent quality. Study monitoring 
is critical to this process. Monitoring has been a very effective tool for maintaining data quality 
in previous PECARN studies, and we will use this process to ensure excellent quality data in the 
proposed study. The DCC uses risk-based methods to identify and correct problems that may arise 
at sites. The risk-based approach to monitoring focuses on oversight activities and preventing or 
mitigating key risks to data quality, as well as to processes critical to human participant protection 
and integrity of the trial or study. 
Study monitors must be provided with appropriate access to study materials and the medical records 
for study participants. If the medical records are in electronic form, the clinical investigator or an 
authorized individual must provide any assistance necessary to facilitate the study monitor’s review 
of data in the electronic medical record. 
 
7.4.1 Site Monitoring Plan 
 
A supplemental study-specific risk-based monitoring plan, separate from the protocol, will be 
completed which outlines specific criteria for monitoring. This plan may include the number of 
planned site visits, criteria for focused visits, additional visits or remote monitoring, a plan for 
medical record review and a follow up plan for non-compliant sites. The monitoring plan also 
describes the type of monitoring that will take place (e.g., sample of all participants within a site; 
key data or all data), the schedule of visits, how they are reported and a time frame to resolve any 
issues found. 
Site monitoring visits may be performed in-person or remotely by a trained site monitor during 
the study period to ensure regulatory compliance, patient safety, and to monitor the quality of data 
collected. Essential document binders, regulatory documents and data collection forms may be 
reviewed. Interim visits will take place depending on grant budget, site enrollment, and compliance 
issues identified. The site monitor will provide each site with a written report, and sites will be 
required to follow up on any deficiencies. It is anticipated that the study monitoring visits for this 
protocol will consist of a site initiation visit (prior to patient enrollment), interim visit, and a close 
out visit. The site initiation may take place as group training made up of site investigators and 
research assistants. 
 
7.4.2 Remote Monitoring 
 
Remote monitoring involves detailed review of the data entered by the Clinical Center and con- 
sultations with the Clinical Center investigator and/or research coordinator to review safety and 
data quality. This may require uploading copies of medical records, patient study files, regulatory 
documentation, or other source documents for the monitor to review. Alternatively, other methods, 
such as remotely viewing source documentation, may be utilized. This helps assure protocol 
compliance and accurate data collection. The Data Coordinating Center may conduct more remote 


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monitoring activities early in the trial to assure protocol compliance and identify any training 
issues that may exist. Remote monitoring documents will be retained in accordance with federal 
requirements. Safety of participants will be monitored and ensured in accordance with the Data and 
Safety Monitoring Board (DSMB) plan. 
 
 
 
7.4.3 Pharmacy Monitoring 
 
Each Clinical Center pharmacy must maintain adequate records of all dispensed study drug. Since 
the study will use a central pharmacy to distribute study medication to each site’s local pharmacy, 
adequate records at that location must be maintained as well. Monitoring will take place at both 
the central pharmacy and the clinical center pharmacies to ensure adequate storage and drug 
accountability records, as well as adherence to appropriate dispensing and destruction procedures. 
 
 
 
7.5 Record Access 
 
The medical record and study files (including informed consent, permission, and assent documents) 
must be made available to authorized representatives of the Data Coordinating Center, upon request, 
for source verification of study documentation. In addition, medical information and data generated 
by this study must be available for inspection upon request by representatives (when applicable) of 
the Food and Drug Administration (FDA), NIH, other Federal funders or study sponsors, and the 
Institutional Review Board (IRB) for each study site. 
 
 
 
8 Protection of Human Participants 
 
8.1 Institutional Review Board (IRB) Approval 
 
A Central IRB (CIRB) will be used for this study. The University of Utah IRB will serve as the 
IRB of record. Study sites will rely on the University of Utah IRB to act as central IRB. The Data 
Coordinating Center and each clinical center must obtain IRB approval prior to participating in the 
study. 
The Data Coordinating Center will track IRB approval status at all participating centers and will 
not permit participant enrollment without documentation of initial CIRB approval and local review 
sign-off. The Data Coordinating Center will also track the maintenance of that approval throughout 
subsequent years of the project. 


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8.2 Informed Consent 
 
Parental Permission 
 
Participants who are eligible for this study are younger than 18 years, and written permission from a 
parent or legal guardian will be required for participation. After determining that a subject is eligible, 
the site investigator or designee will approach the parent or legal guardian to offer participation for 
their child in the study. The parent or legal guardian will be informed about the objectives of the 
study and the potential risks and benefits of participation. Eligible subjects will only be enrolled if 
their parent or guardian provides permission for their child to participate. 
 
8.3 Potential Risks 
 
The potential risk of receiving placebo is that clinical outcomes may not be equivalent to amoxicillin 
therapy. Specifically, the proportion of children with adequate clinical response or symptom 
resolution may be lower in children who receive placebo. Adequate clinical response, as defined 
above, is lack of a visit to a clinic, acute care setting, ED or hospitalization due to persistent or 
worsening pneumonia, as defined by receipt of a new antibiotic for pneumonia or treatment for 
pneumonia complications. Included in this would be lack of need for additional antibiotic therapy, 
additional contacts with the healthcare system, or surgical procedures for worsening pneumonia. 
Symptom resolution is defined as absence of fever, tachypnea (respiratory rate <50 breaths/minute in 
children aged <24 months and >40 breaths/minute in those aged 24-71 months), work of breathing 
(i.e., retractions, grunting or flaring) and moderate to severe cough (i.e., frequent coughing fits more 
than 3-4 times per hour that is interfering with sleep). 
The magnitude of this risk is not well established, although a randomized trial of amoxicillin vs 
placebo in 1126 young children with fast-breathing pneumonia in Malawi found that at Day 4, 
93% of children who received placebo and 97% of those receiving amoxicillin did not experience 
treatment failure with no differences in the groups by Day 14. There were no deaths in either study 
group in this study. Additional data comes from a trial that used PCT to guide antibiotic decisions 
in children. In one trial of 319 children hospitalized with CAP, 21 children with mild CAP and 3 
with severe CAP who had PCT<0.25 ng/mL were never treated with antibiotics – none experienced 
respiratory problems, and all were considered cured during follow-up.42 These data suggest that 
the degree of risk is small, however there are no similar trials in the U.S. We are limiting our study 
population to a very low risk group of children based on: 
 
(a) inclusion/exclusion criteria that exclude children with any disease severity greater than mild, 
(b) the use of very low PCT levels to include patients, which provides an objective measure of a 
very low risk of serious bacterial infection using previously studied outcomes using PCT, and 
(c) concordance with evidence supporting national CAP guidelines that most infections in the 
study age group are viral and routine antibiotics are not recommended in children well enough 
to be managed as outpatients. 


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The degree of risk will, nevertheless, be fully evaluated during this pilot trial, and the subsequent 
large-scale trial. 
In addition, amoxicillin is known to have several potential adverse effects. Common side effects 
include rash, diarrhea, nauseas, vomiting and mucocutaneous candidiasis. Rare side effects (<1% 
prevalence) include: 
 
• Cardiovascular: hypersensitivity angiitis (rash) 
• Central nervous system: agitation, anxiety, behavioral changes, confusion, dizziness, headache, 
hyperactivity (reversible), insomnia, seizure 
• Dermatologic: acute generalized exanthematous pustulosis (blistering skin reaction), erythema 
multiforme (rash-like skin reaction), exfoliative dermatitis (peeling skin reaction), Stevens- 
Johnson syndrome (blistering and peeling skin reaction), toxic epidermal necrolysis (severe 
blistering and peeling skin reaction), urticarial (hives) 
• Gastrointestinal: dental discoloration (brown, yellow, or gray; rare), hemorrhagic colitis 
(bloody diarrhea), melanoglossia (black tongue), pseudomembranous colitis (swelling/irritation 
of the colon) 
• Genitourinary: crystalluria (cloudy urine) 
• Hematologic & oncologic: agranulocytosis (low white blood cell count), anemia (low red 
blood cell count), eosinophilia (high eosinophils, a type of white blood cell), hemolytic 
anemia (low red blood cell count), leukopenia (low white blood cell count), thrombocytopenia 
(low platelet count), thrombocytopenic purpura (clotting disorder that causes bleeding) 
• Hepatic: cholestatic hepatitis (blocked bile duct), cholestatic jaundice (yellowing of the skin), 
hepatitis-acute cytolytic (liver inflammation), increased hepatic enzymes 
• Hypersensitivity: anaphylaxis (severe allergic reaction) 
• Immunologic: serum sickness-like reaction (a type of allergic reaction) 
 
Amoxicillin is an approved drug with a long prescribing history and is considered first-line therapy 
in children with CAP for whom antibiotics are warranted. The risk of these effects is no greater in 
this trial than the current practice of providing amoxicillin to most children with CAP and may be 
less in this trial due to vigilant monitoring of study participants. 
 
8.4 Protections Against Potential Risks 
 
As noted above, our study is limited to a low-risk population of children with CAP for whom 
antibiotics are not routinely recommended by the Pediatric Infectious Diseases Society and the 
Infectious Diseases Society of America and whose PCT levels suggest a low risk of bacterial 
infection. In addition to our careful choice of inclusion and exclusion criteria, several safeguards 
will be implemented during the trial to protect against potential risks. 


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1. First, documentation will be provided to participants with detailed instructions on reasons to 
return to medical care. 
2. Second, contact with participants will be attempted on day 7 (±2 days) and on day 21 (±2 
days) after the study ED visit to collect data regarding symptoms, side effects, adverse events 
and return to medical care, in addition to assessing adherence to study procedures (i.e., 
medication adherence and daily symptom diary completion). 
3. Third, a video telehealth visit will be initiated, when possible, on or around day 7 to assess 
the primary outcome. If use of video technology is not available or feasible, a telephone call 
will occur for this follow-up encounter. This will include an assessment of, clinical course, 
side effects, adverse effects and other risk concerns. 
4. Fourth, a safety monitoring plan and data safety monitoring board will be established for this 
trial to assess and address risk concerns. 
 
The only personnel who will have access to identifiable private information will be the research 
personnel (a site principal investigator and a research coordinator) at the study site where the 
participant was enrolled and the study's principal investigator. Data collection will be electronic; 
using password protected computing devices that wirelessly transmit data to a secure network drive. 
These devices will be kept in locked cabinets, in locked suites when not in use. Each participant 
will be assigned a unique patient identifier for purposes of analysis, and this will be used to link any 
paper records to an electronic research record within the analytic database. Study site personnel will 
be responsible for entering the data through the electronic interface into a secure, web-based data 
management system hosted at the PECARN DCC; thus, the analytic database will be maintained in 
a secure encrypted HIPAA compliant computing system. Most research results will be presented 
in aggregate fashion. HIPAA identifiers will be stripped from findings that reference individual 
participants. While the majority of the data will be stored electronically, there is a chance that we 
will need to retain some information on paper records. All paper research records with patient 
identifiers, if any, will be kept at the site from which they were obtained in locked cabinets, in 
a locked office, within a locked office suite. Patient identifiers will not be part of the analytic 
database. Any paper participant records will be destroyed upon completion of analysis. Due to 
these precautions the likelihood of a loss of privacy or confidentially is very minimal. 
 
8.5 Potential Benefits 
 
Potential benefits to the individual child include avoidance of potentially unnecessary antibiotics, 
a lower risk of an adverse event or effect associated with antibiotic therapy (e.g., diarrhea, rash, 
allergy mislabeling, C. difficile infection), and a lower risk of colonization with antibiotic resistant 
bacteria. Potential population-level societal benefits if the future clinical trial is successful include a 
lower prevalence of colonization with pathogenic antibiotic-resistant bacteria in children with CAP. 
This lower colonization rate offers a lower colonization risk among the larger population given 
the transmissibility of pathogenic bacteria across all persons regardless of whether or not they are 
treated with antibiotics. 


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8.6 Risk Benefit Assessment 
 
Due to the prospect of direct benefit to patients, the risk-benefit ratio seems favorable to patients, 
parents and providers. 
 
 
9 Data and Safety Monitoring Plan 
 
9.1 Data Safety Monitoring Board (DSMB) 
 
The study will have a Data Safety Monitoring Board (DSMB). The DSMB will have a charter, 
will approve the protocol prior to implementation, and will review interim analyses as applicable. 
The purpose of the DSMB is to advise the sponsors and Principal Investigator(s) regarding the 
continuing safety of study subjects and the continuing validity and scientific merit of the study. The 
DSMB is responsible for monitoring accrual of study subjects, adherence to the study protocol, 
assessments of data quality, performance of individual Clinical Center, review of serious adverse 
events and other subject safety issues, and review of formal interim statistical analyses of treatment 
efficacy. 
Participant safety data will be reviewed on a regular basis. Study halting rules will be developed, 
and further study enrollment will be halted for DSMB review and recommendation if any halting 
events are reported. 
 
 
9.2 Safety Monitoring 
 
This protocol has extensive safety monitoring in place. The study site investigators will be re- 
sponsible for close safety monitoring of all children participating in the study, and for alerting the 
protocol team if unexpected concerns arise. All children will undergo a targeted physical exam 
at screening and enrollment to ensure that children are medically stable and do not demonstrate 
any exclusion criteria. For the first 6 days of the study, participants will complete a daily online 
survey to monitor their health and ensure study adherence. During days 7 and 21, study staff will 
perform follow-up via telehealth, or telephone. Every effort will be made to trace all children in 
the study for the final outcome assessment. The day 7 primary outcome will be a telehealth visit, 
whenever possible, allowing the site study clinician to visualize the child during the telehealth 
examination. Participants’ caregivers will be been instructed to contact their primary care provider, 
return to the ED or call 911 should symptoms worsen. Any SAE’s will be collected by site study 
staff. (See section, 9.3 on the following page). As needed, children in the study may be evaluated at 
interim visits and/or referred for additional care. In the case of a life-threatening event, they will 
be instructed to seek immediate emergency care. These “safety net” procedures are intended to 
identify all instances of potential treatment failure and clinical relapse so that those children failing 
treatment can be provided appropriate antibiotics and clinical care. 


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9.3 Adverse Event Reporting 
 
The site investigator is responsible for evaluating all adverse events at their Clinical Center and 
ensuring that they are properly reported. Specified adverse events that occur during this study will 
be recorded. The nature of each experience, date and time (where appropriate) of onset, outcome, 
course, and relationship to treatment will be documented. The safety profile of amoxicillin is well 
established, and this trial is not powered to detect new, unknown safety effects, therefore, there will 
be no additional AE collection outside of the daily symptom diary during this study. All serious 
adverse events (SAE) will be collected and recorded. The investigative team anticipates AEs, both 
severe and non-severe, to occur among enrolled children at a similar rate as untoward medical events 
occur in comparable pediatric populations outside of a research setting. 
AEs that the study team expects may occur during the research include, but are not limited to: 
adverse reactions to amoxicillin (e.g., skin rash), progression of pneumonia-related symptoms (e.g., 
work of breathing), and onset of other common and uncommon childhood illnesses (e.g., diarrhea). 
Research staff will obtain information about side effects from scheduled follow-up contacts. 
 
9.3.1 Definition of Adverse Event and Serious Adverse Event 
 
Adverse Event (AE) means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). An 
event constitutes a disease, a set of related signs or symptoms, or a single sign or symptom. 
 
Serious Adverse Event (SAE): A serious adverse event (SAE) for this population is an adverse 
event that: 
• results in death; or 
• is life-threatening (the patient was, in the view of the site investigator, in immediate danger of 
death from the event as it occurred); or 
• requires inpatient hospitalization or prolongs an existing hospitalization; or 
• results in persistent or significant disability or incapacity; or 
• results in congenital anomaly/birth defect; or 
• any other event that, based upon appropriate medical judgment, may jeopardize the partic- 
ipant’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
In addition to the SAEs listed above, the following serious adverse events (SAE) will be collected 
as part of this protocol: 
• death that is not trauma or accident-related, 
• anaphylaxis, 
• laryngospasm or bronchospasm within 1 day of treatment initiation, 
• Stevens-Johnson Syndrome, 
• severe erythema multiforme, or 


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• toxic epidermal necrolysis. 
All SAEs will be assessed for severity and causal relationship by a physician member of the study 
team, recorded on the appropriate SAE report form, follow through to resolution by study physician 
and reviewed by safety monitor and IRB. 
 
A data safety monitoring board (DSMB) will be convened for this study. Participant safety data will 
be reviewed on a regular basis. Study halting rules will be developed, and further study enrollment 
will be halted for DSMB review and recommendation if any halting events are reported. 
 
 
9.3.2 Classification of an Adverse Event (Relatedness, Severity, and Expectedness 
 
Relatedness: The suspected relationship between study interventions and any adverse event will 
be determined by the site investigator using the criteria below. Relatedness must be assessed by an 
investigator and may not be assessed by a research coordinator. 
 
Not Related: The event is clearly related to other factors, such as the participant’s clinical state, 
therapeutic interventions, or concomitant drugs administered to the participant. 
Possibly Related: The event follows compatible temporal sequence from the time of beginning 
the assigned study intervention, but could have been produced by other factors such as the 
participant’s clinical state, therapeutic interventions, or concomitant drugs administered to 
the participant. 
Probably Related: The event follows a reasonable temporal sequence from the time of beginning 
the assigned study intervention, and cannot be reasonably explained by other factors such as 
the participant’s clinical state, therapeutic interventions, or concomitant drugs administered 
to the participant. 
 
 
Severity: The severity, which is a measure of intensity, of clinical adverse events and laboratory 
abnormalities will be recorded by the site investigator and categorized. The following guidelines 
will be used to describe severity. 
 
Mild: The event requires minimal or no treatment and does not interfere with the participant’s daily 
activities. 
Moderate: The event results in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe: The event interrupts a participant’s usual daily activity and may require systemic drug ther- 
apy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
Of note, the term “severe” does not necessarily equate to “serious”. 


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Expectedness of the Event: All adverse events, including serious adverse events, will be evaluated 
as to whether their occurrence was expected or unexpected. An AE will be considered unexpected 
if the nature, severity, or frequency of the event is not consistent with the risk information described 
for the study intervention. 
 
Expected: An event is considered expected if it is known to be associated with the underlying 
condition or is related to the study intervention and is mentioned in the protocol, informed 
consent, or other study documents. An event may be expected despite the study participant’s 
clinical state immediately prior to the event. 
Unexpected: An event is considered unexpected if there are no prior data linking this event with 
either the condition or intervention under study or an event that occurred unexpectedly in the 
course of treatment. 
 
Treatment or Action Taken: For each adverse event, the site investigator will record whether an 
intervention was required: 
• Medical or surgical procedure 
• Concomitant medication: started, changed, or discontinued 
• Other, specify 
• No action taken 
 
Outcome of Event: Finally, the site investigator will record the clinical outcome of each adverse 
event as follows: 
• Death 
• Recovered and the patient returned to baseline status 
• Recovered with permanent sequelae 
• Symptoms persist 
 
9.3.3 Time Period for Adverse Events 
 
For purposes of this study, all SAEs will be recorded from randomization through 21 days after 
randomization. Specifically, events that occur following parental permission to participate in the 
study, but prior to actual randomization, are not adverse events. These should be recorded as 
baseline conditions. 
 
9.3.4 Data Collection Procedures for Adverse Events 
 
After patient randomization, all serious adverse events will be assessed for relatedness, severity, and 
expectedness, as well as their duration and any treatment prescribed. Any medical condition present 
at the time of randomization, recorded in the patient’s baseline history at study entry, which remains 


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unchanged or improves (unless the clinician feels it is clinically relevant), will not be recorded as 
an adverse event at subsequent evaluations. However, worsening of a medical condition that was 
present at the time of randomization will be considered a new adverse event and reported if on the 
list of solicited adverse events. 
Adverse events will be coded using the MedDRA coding vocabulary. Coding will be done centrally 
at the Data Coordinating Center as this requires specific training. 
 
 
9.3.5 Unanticipated Problems (UP) 
 
Unanticipated problems (UP) are defined as incidents, experiences, or outcomes that are unexpected, 
related or possibly related to participation in the study, and suggest that the research places par- 
ticipants at a greater risk of harm than was previously known or recognized. The site investigator 
will report unanticipated problems to the DCC within 24 hours of becoming aware of the event. 
A detailed completed report will be required to be sent to the DCC within 3 working days of the 
event. After receipt of the complete report, the DCC will report these unanticipated problems to 
the NHLBI Program Official or Project Officer in an expedited manner (as close to 24 hours as 
possible). In accordance with local IRB requirements, the site investigator may be required to report 
such unanticipated problems to the IRB in addition to notifying the Data Coordinating Center. In 
the event that the medical monitor believes that such an event warrants emergent suspension of 
enrollment in the trial, and NHLBI staff cannot be reached expeditiously, the DCC will notify the 
study principal investigator (Dr. Florin) and all site investigators to cease enrollment in the trial. 
Resumption of enrollment will not occur without consent of the NHLBI staff after discussion with 
the DSMB. 
 
 
9.3.6 Monitoring Serious Adverse Events 
 
A qualified physician will be designated to fulfill the function of the medical monitor for this study. 
Site investigators and/or research coordinators will report serious adverse events to the DCC within 
24 hours of becoming aware of the event. A detailed completed report will be required to be sent to 
the DCC within 3 working days of the event, and the medical monitor will assess all serious adverse 
events reported from site investigators. 
For each of these serious adverse events, the site investigator will provide sufficient medical history 
and clinical details for a safety assessment to be made with regard to continuation of the trial. The 
medical monitor will sign off on each SAE report after review. All SAE reports will be retained at 
the DCC, and all SAE reports will be available for review by DSMB members and NHLBI staff. 
The SAE reporting process may be incorporated into the Electronic Data Capture (EDC) System in 
use for the study. 
In the unlikely event that the medical monitor believes an unexpected and study-related SAE 
warrants emergent cessation of enrollment in the trial, NHLBI staff and the DSMB chairperson will 
be immediately consulted. If these individuals concur with the judgment of the medical monitor, or 


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if the NHLBI staff and the DSMB chairperson cannot be reached expeditiously, the DCC will notify 
the study principal investigator (Dr.Florin) and all site investigators to cease enrollment in the trial. 
Resumption of enrollment will not occur without consent of the NHLBI staff after discussion with 
the DSMB. 
In accordance with local IRB requirements, the site investigator may be required to report such 
events to the IRB in addition to notifying the Data Coordinating Center. 
After notification of the NHLBI Program Official or Project Officer, and the DSMB chairperson, of 
serious, unexpected, and study-related adverse events or unanticipated problems (UP), decisions 
will be made whether to continue the study without change, and whether to convene the entire 
DSMB for an emergent meeting. If a decision is made to suspend enrollment in the trial, this will be 
reported to the study investigator (Dr. Florin) and all clinical investigators, who will be instructed to 
report this to their local IRB. 
The DSMB will review all adverse events (not necessarily serious, unexpected, and study-related) 
during scheduled DSMB meetings. The Data Coordinating Center will prepare a Summary Report 
of Adverse Events for the DSMB meetings, classified with the MedDRA coding system. 
 
 
 
9.3.7 Follow-up of Serious, Unexpected and Related Adverse Events 
 
All serious, unexpected and related adverse events, that are unresolved at the time of the patient’s 
termination from the study or discharge from the hospital, will be followed by the Clinical Center 
investigators until the events are resolved, participant is lost to follow-up, the adverse event is 
otherwise explained or has stabilized, or 30 days have passed from the time of last study dose. 
 
 
 
10 Study Training 
 
10.1 Study Training 
 
A formal training program for investigators and research staff will be held prior to the start of 
enrollment. The training program will cover regulatory topics and Good Clinical Practice. The 
training will also provide in depth explanations regarding study procedures, clinical care, adverse 
event reporting, data entry procedures, quality assurance, site monitoring, and the informed consent 
process. A manual of operations will be provided to each investigator prior to the start of enrollment. 
The manual will detail specific information about the study procedures, regulatory information, 
safety reporting, and other necessary information. Updates and revisions to the manual will be made 
available electronically. The Data Coordinating Center, in collaboration with the study investigator 
(Dr. Florin), will be the main contact for study questions. 


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11 Regulatory Considerations 
 
11.1 Food and Drug Administration 
 
The Food and Drug Administration has deemed that an investigational device exemption (IDE) or 
investigational new drug (IND) exemption is not required for this pilot trial, as procalcitonin is 
being used in an FDA-approved manner and amoxicillin is the current first-line standard of care for 
pediatric pneumonia. The FDA deemed this study a non-significant risk (NSR) study, thus an IDE 
application is not required. 
 
11.2 Health Insurance Portability and Accountability Act 
 
Data elements collected include the date of birth and date of admission. Prior to statistical analyses, 
dates will be used to calculate patient age at the time of the study events. The final data sets (used 
for study analyses and archived at the end of the study) will be de–identified, and will exclude these 
specific dates. 
Data elements for race, ethnicity, and gender are also being collected. These demographic data are 
required for Federal reporting purposes to delineate subject accrual by race, ethnicity, and gender. 
For purposes of the DCC handling potential protected health information (PHI) and producing the 
de–identified research data sets that will be used for analyses, all study sites have been offered a 
Business Associate Agreement with the University of Utah. Copies of executed Business Associate 
Agreements are maintained at the DCC. 
 
11.3 Inclusion of Women and Minorities 
 
There will be no exclusion of patients based on gender, race, or ethnicity. 
 
 
11.4 ClinicalTrials.gov Requirements 
 
This trial will be registered at ClinicalTrials.gov in accordance with Federal regulations. 
 
 
11.5 Retention of Records 
 
For federally funded studies subject to the Common Rule, records relating to the research conducted 
shall be retained for at least 3 years after completion of the research. Completion of the research 
for this protocol should be anticipated to include planned primary and secondary analyses, as 
well as subsequent derivative analyses. Completion of the research also entails completion of all 












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SAP_001.pdf: 
Statistical Analysis Plan
Protocol Title (Number): Procalcitonin to Reduce Antibiotic Use in Pediatric Pneumonia
(047)
Protocol Version and Date: 1.04; September 17, 2021
SAP Author: John M. VanBuren, Ph.D.
SAP Version and Date: 1.00; October 5, 2021
SAP Version 1 Date: October 5, 2021
CONFIDENTIAL
i


P-RAPP: Statistical Analysis Plan
Page ii
Approvals:
Approved By:
Name
Title
Date
Name
Title
Date
October 5, 2021
SAP Version 1.00
CONFIDENTIAL


P-RAPP: Statistical Analysis Plan
Page iii
Contents
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi
1
PREFACE
1
1.1
Purpose of SAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1.2
Auxiliary/Other Documents
. . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2
STUDY OBJECTIVES AND OUTCOMES
1
2.1
Study Objectives
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2.1.1
Primary Objective(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2.2
Study Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.1
Primary Outcome(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.2
Secondary Outcome(s) . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
2.2.4
Safety Outcome(s)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
3
STUDY DESIGN AND METHODS
3
3.1
Overall Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
3.2
Method of Treatment Assignment and Randomization . . . . . . . . . . . . .
3
3.2.1
Delivery of Randomization and Emergency Backup . . . . . . . . . .
4
3.3
Treatment Masking (Blinding) . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
4
STUDY SUBJECTS AND ANALYSIS POPULATIONS
4
4.1
Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
4.2
Populations for Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
4.2.1
Screening Population . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
4.2.2
Study Eligible Population . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.3
Stage I Approached Population . . . . . . . . . . . . . . . . . . . . . .
5
4.2.4
Stage I Consented Population . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.5
Blood Draw Population . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.6
RCT Eligible Population . . . . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.7
Stage II Approached Population . . . . . . . . . . . . . . . . . . . . .
5
4.2.8
Stage II Consented Population
. . . . . . . . . . . . . . . . . . . . . .
5
4.2.9
Intention-to-Treat Population . . . . . . . . . . . . . . . . . . . . . . .
5
4.2.10 Safety Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
5
GENERAL ISSUES FOR STATISTICAL ANALYSES
6
5.1
Analysis Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
5.2
Methods for Withdrawals, Missing Data, and Outliers . . . . . . . . . . . . .
6
5.3
Multiple Comparisons and Multiplicity . . . . . . . . . . . . . . . . . . . . .
6
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5.4
Planned Subgroups, Interactions, and Covariates . . . . . . . . . . . . . . . .
6
5.5
Derived and Computed Variables . . . . . . . . . . . . . . . . . . . . . . . . .
7
5.5.1
Enrollment Rates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
5.5.2
Consent Rate between Stage I and Stage II
. . . . . . . . . . . . . . .
7
5.5.3
Feasibility and Usability of Video Chat Follow-Up . . . . . . . . . . .
7
5.5.4
Lost to Follow-up Rates . . . . . . . . . . . . . . . . . . . . . . . . . .
7
5.5.6
Clinic or ED Visits
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
5.5.7
Hospitalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
5.5.9
Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
5.5.13 Frequency and Types of Adverse Events
. . . . . . . . . . . . . . . .
14
5.6
Independent Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
6
INTERIM ANALYSES
15
6.1
Frequency of and Timepoints for Interim Analysis . . . . . . . . . . . . . . .
15
6.2
Stopping Rules for Interim Efﬁcacy Analysis
. . . . . . . . . . . . . . . . . .
15
6.3
Futility Monitoring in the Interim Analysis . . . . . . . . . . . . . . . . . . .
15
6.4
Subgroups in the Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . .
16
7
PLANNED ANALYSES
16
7.1
Description of Subject Characteristics
. . . . . . . . . . . . . . . . . . . . . .
16
7.2
Primary Outcome Analysis
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
7.3
Secondary Outcome(s) Analyses
. . . . . . . . . . . . . . . . . . . . . . . . .
16
7.3.1
Consent and drop-out rates between the two stages of consent . . . .
16
7.3.2
Parental attitudes and beliefs about trial procedures . . . . . . . . . .
16
7.3.3
Feasibility and usability of video chat follow-up . . . . . . . . . . . .
16
7.3.4
Lost to follow-up rates . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
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SAMPLE SIZE DETERMINATION
18
9
References
18
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Abbreviations
Abbreviation
Deﬁnition
BLOOD DRAW
Blood Draw Population
CAP
Community Acquired Pneumonia
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DCC
Data Coordinating Center
DOOR
Desirability of Outcome Ranking
DSMB
Data and Safety Monitoring Board
ED
Emergency Department
ELIGIBLE
Eligible Population
ITT
Intent-To-Treat Population
PCT
Procalcitonin
RADAR
Response-Adjusted Duration of Antibiotic Risk
RCT ELIGIBLE
RCT Eligible Population
(S)AE
(Serious) Adverse Event
SAFETY
Safety Population
SCREEN
Screening Population
SAP
Statistical Analysis Plan
STAGE I APPROACHED
Stage I Approached Population
STAGE I CONSENTED
Stage I Consented Population
STAGE II APPROACHED
Stage II Approached Population
STAGE II CONSENTED
Stage II Consented Population
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1
PREFACE
1.1
Purpose of SAP
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for the
protocol: Procalcitonin to Reduce Antibiotic Use in Pediatric Pneumonia (P-RAPP).
The structure and content of this SAP provides sufﬁcient detail to meet the requirements
and standards set by the Data Coordinating Center (DCC).
1.2
Auxiliary/Other Documents
The following documents were reviewed in preparation of this SAP:
• Protocol: Procalcitonin to Reduce Antibiotic Use in Pediatric Pneumonia.
• Case Report Forms (CRFs) for the P-RAPP protocol
The reader of this SAP is encouraged to read the protocol for details on the conduct of
this study, and the operational aspects of clinical assessments.
The purpose of this SAP is to outline the planned analyses to be completed for the P-
RAPP trial. The planned analyses identiﬁed in this SAP will be included in future study
abstracts and manuscripts. Also, exploratory analyses not necessarily identiﬁed in this
SAP may be performed. Any post hoc, or unplanned, analyses not explicitly identiﬁed in
this SAP will be clearly identiﬁed as such in any published reports from this study.
It is possible that, due to updates or identiﬁcation of errors in speciﬁc statistical software
discussed in this SAP, the exact technical speciﬁcations for carrying out a given analy-
sis may be modiﬁed. This is considered acceptable as long as the original, prespeciﬁed
statistical analytic approach is completely followed in the revised technical speciﬁcations.
2
STUDY OBJECTIVES AND OUTCOMES
2.1
Study Objectives
2.1.1
Primary Objective(s)
The primary objective of the P-RAPP trial is to demonstrate the feasibility to efﬁciently
and effectively enroll low-risk children with Community Acquired Pneumonia (CAP) and
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Procalcitonin (PCT) levels < 0.25 into a multicenter randomized controlled trial evaluat-
ing antibiotics vs placebo, while reﬁning study procedures for the subsequent large clini-
cal trial.
2.2
Study Outcomes
2.2.1
Primary Outcome(s)
The primary outcome in this pilot study is the enrollment rate per site per month.
Eligibility for Primary Analysis
The enrollment rate will be derived for those subjects
who are randomized into the second stage of the trial.
2.2.2
Secondary Outcome(s)
Secondary outcomes of this pilot study include:
1. Consent and drop-out rates between the two stages of consent
2. Parental attitudes and beliefs about trial procedures
3. Feasibility and usability of video chat follow-up
4. Lost to follow-up rates
Eligibility for Secondary Analysis
Secondary outcome 1 will include all patients who
have a PCT < 0.25 from Stage I of the trial. Secondary outcome 2 will be analyzed through
interview data which are collected separate from the clinical trial. Secondary outcomes
3 and 4 will be analyzed among those subjects who are randomized into Stage II of the
trial.
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2.2.4
Safety Outcome(s)
There are no pre-speciﬁed safety outcomes. Several exploratory outcomes capture safety
events.
3
STUDY DESIGN AND METHODS
3.1
Overall Study Design
This pilot clinical trial is a 3-site, randomized, placebo-controlled, double-blinded trial.
There are two stages of enrollment in this study. The ﬁrst stage (Stage I) will collect data
on any eligible and consented subject. Blood will be collected on these subjects in Stage
I and the subjects PCT will be evaluated. If the PCT is less than 0.25 ng/mL, then the
subject will be approached for consent to participate in the RCT (Stage II). If the subject
is consented for Stage II, randomization is performed and the subject is enrolled into the
clinical trial. Randomized subjects will be followed daily for 7 days. At 7 and 21 days after
the ED visit, a follow-up phone/video call will be made to assess further outcomes for
randomized subjects. After 21 days, a medical chart review will be performed to assess
additional outcomes on all subjects in both Stage I and Stage II.
3.2
Method of Treatment Assignment and Randomization
After enrollment and conﬁrmation of a PCT <0.25 ng/mL, subjects will be randomized
to a 7-day course of either amoxicillin or placebo. Randomization will be stratiﬁed at a
1:1 ratio stratiﬁed by site with block sizes of 2 and 4.
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3.2.1
Delivery of Randomization and Emergency Backup
Randomization will occur within the database. There are no emergency backup envelopes
for this study. The randomization process will produce a randomization ID which the
site coordinator will then provide to the site pharmacist (who will have a mechanism to
identify arm and produce study drug).
3.3
Treatment Masking (Blinding)
The P-RAPP trial will be performed in a double-blind fashion. All study personnel, in-
cluding investigators and research coordinators, shall be blinded to assigned treatment
arm for each enrolled subject. Of necessity, biostatisticians involved in presenting interim
analyses to the DSMB will be aware which subjects have received which arm due to the
derivation of some outcomes.
Unblinded personnel in this study will include: the site research pharmacist and, possi-
bly, a pharmacy monitor contracted by the DCC expressly for the purpose of ensuring
assigned treatments have been correctly prepared and delivered in this study. The DSMB
may request to be unblinded to treatment assignment at any time. If this occurs, the DCC
biostatisticians will also be unblinded.
4
STUDY SUBJECTS AND ANALYSIS POPULATIONS
4.1
Eligibility
Study eligibility details can be found in the protocol.
4.2
Populations for Analyses
There are several populations considered for analyses. These are described in detail be-
low.
4.2.1
Screening Population
The screening population (SCREEN) includes all subjects who are screened for eligibility
into the trial, regardless of whether or not they are approached for consent for Stage I.
This population represents all patients who meet inclusion criteria outlined in the study
protocol. This population will be used for reporting of study ﬂow per Consolidated Stan-
dards of Reporting Trials (CONSORT) guidelines.
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4.2.2
Study Eligible Population
The study eligible population (ELIGIBLE) includes all SCREEN subjects who meet study
inclusion/exclusion criteria (regardless of whether they consent in Stage I).
4.2.3
Stage I Approached Population
The Stage I approached population (STAGE I APPROACHED) includes all ELIGIBLE
subjects who were approached by a study team member to participate in the study.
4.2.4
Stage I Consented Population
The Stage I consented population (STAGE I CONSENTED) includes all STAGE I AP-
PROACHED subjects who have consented to get their blood draw.
4.2.5
Blood Draw Population
The blood draw population (BLOOD DRAW) includes all STAGE I CONSENTED who
have a blood draw obtained to evaluate PCT.
4.2.6
RCT Eligible Population
The RCT eligible population (RCT ELIGIBLE) includes all BLOOD DRAW subjects whose
PCT value is <0.25 ng/mL.
4.2.7
Stage II Approached Population
The Stage II approached population (STAGE II APPROACHED) includes all RCT ELIGI-
BLE subjects who were approached by a study team member to participate in the RCT.
4.2.8
Stage II Consented Population
The Stage II consented population (STAGE II CONSENTED) includes all STAGE II AP-
PROACHED subjects who have consented to participate in the RCT.
4.2.9
Intention-to-Treat Population
The Intention-to-Treat (ITT) population includes all subjects who are randomized into the
trial, regardless of adherence to the protocol, including, for example, subjects who receive
no study drug. The ITT population will be used for all exploratory outcome analyses
where differences are evaluated between arms. All analyses using the ITT population
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will be based on each subject’s assigned treatment arm, regardless of treatment actually
received.
4.2.10
Safety Population
The safety population (SAFETY) includes all subjects who receive any study drug. Re-
porting of results based on this population will be summarized according to treatment
received. This population will be used for analysis of adverse events.
5
GENERAL ISSUES FOR STATISTICAL ANALYSES
5.1
Analysis Software
Analysis will be performed using SAS R⃝Software version 9.4 or later whenever possi-
ble. Other software packages, including R and StatXact R⃝, may be used for particular
specialized procedures.
5.2
Methods for Withdrawals, Missing Data, and Outliers
Per the intention-to-treat principle, subjects who withdraw from the study or are lost to
follow-up will have all available data used in the analysis. In the event that a substan-
tial number of subjects are withdrawn or lost to follow-up, baseline characteristics and
available information on hospital course will be reviewed and compared to subjects not
withdrawn or lost, to assess empirically if these subjects differ from those remaining in
the study for the scheduled treatment and follow-up time.
Outliers will be reviewed for validity. Outliers that are valid, for example, high number
of vomiting episodes, will be included in all primary reports from this trial.
Due to this being a pilot study, missing data will remain missing instead of being imputed.
5.3
Multiple Comparisons and Multiplicity
As this is a pilot study, no adjustments will be made for multiple comparisons. It will
be noted that no adjustments were made in any manuscript that publishes data from this
pilot study.
5.4
Planned Subgroups, Interactions, and Covariates
There are no subgroup analyses planned for this pilot study.
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5.5
Derived and Computed Variables
5.5.1
Enrollment Rates
The enrollment rate will be calculated as the number of subjects in the ITT population
divided by the total time all sites were open for enrollment. The time (in months sum-
marized as continuous) will be computed for each site based on the site‘s activation date
and the site‘s closure date. The sum of all of these individual times is used to calculate
the total time all sites were open for enrollment.
5.5.2
Consent Rate between Stage I and Stage II
The consent rate (which is 100% minus the dropout rate) will be calculated as the ratio of
STAGE II CONSENTED and RCT ELIGIBLE (summarized as a proportion).
5.5.3
Feasibility and Usability of Video Chat Follow-Up
Secondary outcomes 3 and 4 will be analyzed among those subjects who are randomized
into Stage II of the trial. On the Day 7 follow-up visit, we record the type of device used
to conduct the visit. If the device is ‘Mobile Phone (phone call)’, then the visit will be cate-
gorized as a phone visit. If the type of device is ‘Mobile Phone (video)’, ‘Tablet’, ‘Laptop’,
or ‘Desktop computer’, then the visit will be categorized as a video visit. The proportion
of video visits out of all Day 7 follow-up visits will be computed. Subjects without a Day
7 visit (i.e., missed the Day 7 follow-up) will not be included in the denominator.
Among the subjects who are categorized as a video follow-up, we will also summarize the
proportion of subjects where the entire assessment was able to be completed using video
follow-up. Among those subjects who are categorized as a video follow-up but WERE
NOT able to be completed, we will summarize the reasons why with frequencies and
percentages. Among those subjects who are categorized as a video follow-up and WERE
able to be completed, we will summarize the experience of the calls (video quality, sound
quality, ease of use, overall experience) using frequencies and percentages. Categories
of these experiences may be combined when summarizing results (e.g., combine Very
Negative with Negative in a summary).
5.5.4
Lost to Follow-up Rates
The primary lost to follow-up rate will be summarized for the Day 7 follow-up. A subject
will be categorized as having a Day 7 follow-up if the Date of Day 7 Follow-up is not miss-
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ing (regardless if the date is within the 7-day window). If the date is missing, the subject
will be categorized as missing the Day 7 follow-up. The rate of Day 7 follow-ups will be
summarized as a proportion. A similar analysis will be done for the Day 21 follow-up.
For the daily assessments, we will calculate whether the subject completed at least ﬁve
out of the six possible daily assessments. The proportion of subjects who completed at
least ﬁve assessments will be summarized.
5.5.6
Clinic or ED Visits
Two deﬁnitions of clinic or ED visits will be derived. These are described in the following
paragraphs:
Any Visit
A subject will be categorized as having seen a provider if the subject indicates
that they have seen a doctor (in the ED or primary care provider) since the study ED visit
on the Day 7 follow-up (regardless of whether it is planned or unplanned).
Unplanned Visit
A subject will be categorized as having seen a provider if the subject
indicates that they have seen a doctor (in the ED or primary care provider) since the study
ED visit on the Day 7 follow-up (only an unplanned study visit for a non-ED visit).
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The proportions of subjects for the two deﬁnitions above will be summarized out of the
proportion of subjects with a Day 7 follow-up visit (categorized as having a Day 7 follow-
up if the Date of Day 7 Follow-up is not missing). A repeat of these two summaries will
be performed for the Day 21 follow-up visit.
5.5.7
Hospitalization
A subject will be categorized as having been hospitalized if the subject indicates that
they were hospitalized since the study ED visit on the Day 7 follow-up. The proportion
of subjects who were hospitalized will be summarized out of the proportion of subjects
with a Day 7 follow-up visit (categorized as having a Day 7 follow-up if the Date of Day
7 Follow-up is not missing). A repeat of this summary will be performed for the Day 21
follow-up visit.
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5.5.9
Adverse Events
Adverse events will be captured through the daily assessments. On the daily log and on
Day 7, we ask about several symptoms. On any daily assessment or Day 7, whatever
the worst category reported across the week is the category assigned to the subject. For
example, on the ﬁrst day following the ED visit, if the parent reports the child had 4+
episodes of vomiting that day, then the child will be categorized as ‘Severe’ AEs regardless
of how quickly they might improve the remaining part of the week. Allergic reactions is
captured as ‘rash’, stomatitis is captured as ‘had any ulcers in the mouth’, and candidiasis
is captured as ‘had any white patches in the mouth or a rash in the groin region’. The
categorization of mild, moderate, and severe can be seen in Figure 1.
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5.5.13
Frequency and Types of Adverse Events
For each of the adverse events summarized in Figure 1, we will categorize each subject as
whether or not the AE was observed based on:
• the daily assessments
• the Day 7 survey
If the subject experiences the AE at any reported period, the subject will be labeled as
having experienced the AE. If the subject has at least one assessment completed (either
daily or Day 7) and all observed assessments do not indicate the AE occurring, the subject
will be labeled as not experiencing the AE.
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5.6
Independent Review
All statistical analyses for primary reporting of trial results will be independently veriﬁed
through dual programming. Two statisticians will each program all datasets and analyses
for the DSMB reports and the primary manuscript(s) and the results will be compared.
This process will begin at the analysis design stage and will continue through writing of
abstracts and manuscripts.
6
INTERIM ANALYSES
6.1
Frequency of and Timepoints for Interim Analysis
This is a pilot study evaluating the feasibility of the trial so no formal interim analyses will
be performed. The DSMB will meet prior to study start and then once study is completed.
If enrollment is anticipated to go longer than 8 months, then the DSMB will have the
option to meet to perform a safety review of the data.
6.2
Stopping Rules for Interim Efﬁcacy Analysis
There is no formal efﬁcacy monitoring in this pilot study.
6.3
Futility Monitoring in the Interim Analysis
There is no formal futility monitoring in this pilot study.
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6.4
Subgroups in the Interim Analysis
There are no formal pre-speciﬁed subgroups of interest in this pilot study that will be
evaluated due to the small number of enrollments.
7
PLANNED ANALYSES
7.1
Description of Subject Characteristics
Publication of the primary results will include reporting of key baseline characteristics
overall, and by assigned treatment arm. These will include, but are not limited to
• gender
• race
• age
• ethnicity
7.2
Primary Outcome Analysis
The primary outcome, enrollment rate, and the 95% conﬁdence interval around the en-
rollment rate will be summarized overall.
7.3
Secondary Outcome(s) Analyses
7.3.1
Consent and drop-out rates between the two stages of consent
The consent rate between Stage I and Stage II (summarized as a proportion) and exact
95% conﬁdence interval of the proportion will be reported.
7.3.2
Parental attitudes and beliefs about trial procedures
Parental attitudes and beliefs about trial procedures will be evaluated outside of the clin-
ical trial. Qualitative analyses will be performed by the lead investigator and his team
and details are not discussed in this SAP.
7.3.3
Feasibility and usability of video chat follow-up
The video follow-up rate and entire assessment completed through video (summarized
as a proportions) and exact 95% conﬁdence intervals of the proportions will be reported.
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7.3.4
Lost to follow-up rates
Lost to follow-up rates (summarized as a proportions) and exact 95% conﬁdence intervals
of the proportions will be reported.
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8
SAMPLE SIZE DETERMINATION
We are seeking to enroll and randomize 2 children per site per month as part of this pilot
trial. Using 40% as an estimate of children enrolled in Stage I being eligible for Stage
II (PCT <0.25), we anticipate that we will need to obtain PCT and baseline data from 5
children per site per month to enroll 2 with PCT <0.25 at each site.; Thus, over a 6 month
period, we anticipate obtaining baseline data and PCT on 90 children across 3 sites and
enrolling 36 of these children into this pilot RCT. As soon as 36 children are enrolled in
the RCT, the pilot trial will stop.
9
References
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