Procalcitonin Antibiotic Consensus Trial (ProACT)
Phase: NA
Conditions: Lower Respiratory Tract Infection (LRTI)
Sponsor: University of Pittsburgh

 
 
 
TITLE: Procalcitonin Antibiotic Consensus Trial (ProACT) 
 
NCT# NCT02130986 
 
FINAL PROTOCOL DATE: Version 1.4, March 8, 2017 
 

 
 
 
 
 
 
ProACT 
 
(Procalcitonin Antibiotic Consensus Trial)  
 
 
 
 
 
 
 
 
 
 
 
 
PI:  David T. Huang, MD, MPH 
Director, Multidisciplinary Acute Care Research Organization (MACRO) 
Associate Director, Abdominal Organ Transplant ICU 
CRISMA Center 
Department of Critical Care Medicine 
Department of Emergency Medicine 
Clinical and Translational Science Institute 
606B Scaife Hall 
3550 Terrace Street 
University of Pittsburgh 
Pittsburgh, PA 15261, USA 
(412) 647-6818 (office) 
(412) 647-3791 (fax) 
 

 
 
2 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
ProACT Trial Registration Data 
 
Primary registry and trial identifying number:  
ClinicalTrials.gov 
 
Date of registration in primary registry: 
 
May 1, 2014 
 
Primary sponsor:  
National Institutes of General Medical  
 
Sciences (NIGMS)  
(1R01GM101197 and 1R34GM102696) 
 
Contact for public inquiries:  
 
 
Elizabeth Gimbel, BS 
gimbele@upmc.edu 
 
Ashley M. Ryman, BS, BA 
 
 
 
 
 
 
 
rymanam@upmc.edu 
 
Contact for scientific inquires: 
 
 
David T. Huang, MD MPH  
 
 
 
 
 
 
 
huangdt@upmc.edu 
 
Public title: 
 
 
 
 
 
Procalcitonin Antibiotic Consensus Trial  
(ProACT) 
 
Countries of recruitment: 
 
 
 
United States 
 
Health condition(s) or problem(s) studied: 
Procalcitonin-guided antibiotic use in lower 
respiratory tract infection (LRTI)  
 
Intervention(s): 
Experimental:  Reporting of serial procalcitonin 
results and antibiotic guideline to treating 
clinicians. Clinicians retain complete decision-
making autonomy. 
Control: Usual care; no procalcitonin results will 
be reported to treating clinicians. 
 
 
 
 
 
 
 
 
Key inclusion and exclusion criteria: 
Inclusion - ≥ 18 years old; a primary clinical 
diagnosis in the ED (emergency department) of 
acute LRTI (< 28 days duration); clinician willing 
to consider procalcitonin in antibiotic decision-
making. 
Exclusion – systemic antibiotics before ED 
presentation; current vasopressor use; 
mechanical ventilation (via endotracheal tube); 
known severe immunosuppression; 
accompanying non-respiratory infection; known 
lung abscess/empyema; chronic dialysis; 
metastatic cancer; surgery in the past 7 days 
(excluding minor surgery); incarcerated or 
homeless; enrolled in ProACT in the past 30 
days.  

 
 
3 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
Study type: 
Patient-level, multi-center, randomized, 
combined superiority (primary outcome) and 
non-inferiority (primary safety outcome) trial 
 
Date of first enrollment: 
 
 
 
November 2014 
 
Target sample size: 
 
 
 
 
1674 
 
Recruitment status: 
 
 
 
 
Enrollment phase 
 
Primary outcome(s): 
 
 
 
 
Total antibiotic exposure, defined as the  
total number of antibiotic-days by Day 30 
 
Primary safety outcome(s): 
 
 
 
Combined endpoint of adverse outcomes  
that could be attributable to withholding 
antibiotics in LRTI, by Day 30 
 
Key secondary outcome(s): 
 
 
 
Rate of antibiotic initiation by the initial ED  
clinician 
 
 
Protocol Version: 
 
 
 
 
Version 1.4; March 8, 2017 
 
Source(s) of monetary or material support: 
 
NIGMS, BioMerieux  
 
Purpose: 
To test the effect of implementation of a novel 
procalcitonin guideline on antibiotic and adverse 
outcomes in ED patients with LRTI   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
4 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
 
 
 
ProACT Coordinating Center Team  
Investigators  
 
 
 
David T. Huang, MD, 
MPH  
PI 
Associate Professor  
CRISMA Center  
Departments of Critical 
Care Medicine, 
Emergency Medicine, 
and Clinical and 
Translational Science 
University of Pittsburgh 
 
Derek C. Angus, MD, 
MPH, FRCP  
Co-I  
Chair, Department of 
Critical Care Medicine 
Professor of Critical 
Care Medicine, 
Medicine, Health Policy 
and Management, and 
Clinical And 
Translational Science  
Director, CRISMA 
Center 
University of Pittsburgh 
 
Donald M. Yealy, MD 
Co-I 
Chair, Department of 
Emergency Medicine 
Professor of Emergency 
Medicine 
University of Pittsburgh 
 
Yohei Doi, MD 
Co-I 
Assistant Professor, 
Department of 
Medicine/Infectious 
Diseases 
University of Pittsburgh 
 
 
 
 
Investigators 
 
 
 Michael J. Fine, MD 
 Co-I 
 Professor, Department of 
 Medicine 
 University of Pittsburgh 
 
  
 
John A. Kellum, MD 
Co-I 
Professor of Critical Care 
Medicine, Medicine, 
Bioengineering and 
Clinical & Translational 
Science 
Director, Center for Critical 
Care Nephrology 
Vice Chair for Research 
Department of Critical 
Care Medicine 
University of Pittsburgh 
 
Octavia M. Peck Palmer, 
Ph.D. 
Assistant Professor 
Departments of Pathology 
& Critical Care Medicine  
University of Pittsburgh 
School of Medicine  
 
 
 
 
 
 
 
 
 
 
 
Staff  
 
 
Ashley Ryman, BS, BA 
Project Manager 
CRISMA Center  
Department of Critical 
Care Medicine  
University of Pittsburgh 
 
Elizabeth Gimbel, BS 
Project Manager 
CRISMA Center 
Department of Critical 
Care Medicine 
University of Pittsburgh 
 
Kourtney Wofford, BS 
Project Coordinator 
CRISMA Center 
Department of Critical 
Care Medicine 
University of Pittsburgh 
 
Carrie Pidro, BA 
Long-term Follow-up 
Manager 
CRISMA Center 
Department of Critical 
Care Medicine 
University of Pittsburgh 
 
 
 
 
 

 
 
5 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
Table of Contents 
1     INTRODUCTION .................................................................................................................................... 8 
A.  OBJECTIVE AND SPECIFIC AIMS ............................................................................................................. 8 
B.  BACKGROUND AND RATIONALE ............................................................................................................ 8 
C.  TRIAL DESIGN .............................................................................................................................................. 9 
2     METHODS ........................................................................................................................................... 10 
A.  PARTICIPANTS, INTERVENTIONS, AND OUTCOMES ........................................................................ 10 
i. STUDY SETTING .............................................................................................................................................. 10 
ii. ELIGIBILITY CRITERIA .................................................................................................................................. 10 
a. PARTICIPANT INCLUSION CRITERIA ................................................................................................... 10 
b. PARTICIPATION EXCLUSION CRITERIA ............................................................................................. 10 
iii. STUDY INTERVENTIONS AND PROCEDURES ...................................................................................... 11 
v. SAMPLE SIZE .................................................................................................................................................. 14 
vi. RECRUITMENT AND CONSENT ................................................................................................................ 14 
vii. POTENTIAL RISKS AND BENEFITS ........................................................................................................ 15 
B.  ASSIGNMENT OF INTERVENTIONS ....................................................................................................... 16 
i. ALLOCATION .................................................................................................................................................... 16 
a. SEQUENCE GENERATION ....................................................................................................................... 16 
b. ALLOCATION CONCEALMENT MECHANISM ..................................................................................... 16 
c. IMPLEMENTATION ..................................................................................................................................... 16 
d. BLINDING ..................................................................................................................................................... 16 
ii. DATA COLLECTION, MANAGEMENT, AND ANALYSIS ........................................................................ 16 
a. DATA COLLECTION METHODS .............................................................................................................. 16 
b. DATA MANAGEMENT ............................................................................................................................... 17 
c. STATISTICAL METHODS .......................................................................................................................... 17 
iii. MONITORING .................................................................................................................................................. 19 
a. DATA MONITORING ................................................................................................................................... 19 
b. HARMS .......................................................................................................................................................... 19 
c. INTERVENTION ADHERENCE ................................................................................................................. 21 
d. AUDITING ..................................................................................................................................................... 21 
3.  ETHICS AND DISSEMINATION ........................................................................................................... 21 
A.  RESEARCH ETHICS APPROVAL ............................................................................................................ 21 
B.  PROTOCOL AMENDMENTS ..................................................................................................................... 22 
C.  CONFIDENTIALITY .................................................................................................................................... 22 

 
 
6 
ProACT protocol 
Version 1.4;  March 8, 2017 
D.  DECLARATION OF INTERESTS .............................................................................................................. 22 
E.  ACCESS TO DATA ..................................................................................................................................... 22 
F.  ANCILLARY AND POST-TRIAL CARE .................................................................................................... 23 
G.  DISSEMINATION POLICY ......................................................................................................................... 23 
H. COSTS AND PAYMENTS ........................................................................................................................... 23 
References ........................................................................................................................................................ 24 
Appendix 1:  ProACT Informed Consent Form Template ..................................................................... 26 
Appendix 2:  Biological Specimen Flowchart ............................................................................................ 32 
Appendix 3:  Participant Timeline ........................................................................................................... 33 
Appendix 4:  ProACT Telephone Interview Script ..................................................................................... 35 
Appendix 5:  Sample Discharge Letter to PCP ...................................................................................... 41 
Appendix 6: Discharge Letter to Participant .......................................................................................... 42 
Appendix 7:  30 Day Antibiotic Use Calendar ............................................................................................ 44 
Appendix 8:  Airway questionnaire 20 (AQ-20)  ......................................................................................... 45 
Appendix 9:  Honest Broker Standard Operating Procedures ................................................................ 46 
Appendix 10:  ProACT Medical Records Release Form ........................................................................... 50 
 
 
 

 
 
7 
ProACT protocol 
Version 1.4;  March 8, 2017 
Glossary of Terms 
 
AE 
 
Adverse events 
ANC 
 
Absolute neutrophil count 
CAP 
 
Community acquire pneumonia 
CD4 
 
cluster of differentiation 4 (glycoprotein) 
COPD  
Chronic obstructive pulmonary disease 
CRISMA 
Clinical Research, Investigation and Systems Modeling of Acute Illness 
DCF 
 
Data collection form 
DSMB  
Data Safety and Monitoring Board 
eDCF  
Electronic data collection form 
ED 
 
Emergency Department 
FDA 
 
Food and Drug Administration 
GenIMS 
Genetic and Inflammatory Markers of Sepsis (GenIMS) Study 
HIPAA  
Health Insurance Portability and Accountability Act 
ICU 
 
Intensive care unit 
IRB 
 
Institutional Review Board 
KDIGO  
Kidney Disease: Improving Global Outcomes  
LAR 
 
Legally authorized representative 
LRTI 
 
Lower respiratory tract infection 
NDI 
 
National Death Index 
NIH 
 
National Institutes of Health 
NIGMS  
National Institute of General Medical Sciences 
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
ProACT 
Procalcitonin Antibiotic Consensus Trial 
ProHOSP 
Procalcitonin-Guided Antibiotic Therapy and Hospitalization in Patients with Lower  
 
 
Respiratory Tract Infections (ProHOSP) Study 
PSI 
 
Pneumonia severity index 
SAE 
 
Serious adverse event 
SAS 
 
Statistical analysis software 
Site SC  
Site study coordinator 
UAP 
 
Unanticipated problem 
WBC 
 
White blood cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
8 
ProACT protocol 
Version 1.4;  March 8, 2017 
Procalcitonin Antibiotic Consensus Trial (ProACT) 
1     INTRODUCTION 
 
A.  OBJECTIVE AND SPECIFIC AIMS 
 
The study objective is to target emergency department (ED) patients with clinically diagnosed 
lower respiratory tract infection (LRTI) and test the effects of implementation of a procalcitonin 
antibiotic guideline for LRTI.   
Aim #1:  To determine the effect of implementation of a procalcitonin guideline on antibiotic 
exposure in clinically diagnosed LRTI. 
Aim #2:  To determine the effect of implementation of a procalcitonin guideline on a 30-day 
combined adverse outcome. 
The primary study outcome (Aim 1) is total antibiotic exposure (defined as the total number of 
antibiotic days by Day 30). The primary safety outcome (Aim 2) is a combined endpoint of 
adverse outcomes that could be attributable to withholding antibiotics in LRTI. 
B.  BACKGROUND AND RATIONALE 
 
There is a need for improved decision-making for antibiotic prescription in acute 
suspected infection.  Infections, particularly in the early stages, can have protean 
manifestations, often do not manifest with “classic” signs, and clinically overlap with non-
infectious conditions. However, the imperative to quickly give antibiotics for bacterial infection has 
led to antibiotic overuse and resistance.  
Strategies that combine novel diagnostics with therapeutics have improved decision-
making in oncology, cardiology, and other fields. These strategies aim to identify those 
patients most likely to be helped or harmed by the therapeutic intervention and allow more 
individualized care. This approach takes diagnostics to the next level, by demanding a test not 
only measure well, but also that clinical care be improved by tying the test to a treatment strategy.  
Procalcitonin, a novel biomarker of bacterial infection, may help physicians make more 
appropriate antibiotic decisions. Of the many proposed biomarkers of infection and sepsis, 
procalcitonin is currently the most studied, feasible, and clinically promising.1 Procalcitonin is a 
calcitonin precursor measurable in serum and elevated in bacterial infections, yet low in viral 
infections.2 Distinct from traditional endocrine pathways, bacterial infection induces a ubiquitous 
increase of calcitonin-I gene expression and subsequent constitutive release of procalcitonin from 
multiple tissue and cell types.3 Importantly, in 2008, the FDA cleared for marketing a new, rapid 
(< 1 hour), high-sensitivity procalcitonin assay. The difference in functional assay sensitivity 
between the new and older assays contributed to initial conflicting studies on utility.4-6  
Procalcitonin outperforms traditional means of detecting bacterial infection. Recent 
observational studies using the high-sensitivity assay show procalcitonin has superior 
discrimination for bacterial infections over other markers and correlates well with outcome.7-13     
A study of 545 LRTI patients found procalcitonin, but not high-sensitivity C-reactive protein or 
leukocyte count, increased with higher CAP severity, and had superior performance for 
differentiation of CAP from non-CAP LRTI and prediction of bacteremia.14 A recent meta-analysis 
found procalcitonin had superior performance for detection of bacterial infection versus C-reactive 
protein, with 92% sensitivity for differentiating bacterial from viral infection.7 A 2011 study of 
severe influenza pneumonia found procalcitonin levels in isolated viral pneumonia were 60-fold 
lower than cases with bacterial co-infection.15 Our group recently demonstrated in a large CAP 

 
 
9 
ProACT protocol 
Version 1.4;  March 8, 2017 
cohort that low procalcitonin not only correlated well with low subsequent positive cultures, but 
also portended low morbidity and mortality, even in high-risk subjects.13 All observational studies 
of infection are challenged by lack of a “gold standard.” Cultures are often negative and cannot 
distinguish between colonization and infection, and physician adjudication panels are subjective. 
Biomarker-guided trials offer a novel solution to this well-known methodological problem by using 
patient outcome as the primary measure of biomarker performance. 
Lower respiratory tract infection (LRTI) is an ideal trial population. LRTI accounts for a large 
proportion of antibiotic prescription, and exemplifies the imprecise clinical phenotype of infection. 
Respiratory infection is the most common reason for ambulatory care visits, and accounts for >12 
million annual ED visits.16 Determining which patients require antibiotics is difficult due to 
overlapping clinical presentations between LRTI subtypes and non-infectious conditions, and 
insensitivity of clinical exam and standard diagnostics for distinguishing bacterial from viral 
infection.  
Important “proof of concept” trials using procalcitonin have been conducted. In 2004, a 
single center trial of 243 LRTI patients presenting to the ED of a Swiss academic hospital 
randomized patients to standard care or procalcitonin-guided care.17 In the procalcitonin arm, 
physicians were advised to withhold antibiotics if procalcitonin was low, and to administer 
antibiotics if procalcitonin was high. Procalcitonin-guided care halved antibiotic initiation with no 
apparent harm. The same research group achieved similar results in a 2007 single center trial of 
208 COPD patients18 and a 2009 six center trial of 1359 LRTI patients powered for safety 
(ProHOSP).19 A recent single-center Shanghai study had similar findings.20 However, key 
questions remain. 
Questions of generalizability and safety preclude widespread application. In these trials, a 
senior investigator potentially influenced ED staff by directly providing procalcitonin guideline 
advice. In ProHOSP, “enforcement” was accomplished by requiring physicians to follow Web-
based instructions before registering their patient in the study. Physicians could only overrule the 
guideline after consulting the coordinating center. In routine US practice, neither method is ideal 
nor practical. Senior investigator influence threatens generalizability and direct interference with 
physician decision-making is counter to practice norms. US physician and patient expectations 
also likely differ from their Swiss counterparts and will require contemporaneous, individual data 
to alter. Further, only ProHOSP was powered to test safety. ProHOSP found no difference 
between groups in a composite adverse outcome endpoint, but used a relatively large non-
inferiority margin. Their combined endpoint included an adverse outcome already potentially 
present at enrollment and subject to non-physiologic factors such as bed availability (ICU 
admission). The authors also observed in the procalcitonin arm a slightly higher mortality rate and 
did not report outcomes past 30 days. 
C.  TRIAL DESIGN 
 
We propose a patient-level randomized trial to test an evidenced-based implementation strategy 
of a novel procalcitonin antibiotic guideline for LRTI. We will test the impact of serial procalcitonin 
measurement on total antibiotic exposure by Day 30. ProACT is powered to demonstrate safety 
with a 4.5% non-inferiority margin for a combined adverse event endpoint of the primary concerns 
of withholding antibiotics, and to detect a reduction of > 1 antibiotic-day. We will enroll all LRTI as 
initial clinical presentations, embracing the clinical overlap that exists in practice and to optimize 
enrollment. 
 
 

 
 
10 
ProACT protocol 
Version 1.4;  March 8, 2017 
2     METHODS 
 
A.  PARTICIPANTS, INTERVENTIONS, AND OUTCOMES 
 
 
i. STUDY SETTING 
Screening and enrollment will occur in the EDs from approximately 14 sites across the 
US, with the University of Pittsburgh serving as the Coordinating Center.  Sites were 
chosen based on the following considerations:  sample size and projected recruitment 
rates; site willingness and ability to institute all required study interventions successfully 
and appropriately; and generalizability of findings.   
 
 
ii. ELIGIBILITY CRITERIA 
 
 
a. PARTICIPANT INCLUSION CRITERIA  
1. ≥ 18 years old 
2. A primary clinical diagnosis in the ED of acute LRTI (< 28 days duration) 
3. Clinician willing to consider procalcitonin in antibiotic decision-making 
 
 
 
LRTI will be classified after enrollment into the following categories: 
 
 
(i) Community acquired pneumonia (CAP) 21 
(ii) COPD exacerbation 
(iii) acute asthma exacerbation  
(iv) acute bronchitis  
(v) other LRTI  
 
 
b. PARTICIPATION EXCLUSION CRITERIA 
 
 
Conditions where physicians are unlikely to withhold antibiotics 
1. Systemic antibiotics before ED presentation 
a. All prophylactic antibiotic regimens, OR 
b. Received >1 dose within 72 hours prior to ED presentation 
2. Current vasopressor use 
3. Mechanical ventilation (via endotracheal tube) 
4. Known severe immunosuppression 
5. Accompanying non-respiratory infections 
6. Known lung abscess or empyema 
Conditions where PCT can be > 0.25 ug/L without infection 
7. Chronic dialysis  
8. Metastatic cancer 
9. Surgery in the past 7 days (excluding minor surgery such as skin biopsy) 
Conditions rendering follow-up difficult: 
10. Incarcerated or homeless 
11. Enrolled in ProACT in the past 30 days  
 
 
 
 
  
 

 
 
11 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
iii. STUDY INTERVENTIONS AND PROCEDURES 
After written informed consent is obtained, participants will be randomized and enrolled 
into one of two different study groups:  the procalcitonin group or the usual care (UC) 
group.   
 
 
Study procedures specific to the procalcitonin group: 
In the procalcitonin group, the intervention consists of reporting procalcitonin results and 
the procalcitonin antibiotic guideline to clinicians, while embracing clinician autonomy. 
Study staff will be trained to inform clinicians that the procalcitonin information is 
available, and not to otherwise influence care. At all times, the clinician retains complete 
decision-making authority. The final decision to give antibiotics is at the discretion of 
the treating clinician. 
Participants in the procalcitonin group will have one teaspoon of blood drawn for a 
procalcitonin level (≤ one hour after randomization goal) in the ED, and if hospitalized, 6-
24 hours after the initial ED blood draw, and on Days 3, 5, and 7.  Days 3, 5, and 7 blood 
draws for procalcitonin will only occur in hospitalized patients on antibiotics and/or at the 
treating clinician’s discretion.  For the purpose of this study, time zero is at randomization 
and Day 1 is defined as time of enrollment through 11:59PM of the same day.   
In the ED, we will quickly (<1 hour goal) provide clinicians the procalcitonin result, 
accompanied by the procalcitonin antibiotic guideline (provided below). For participants 
who have not yet received antibiotics, we will ask the clinician to consider waiting for the 
procalcitonin result.  
For patients admitted to hospital (or to an observation unit), we will inform the hospital 
clinician of the ED procalcitonin result, and that serial procalcitonin levels will be 
obtained, including a second one in 6 - 24 hours after the initial ED blood draw. During 
the hospital stay, study staff will inform clinicians when new serial procalcitonin results 
are available. The same procalcitonin guideline will be provided with both the initial and 
serial procalcitonin measurements - withhold or cease antibiotics if low, administer or 
continue if high. 
Procalcitonin antibiotic guideline 
 
 
 
 
 
 
 
 
 
 
1. Initial antibiotics can be considered for critical illness, Legionella pneumophilia. Procalcitonin should be 
evaluated in context with all findings and the total clinical status; clinical judgment always necessary. 
2. For outpatients, antibiotic duration based on level (> 0.25-0.5 ug/L:3 days; > 0.5-1.0 ug/L:5 days; >1.0 
ug/L:7 days). Physician follow-up is recommended. 
 
Upon discharge (from ED or hospital) in the procalcitonin group, participants will receive 
a ProACT study information  packet which includes a letter for their primary care clinician 
which provides an explanation of the study and the study guideline (Appendix 5), an 
instructional letter (Appendix 6), and a 30 day antibiotic use calendar (Appendix 7). This 
information packet will be provided to the participant as a tool to boost study awareness 
Procalcitonin 
level (g/L) 
Bacterial etiology 
Recommendation 
< 0.1 
Very unlikely 
Antibiotics strongly discouraged1 
0.1 - 0.25 
Unlikely 
Antibiotics discouraged1 
> 0.25 - 0.5 
Likely 
Antibiotics recommended2 
> 0.5 
Very likely 
Antibiotics strongly recommended2 

 
 
12 
ProACT protocol 
Version 1.4;  March 8, 2017 
and a reminder of the two subsequent phone visits described below.  The 30 day 
antibiotic use calendar is an optional tool for the participant to aid in antibiotic use recall.    
 
 
Study procedures specific to the usual care group: 
After randomization, study staff will inform the treating clinician that the patient was 
assigned to the usual care group, and that procalcitonin will not be provided. At all times, 
all patient care is at the discretion of the treating clinician. 
 
Upon discharge (from ED or hospital), usual care participants will receive a ProACT study 
information packet which includes an instructional letter (Appendix 6) and a 30 day 
antibiotic use calendar (Appendix 7).  As stated above, this information packet will be 
provided to the participant as a tool to boost study awareness and a reminder of the two 
subsequent phone visits described below.  The 30 day antibiotic use calendar is an 
optional tool for the participant to aid in antibiotic use recall.    
 
Study procedures common to both groups: 
1. All participants will have approximately four teaspoons of blood drawn in the ED after 
randomization. This blood sample will be sent to the CRISMA Molecular Core Laboratory 
at the University of Pittsburgh for research purposes related to procalcitonin, infection, 
and outcome. 
 
2. All participants will have the following data collected during their ED visit: 
• 
Sociodemographic information  
• 
Comorbidities and current medications 
• 
Vital signs 
• 
Respiratory history 
• 
Test results and therapeutics relevant to current illness, including 
medications, significant lab values and imaging results   
• 
Antibiotics prescribed and received  
• 
Patient disposition upon ED discharge and ED final diagnosis 
3.  If admitted to hospital, both groups will have the following information collected from 
the medical record: 
• 
Antibiotics prescribed and received 
• 
Therapeutics and diagnostics (steroids, bronchodilators, radiologic test 
results) 
• 
Clinically obtained microbiology results  
• 
Disposition upon discharge 
4.  Safety outcomes will be collected from the medical record on both groups and include: 
• 
death, vasopressor use for >1h, mechanical ventilation, new renal 
replacement therapy, all creatinine results, diagnosis of lung 
abscess/empyema, new diagnosis and/or treatment of pneumonia for non-
CAP LRTI, length of hospital stay which includes any ICU admissions.  
5.  All participants will participate in 2 telephone visits, lasting approximately 10 minutes 
each.  These visits will be conducted by the ProACT Coordinating Center Long-Term 
Follow-Up Core, located at the University of Pittsburgh.  These visits will occur on Day 15 
(+/- 5 days) and Day 30 (+ 10 days).  Data collected from these calls will primarily 
include: antibiotic use, the AQ-20 questionnaire (Appendix 8), and post discharge 
resource use (Appendix 4).  If the participant is hospitalized at either time point, the site 
SC will be responsible for collecting medical record data only, listed above in items 3 & 4, 
and the telephone visit will not be conducted at that time point. 
 

 
 
13 
ProACT protocol 
Version 1.4;  March 8, 2017 
During data collection in the ED, the participant’s Protected Health Information (PHI) (e.g. 
SSN, name, DOB, address, phone number, etc.) will be collected and sent directly from 
the local study site to the ProACT Coordinating Center Honest Broker.  This information 
will be maintained in strict confidentiality according to the Honest Broker’s standard 
operating procedure (Appendix 9).  The PHI will be used for Day 15 and Day 30 
telephone visits as well as obtaining long-term survival information.  Long-term survival 
status (Day 90 and 1 year post study enrollment date) will be obtained through the 
NCHC/NDI (National Center for Health Statistics/National Death Index).  The following 
data is needed for the NDI search: name, father’s surname, SSN, DOB, race, sex, marital 
status, state of residence, and state of birth.  Contact information (name, address, 
telephone number) will also be obtained for 2 relatives or close friends.  This will be used 
to minimize “lost to follow-up” in cases where the ProACT Coordinating Center Long-
Term Follow-Up Core is unable to contact the participant for Day 15 and Day 30 visit data 
collection. The Long-Term Follow-Up Core will also utilize text messaging for reminders, 
setting up appointments for interviews, and in some instances questionnaire responses in 
an attempt to minimize “lost to follow-up” cases.  Texting will only be utilized for subjects 
that agree to receive study text messages. 
 
For subjects that we have been unable to reach to complete 30 day interviews via phone 
call, we will send a letter informing the subject that we have attempted to reach them 
without success.  This letter will include a toll-free number that subjects may call in order 
to schedule or complete their interview.  Alternatively, we will also provide a paper 
version of the interview questions for those subjects that prefer to complete via paper.  
Subjects will be provided with a prepaid envelope to send back completed paper 
interviews.  Subjects may receive an email message reminder for the interview that will 
include a link to a Qualtrics version of the survey that is identical to the paper version.  
Subjects who have agreed to receive text messages may also be prompted to complete 
the survey via text messaging. 
In the event that the participant is hospitalized between ProACT study enrollment and 
Day 30 at a facility different from the enrolling site, a medical release will be requested for 
feasibility of long-term follow-up to ascertain clinical events related to the study (Appendix 
10). 
 
 
 
 
iv. OUTCOMES 
Our primary outcome is total antibiotic exposure, defined as the total number of 
antibiotic-days by Day 30. We define an antibiotic-day as each day a participant receives 
any oral or intravenous antibiotics, excluding antibiotics given for non-infectious 
indications (e.g. neomycin for hepatic encephalopathy) and antivirals. Secondary 
outcomes include the rate of antibiotic initiation by the initial ED clinician. 
Our primary safety outcome is a combined endpoint of adverse outcomes that could be 
attributable to withholding antibiotics in LRTI, that occur by study Day 30, as below. Our 
combined endpoint captures the components of the treatment failure endpoint used in a 
recent study of 80,000 COPD patients (death, mechanical ventilation, readmission).22  
We assume no patient discharged from ED has met primary safety outcome endpoint at 
time of discharge (death, organ failure, empyema); post-discharge events are captured in 
follow-up. Secondary outcomes include vital status at Day 90 and 1 Year, as determined 
by National Death Index (NDI) query. 
Measurable adverse events for primary safety outcome: 
i. death 
ii. septic shock (vasopressor use for > 1h) 

 
 
14 
ProACT protocol 
Version 1.4;  March 8, 2017 
iii. mechanical ventilation (via endotracheal tube) 
iv. renal failure (KDIGO-3) 
v. lung abscess/empyema  
vi. development of pneumonia in non-pneumonia LRTI  
vii. subsequent hospitalization (for both those discharged from 
ED and those admitted to hospital) 
 
 
v. SAMPLE SIZE 
We desire at least 80% power to conduct our primary hypothesis tests using a one-sided 
significance level of 0.05. As shown below, determination of sample size was dependent 
on the hypothesis test for the primary safety outcome, as this required a larger sample 
size than the tests for antibiotic exposure. Analyses were performed with SAS 9.1 (SAS 
Institute, Inc., Cary, NC). Allocation of 757 subjects in each arm (total trial sample 
size of 1514) meets our goal of at least 80% power. 
Testing H1: Procalcitonin guideline implementation reduces the total number of antibiotic-
days by Day 30. 
For H1, ProHOSP reduced antibiotic exposure from 8.7 to 5.7 days (35% relative risk 
reduction). We chose a 20% relative reduction as an appropriate minimum threshold and 
to detect a lower effect size than ProHOSP. 
We assumed control arm antibiotic exposure of 8 days, and calculated sample size 
based on a two-sided two-sample test at 0.05 significance. Under these assumptions, the 
sample size of 1514 required for H2 provides >99% power to detect a 20% relative 
reduction, and 80% power to detect a reduction of as low as one antibiotic-day (12% 
relative reduction). Power is preserved under a wide range of assumptions. Thus, we are 
exceptionally well-powered for H1. 
Testing H2: Procalcitonin guideline implementation does not increase the proportion of 
subjects who experience a composite endpoint of adverse outcomes by Day 30. 
ProHOSP estimated a maximum combined adverse outcome rate of 20% (actual – 17%) 
and set their non-inferiority margin as an absolute difference of 7.5%. In addition, a 
multicenter study of CAP (GenIMS), ~11% experienced our combined endpoint (6% 
death by Day 30, 5% septic shock, 7% mechanical ventilation, 10% renal failure). 
Similarly, a recent 80,000 COPD patient study reported 10.6% met a combined endpoint 
of death, mechanical ventilation, and readmission.22 We have therefore chosen an 
estimated combined adverse outcome rate of 11%. We also have set a narrower non-
inferiority margin of 4.5%, approximately half that of ProHOSP’s, to provide a higher 
degree of safety evaluation. A sample size of 1514 patients provides at least 80% 
power to demonstrate that procalcitonin guideline implementation does not 
increase overall adverse outcomes by more than 4.5%, if the true difference 
between arms is zero. This sample size also accounts for an approximately 10% lost to 
follow-up rate. Thus, we are well-powered to test safety. 
 
 
 
vi. RECRUITMENT AND CONSENT 
Each site will follow their IRB’s guidelines regarding HIPAA authorization and informed 
consent (including those guiding the use of genetic material).  
Patients will be screened for in the ED by the ProACT site study team. The ED clinical 
team will obtain potential participant or legally authorized representative (LAR)/proxy 
agreement verbally to be approached by the ProACT study representative to participate.  

 
 
15 
ProACT protocol 
Version 1.4;  March 8, 2017 
This will avoid “cold calling” coercion that could occur if direct contact by research team 
members was the initial method of assessing willingness to enroll.  
Trained ProACT study team members will then discuss the trial with the patient or 
LAR/proxy, and explain the goals, procedures, and risks associated with the study. If 
patient or LAR/proxy agrees to participate, written authorization and consent will be 
obtained. 
Some potential participants will lack capacity for informed consent and therefore 
LAR/proxy consent may be necessary.  Individuals legally authorized to provide consent 
are defined in the Code of Federal Regulations as "an individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective participant to the 
participant’s participation in the procedure(s) involved in the research" (45 CFR 
46.102(c)). Each site will follow their state law guiding LAR/proxy consent for participation 
of a decisionally-impaired participant.  The LAR/proxy will be informed of the risks, 
benefits and alternatives to the research study and will be asked to make a decision 
considering the view of the potential participant while decisionally-capable and to act in 
the best interest of the potential participant.  
If consent is refused, a limited set of demographic data (to the extent allowed by each 
site’s IRB) will be collected to compare patients who did and did not enroll in the study. 
This minimal data set will gather participation rates and variables (sex, age and race), 
permitting analysis of potential selection biases and determination of the generalizability 
of the study results. 
 
vii. POTENTIAL RISKS AND BENEFITS 
Participation in this study involves minimal risk only.  According to 45 CRF 46.102(i), 
minimal risk is defined as the probability and magnitude of physical or psychological harm 
that is normally encountered in the daily lives, or in the routine medical, dental, or 
psychological examination of healthy persons. 
 
 
 
Risks of the procalcitonin guideline: Clinicians may be influenced by the guideline, but 
they are not required to follow it. Best clinical judgment in determining each case will be 
used, just as it would without the procalcitonin guideline.  
 
Risks of blood sampling: The risks of drawing blood include bleeding, bruising, and pain 
at the blood draw site. These risks will be reduced by making every attempt to use blood 
that has already been drawn, or to collect this sample when the participant is having 
other blood drawn. 
 
Risk of release of information: We will minimize this potential breach of confidentiality risk 
by coding study information with a number instead of a name and storing it in a secure 
location.  
 
There may not be a direct benefit from taking part in this research study. For participants 
in the procalcitonin group, clinicians may use the procalcitonin levels to make more 
informed decisions about current treatment planning. It is possible that study findings will 
help future patients with lower respiratory tract infections.   
 

 
 
16 
ProACT protocol 
Version 1.4;  March 8, 2017 
B.  ASSIGNMENT OF INTERVENTIONS 
 
 
i. ALLOCATION 
 
 
 
a. SEQUENCE GENERATION 
Participants will be randomly assigned to control or intervention group with a 1:1 
allocation as per a computer generated randomization schedule stratified by site, 
race, and age using permuted blocks of random sizes for each enrolling site.  
The block sizes will not be disclosed to ensure concealment.  
 
 
 
b. ALLOCATION CONCEALMENT MECHANISM 
Allocation concealment will be ensured, as the ProACT coordinating center data 
management team will not release the randomization group until the participant 
has been recruited into the trial, which takes place after all required pre-
randomization data have been completed and entered into the study eDCF.  
 
 
 
c. IMPLEMENTATION 
All participants who give consent for participation, fulfill inclusion criteria, and do 
not meet exclusion criteria will be randomized.  Randomization will be conducted 
without any influence of the principal investigator, site study team, or ProACT 
coordinating center study team. Following participant recruitment, the site study 
team member will enter participant information into the eDCF and receive from 
the randomization system a study ID # and treatment assignment.  In the rare 
case of eDCF malfunction, manual randomization will occur. Random 
assignment will be determined by a coin-flip method performed by the ProACT 
medical monitor and treatment assignment and subject ID# will be communicated 
to the ProACT coordinating center data team and site study team. All pre-
randomization data will then be sent to the ProACT coordinating center study 
team to be entered into the eDCF.   
 
 
 
d. BLINDING 
Due to the nature of the intervention, neither the treating clinician nor the study 
staff can be blinded to allocation in the ED. ProACT coordinating center research 
staff conducting post-discharge follow up will be blinded to allocation.              
 
 
 
ii. DATA COLLECTION, MANAGEMENT, AND ANALYSIS 
 
 
 
a. DATA COLLECTION METHODS 
Information will be obtained by direct observation, from chart review, and from 
participant and/or family interview by the site study team member.  In the ProACT 
trial, all data collected will subsequently be entered electronically into the eDCF. 
Original study forms (source documents) will be kept on file at the local study 
site.  A subset may be requested later for data monitoring and quality control.  
When this occurs, the participating site staff will pull the requested source 
documents, copy and send securely to the ProACT Coordinating Center for 
review.  All data will be kept for a minimum of five years following the close of the 
study. 
Once a participant is enrolled, the study site and ProACT coordinating center 
long term follow up team will make every reasonable effort to follow the 
participant for the entire study period.  It is projected that the rate of lost-to follow-
up on an annual basis will be approximately 10%. The ProACT coordinating 
center has developed and will implement local standard operating procedures to 
achieve this level of follow-up.   

 
 
17 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
 
b. DATA MANAGEMENT 
Data management will be coordinated by the CRISMA Center at the University of 
Pittsburgh.  The data management system will be based on a PC platform, using 
a relational database server (SQL Server software) and Microsoft .NET 
framework. Enrollment and randomization data will be handled by a web-based 
system that uses Microsoft’s .NET web application. A complete backup of the 
server data is performed every day.  SSL certification ensures encryption of data 
between site and the web server.  All participant data will by entered by the site 
ProACT study staff into the secure web-based data entry system and uploaded 
to the study database server via secure internet connection.  Laboratory data will 
be maintained in a separate, secure location within the CRISMA Center at the 
University of Pittsburgh, with access limited only to laboratory personnel.  Any 
identifying data will be maintained separately from clinical, laboratory and follow-
up data for added security and confidentiality.   
 
c. STATISTICAL METHODS 
 
 
 
Primary analysis 
The primary analysis is an intent-to-treat (ITT) analysis that includes two interim 
analyses at 1/3 and 2/3 enrollment, and a final analysis using Lan-DeMets 
stopping rules. ITT generally biases towards no difference. We therefore will also 
perform per-protocol analyses where the guideline was followed.65 The primary 
test for H1o tests the null hypothesis of no difference between intervention and 
control for antibiotic exposure (superiority). The primary test for H2o tests the null 
hypothesis of a significant difference between intervention and control for a 
combined endpoint of adverse events (non-inferiority).  
As we have two primary outcomes, our overall approach during the interim 
monitoring of the trial is to test H1 at the first interim. Should the null hypothesis 
for H1 be rejected at the first interim, then H2 will be tested and the decision to 
continue the trial would be based on this result.  Should a second interim 
analysis be needed, then H2 would be assessed at this interim and decisions for 
continuation would be based on H2.  In the event that H1 is not rejected at the 
first interim analysis, the study will proceed with no test of H2.  At the second 
interim analysis, H1 will again be tested and if rejected, then H2 will be tested 
and the continuation decision will be based on this results.  If H1 is not rejected 
at the second interim, then H2 will not be tested until the final analysis.  We 
believe the most likely scenario is H1 testing will cross the pre-specified 
boundary at 1st or 2nd interim analysis, but that H2 testing will not meet non-
inferiority until the full sample size is enrolled. 
Each individual adverse event of the combined endpoint will also be reported to 
the DSMB, which can stop the trial for a priori statistical tests for efficacy, futility, 
harm, and as per their judgment. The final analysis will consist of: i.) descriptive 
analyses, ii.) the primary tests of the study hypotheses, and iii.) modeling to 
examine whether confounding factors impact estimates of treatment effect and 
safety. Assessment of randomization quality will consist of an examination of 
potential differences between arms for baseline variables. Chi-square tests will 
be used for categorical measures (race, employment status) and t-tests and/or 
Wilcoxon tests for continuous measures (Charlson score, PSI).  

 
 
18 
ProACT protocol 
Version 1.4;  March 8, 2017 
We will explore main effects models and interaction terms by stepwise fitting a 
series of models. We will retain model(s) with best fit to generate an estimate of 
treatment effect. Fit will be determined by model parsimony and goodness-of-fit 
tests, such as the Hosmer-Lemeshow test for logistic regression and the R2 
measure for linear regression. We will also examine regression diagnostics for 
influential observations and as a second assessment of model fit. For subgroup 
analyses we will use the same methods used for the primary hypotheses, 
including descriptive analyses, regression, and modeling. We anticipate sufficient 
female, African-American, and Hispanic/Latino enrollment to be able to perform 
meaningful a priori analyses in these subgroups. Other a priori subgroup 
analyses include analysis of each LRTI sub-type. We will also fit mixed models 
with center as a random effect to explore potential center effects. 
 
Handling threats to the accuracy of estimated treatment effects 
While many of the proposed analyses are standard for trials, potential threats 
include missing data, handling of participant’s data for individuals who withdraw 
from study, and incorrect randomization. We expect incorrect randomization to 
be very rare. Missing data, from either incomplete data entry or participant 
withdrawal, present a greater challenge. We will minimize missingness by 
creating a concise Web-based data collection form, incorporating extensive logic 
checks to prevent erroneous entry, auto-prompts for missingness, and close site 
coordination. We will apply methods for missingness analyses based on 
weighted estimating equations66, multiple imputation using methods proposed by 
Rubin and Schneker, and/or pattern mixture models.67 We have expertise in this 
area68, including development of the necessary software. 
Potential outcomes of proposed approach  
We anticipate demonstrating an evidence-based implementation strategy of a 
procalcitonin guideline will reduce antibiotic exposure (accept H1), without 
compromising safety (accept H2). These findings should prompt hospitals 
nationwide to incorporate procalcitonin, and we would make available the 
implementation techniques we found most effective. Notably, the patent on the 
Kryptor procalcitonin assay expires in 2014, which should lead to reduction in 
cost (~$15 in Switzerland). We also have considered other outcomes: 
Antibiotic exposure is not reduced. Taking this finding in isolation, we would 
not recommend procalcitonin guideline implementation. However, if this finding is 
due to lower control arm antibiotic use relative to common clinical practice, we 
would conclude hospitals could choose either procalcitonin guideline 
implementation or compliance with current guidelines to reduce antibiotic use. 
Antibiotic exposure is reduced, but safety worsens. Under this situation, we 
would not recommend widespread procalcitonin guideline implementation, but 
would analyze our composite adverse outcome results to determine if select 
adverse outcomes drive the overall finding, and if these outcomes occur 
predominantly in certain patient subgroups (e.g., elderly patients or those 
presenting with high PSI scores). 
 

 
 
19 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
iii. MONITORING 
 
 
 
a. DATA MONITORING 
The ProACT Data Safety and Monitoring Board (DSMB), chosen by the funding 
source, the National Institute of General Medical Sciences (NIGMS), will provide 
a multidisciplinary, independent review of the study design, ethical and scientific 
conduct of the study, monitor interim results and make recommendations with 
respect to continuation, modification, and termination of the study.  Each 
individual is an experienced academician and together will provide clinical, 
research, and statistical expertise. The DSMB will meet at two planned interim 
analyses for safety, at completion, and at any other needed interval. 
 
 
 
 
 
b. HARMS 
Event reporting 
We will capture the major potential adverse events related to antibiotic 
withholding in our combined primary safety outcome.  With this in mind, the 
adverse outcomes that comprise the primary safety outcome will be 
included in outcome reporting, and will not be reported a second time as 
AEs or SAEs.     
However, as with any experimental procedure, there may be adverse events that 
are currently unknown and certain of these unknown risks could be permanent, 
severe, or life threatening. 
Monitoring of adverse events (AEs) is critical to the participant’s safety and data 
integrity.  An adverse event will be defined as any untoward medical occurrence 
(unfavorable and unintended sign, symptoms, or disease) in a participant 
temporarily associated with the study intervention or other aspects of study 
participation, but not necessarily considered related to the participant’s 
participation in the research study.  An untoward medical occurrence that: (1) 
results in death, (2) is life-threatening, (3) requires hospitalization or prolongation 
of existing hospitalization, or (4) results in disability/incapability will be defined as 
a serious adverse event (SAE).   
All adverse events (AEs and SAEs) occurring after study enrollment until the 
study day 30 follow-up visit will be recorded.   
AEs and SAEs will be recorded when reported by the participant, attending 
physician or site SC or PI, or when documented in the medical record.   When a 
reportable SAE occurs, it will be the site PI’s responsibility to review the pertinent 
records, notes, laboratory and radiographic data.  This information will be 
recorded on the eDCF along with the site PI’s impression of the diagnosis.  The 
site PI will assess causality between the event and the study interventions using 
their best clinical judgment.  Notification of coordinating center regarding any 
AE that is serious, unexpected and related (possibly, probably or definitely 
related) to the study intervention will take place within 48 h of recognition 
(expedited reporting); in addition, a copy of all documents submitted to the site 
IRB will be sent to the coordinating center. 

 
 
20 
ProACT protocol 
Version 1.4;  March 8, 2017 
A reportable AE or SAE that also meets ALL of the following criteria is also 
required to be reported as an Unanticipated Problem (UAP) Involving Risk to 
Human Subjects or Others as per local site IRB reporting procedures: 
1.    unexpected in terms of nature, severity, or frequency; 
2.    related, or possibly related, to a participant’s participation in the 
research; 
3.    places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) that was 
previously known or recognized.  
 
 
“Other” Unanticipated Problems (UAPs) Involving Risk to Subjects or Others 
As per local study site IRB reporting procedures, this category includes all other 
incidents not previously included in the above AE reporting section and can 
include protocol deviations, non-compliance, or other unanticipated problems 
that place subjects at risk of harm.   
This includes any accident, experience, or outcome that meets ALL of the 
following criteria: 
1.    Unexpected in terms of nature, severity, or frequency; 
2.    Related, or possibly related, to a participant’s participation in research; 
3.    Places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
 
Incidents falling into this category that require reporting to the ProACT 
Coordinating Center include: 
        Enrollment of a participant that did NOT meet inclusion or met   
           exclusion criteria 
        Incomplete or lack of participant written consent 
        Breach of confidentiality  
        Incomplete data collection 
 
Non-Compliance 
Protocol deviations and incidents of non-compliance, which do NOT involve risk 
to participants or others must be reported as “Non-compliance” as per local site 
IRB reporting procedures.  
Protocol deviations that require reporting to ProACT Coordinating Center by the 
local study site via eDCF documentation: 
     Deviating from the protocol without risk to the participant  
     Obtaining consent using an outdated consent form with no other 
substantive difference other than the date 
 
Please Note: 

 
 
21 
ProACT protocol 
Version 1.4;  March 8, 2017 
    Incidents of non-compliance on the part of the research participant which 
do not involve risk do NOT need to be reported to the ProACT 
coordinating center.  
 
Notification of DSMB  
The ProACT coordinating center will be responsible for notifying the DSMB 
regarding all event reporting. The ProACT coordinating center will notify the 
DSMB and the University of Pittsburgh IRB within 48 hours of their knowledge of 
all AEs that are categorized as serious, unexpected and related.   
All other reportable events and will be recorded on the DCF, entered into the 
database and reported to the DSMB in routine reports. The DSMB will request 
any follow-up information they feel is necessary and will recommend 
modifications to the study protocol or consent as necessary. 
 
 
 
c. INTERVENTION ADHERENCE  
To improve intervention adherence, we will focus site start-up and education 
efforts on the key logistics steps required to accomplish the intervention. We will 
regularly monitor time to procalcitonin reporting (e.g., time to blood draw, lab 
receipt, assay time, assay completion to reporting) and receipt by clinicians 
(coordinators will document information receipt).  
 
We will also conduct basic in-servicing to raise clinician awareness of the study 
and the procalcitonin algorithm. Our primary in-servicing message will be “Please 
look at the procalcitonin value and algorithm recommendation – the final 
antibiotic decision is entirely yours.”  
 
d. AUDITING 
We will conduct ProACT in compliance with all federal regulatory requirements, 
ensuring compliance. Site monitoring will consist of internal monitoring of the 
research database and external/on-site monitoring of source documents. Internal 
monitoring will consist of missingness checks for completeness and chronology, 
logic checks for accuracy, and trend analysis to identify problem areas. External 
monitoring will consist of site visits to evaluate human subject protections and 
source documents. Monitoring will be done by the ProACT project management 
team. The first site visit will occur after initial enrollment to verify consent 
procedures, participant eligibility, reported data, and IRB compliance. If a 
problem is identified during the visit (i.e. poor communication with the ProACT 
coordinating center, inadequate or insufficient staff to conduct the study, missing 
study documents) the monitor will assist the site in resolving the issues. Data 
verification for primary outcomes will be a priority during monitoring visits. A 
follow-up site visit will be conducted if a site is found to have continued and/or 
excessive issues. We will conduct regular site audits to determine reasons for 
study intervention non-adherence and procalcitonin algorithm non-adherence 
(e.g., patient condition worsening). 
3.  ETHICS AND DISSEMINATION 
 
A.  RESEARCH ETHICS APPROVAL 
This protocol, site-specific informed consent forms, participant education and recruitment 
materials, and other requested documents – and any subsequent modifications – will be reviewed 

 
 
22 
ProACT protocol 
Version 1.4;  March 8, 2017 
and approved by the study site ethical review bodies with respect to scientific content and 
compliance with applicable research and human subjects regulation.  Subsequent to initial review 
and approval, the responsible local IRB will review the protocol at least annually.  The site 
investigator will be responsible to make local safety and progress reports to the IRB at least 
annually.  The ProACT Coordinating Center will provide each site with summaries of all ProACT 
data safety and monitoring board (DSMB) reports as well as annual ProACT study progress 
reports.   
 
B.  PROTOCOL AMENDMENTS 
Any modifications to the protocol which may impact the conduct of the study, potential benefit of 
the patient or may affect patient safety, including changes to study objectives, study design, 
patient population, sample sizes, study procedures, or significant administrative aspects, will 
require a formal amendment to the protocol.  Such amendments will be agreed upon by the 
ProACT Coordinating Center research team and will require approval by local site IRB prior to 
implementation.   
 
C.  CONFIDENTIALITY 
All study-related information, including regulatory and source documents, will be stored securely 
at the study site after data is entered electronically into the eDCF.  All participant information will 
be stored in locked areas with limited access.  All laboratory specimens, reports, data collection, 
process, and administrative forms at the local study site will be identified by a coded identification 
number only to maintain confidentiality. Participant data will be entered by the site study team 
member into a secure web-based data entry system and uploaded to the study database server 
via secure internet connection.  PHI (including contact information for participant and 
primary/secondary contact persons) will be collected directly from the research sites via the 
study’s web interface by the ProACT coordinating center’s certified honest broker.  This 
information will be encrypted during transmission and once transmitted it will no longer be 
accessible through the web interface.  The encrypted data will be stored at the ProACT 
Coordinating Center within the project database, which resides on the secure, password 
protected network drive, behind an enterprise firewall.  Permission to access this database is 
restricted to the honest broker. The honest broker will provide necessary PHI and/or related 
contact information to the ProACT Coordinating Center Long Term Follow-Up Core for required 
follow up calls and NDI searches, blinded to study intervention.  All PHI and related contact 
information will be destroyed once long-term follow up survival data is obtained.  No investigator 
or representative/agent of the study sponsor will have access to this protected information.  
 
D.  DECLARATION OF INTERESTS 
The PI (DTH) consulted for BRAHMS Diagnostica in 2006 and 2007, and received one speaking 
honorarium and travel expenses for presentation at a satellite symposium of the September 2006 
European Respiratory Society meeting in Munich, Germany. 
 
E.  ACCESS TO DATA  
In compliance with NIH policy, resources developed through this project will be made readily 
available to investigators and data will be released completely and in a timely manner to facilitate 
use within the broader community. We will work collaboratively after award with the other funded 
sites to prepare a joint dissemination plan. It is our plan to freely allow access to the study data as 
soon as the study is completed and the main manuscripts published.  
Our final study dataset will include de-identified demographic and clinical information, outcome 
data, and procalcitonin values. Protected health information or patient identifiers will not be part of 
any dataset. The recommended data documentation elements will be provided in accordance 
with NIH policy on sharing and releasing data. We will employ methods and procedures for 
sharing data that have been developed and utilized successfully with previous projects within our 

 
 
23 
ProACT protocol 
Version 1.4;  March 8, 2017 
research group. For example, we create a Data Use and Publications Request Form for our large 
federally funded projects. This form will be posted on the project website and, once a request is 
approved, data will be shared with the requestor. Once the data are scrutinized for errors and 
validated, the data team will generate appropriate datasets in response to the specific needs of 
the proposed analysis. Documentation elements necessary to utilize the study data (e.g., data 
dictionary, study operating procedures) will also be shared via the project website. The website 
will be password-protected with access provided only to those who have received approval of 
their data request. 
F.  ANCILLARY AND POST-TRIAL CARE 
Emergency medical treatment for injuries solely and directly related to the participation in the 
ProACT trial will be provided by the local study site.  Costs associated with this care will be directed 
and managed as outlined by each the local study site regulations.  If research-related injury requires 
medical care beyond this emergency treatment, the participant will be responsible for the costs of 
this follow-up care. At this time, there is no plan for any additional financial compensation. 
G.  DISSEMINATION POLICY 
We will publish study results in a PubMed referenced journal, regardless of study findings (i.e., 
whether a “positive” or “negative” trial), and will not use professional writers.  
All core, currently planned manuscripts will be drafted and submitted by the ProACT Publication 
Committee, led by the Principal Investigator from the University of Pittsburgh ProACT 
Coordinating Center. The Publication Committee will invite ProACT site collaborators with 
satisfactory enrollment, protocol adherence, and data quality to participate on the writing 
committee for each planned manuscript. The preferred authorship of core manuscripts is “The 
ProACT Investigators,” with the Publication Committee noted and available from electronic 
searches.  
We will post the protocol outline on ClinicalTrials.gov and plan to publish a trial methodology, 
manuscript and our statistical analysis plan. We will provide public access to data as noted above 
under the above section “Access to Data.” 
H. COSTS AND PAYMENTS 
There will be no additional costs to participants as part of this study.  The study sponsor, the 
National Institute of General Medical Sciences (NIGMS) is providing core funding for the trial.  
BioMerieux will be providing clinical lab procalcitonin equipment and training. Participants and 
their insurers or third party payers will not be billed for research related services.  All research 
related services (central laboratory supplies/services) will be paid for by the study sponsor.   
Participants and their insurers and third party payers will be billed for routine care services, or 
services not connected with the study.  These routine care services include services provided 
during this hospitalization and any ongoing services or medications required after leaving the 
hospital.  Participants will be responsible for any applicable copays, coinsurances, and 
deductibles. 
Research participants will receive a $50 debit card after completing both phone visits (Day 15 and 
Day 30).  
 
 
 
 

 
 
24 
ProACT protocol 
Version 1.4;  March 8, 2017 
References 
 
 
(1)  Meisner M. Biomarkers of sepsis: clinically useful? Curr Opin Crit Care 2005;11:473-480. 
 
(2)  Schuetz P, Christ-Crain M, Muller B. Procalcitonin and other biomarkers to improve assessment 
and antibiotic stewardship in infections--hope for hype? Swiss Med Wkly 2009;139:318-326. 
 
(3)  Muller B, White JC, Nylen ES, Snider RH, Becker KL, Habener JF. Ubiquitous expression of the 
calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 2001;86:396-
404. 
 
(4)  Nylen E, Muller B, Becker KL, Snider R. The future diagnostic role of procalcitonin levels: the 
need for improved sensitivity. Clin Infect Dis 2003;36:823-824. 
 
(5)  Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for 
sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. 
Crit Care Med 2006;34:1996-2003. 
 
(6)  Jones AE, Fiechtl JF, Brown MD, Ballew JJ, Kline JA. Procalcitonin test in the diagnosis of 
bacteremia: a meta-analysis. Ann Emerg Med 2007;50:34-41. 
 
(7)  Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive 
protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect 
Dis 2004;39:206-217. 
 
(8)  Stolz D, Christ-Crain M, Gencay MM et al. Diagnostic value of signs, symptoms and laboratory 
values in lower respiratory tract infection. Swiss Med Wkly 2006;136:434-440. 
 
(9)  Hirakata Y, Yanagihara K, Kurihara S et al. Comparison of usefulness of plasma procalcitonin 
and C-reactive protein measurements for estimation of severity in adults with community-acquired 
pneumonia. Diagn Microbiol Infect Dis 2008;61:170-174. 
 (10)  Prieto B, Llorente E, Gonzalez-Pinto I, Alvarez FV. Plasma procalcitonin measured by time-
resolved amplified cryptate emission (TRACE) in liver transplant patients. A prognosis marker of 
early infectious and non-infectious postoperative complications. Clin Chem Lab Med 2008. 
 (11)  Prat C, Sancho JM, Dominguez J et al. Evaluation of procalcitonin, neopterin, C-reactive protein, 
IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. Leuk 
Lymphoma 2008;49:1752-1761. 
 (12)  Charles PE, Kus E, Aho S et al. Serum procalcitonin for the early recognition of nosocomial 
infection in the critically ill patients: a preliminary report. BMC Infect Dis 2009;9:49. 
 (13)  Huang DT, Weissfeld LA, Kellum JA et al. Risk Prediction With Procalcitonin and Clinical Rules in 
Community-Acquired Pneumonia. Ann Emerg Med 2008. 
 (14)  Muller B, Harbarth S, Stolz D et al. Diagnostic and prognostic accuracy of clinical and laboratory 
parameters in community-acquired pneumonia. BMC Infect Dis 2007;7:10. 

 
 
25 
ProACT protocol 
Version 1.4;  March 8, 2017 
 (15)  Cuquemelle E, Soulis F, Villers D et al. Can procalcitonin help identify associated bacterial 
infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med 
2011;37:796-800. 
 (16)  Schappert SM, Rechtsteiner EA. Ambulatory Medical Care Utilization Estimates for 2007. Series 
13, Number 169. 2011.  Center for Disease Control and Prevention, National Center for Health 
Statistics. Vital and Health Statistics.  
 (17)  Christ-Crain M, Jaccard-Stolz D, Bingisser R et al. Effect of procalcitonin-guided treatment on 
antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded 
intervention trial. Lancet 2004;363:600-607. 
 (18)  Stolz D, Christ-Crain M, Bingisser R et al. Antibiotic treatment of exacerbations of COPD: a 
randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 
2007;131:9-19. 
 (19)  Schuetz P, Christ-Crain M, Thomann R et al. Effect of procalcitonin-based guidelines vs standard 
guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized 
controlled trial. JAMA 2009;302:1059-1066. 
 (20)  Long W, Deng X, Zhang Y, Lu G, Xie J, Tang J. Procalcitonin-guidance for reduction of antibiotic 
use in low-risk outpatients with community acquired pneumonia. Respirology 2011. 
 (21)  Fine MJ, Auble TE, Yealy DM et al. A prediction rule to identify low-risk patients with community-
acquired pneumonia. N Engl J Med 1997;336:243-250. 
 (22)  Lindenauer PK, Pekow PS, Lahti MC, Lee Y, Benjamin EM, Rothberg MB. Association of 
corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation 
of chronic obstructive pulmonary disease. JAMA 2010;303:2359-2367. 
 (23)  Gotzsche PC. Lessons from and cautions about noninferiority and equivalence randomized trials. 
JAMA 2006;295:1172-1174. 
 (24)  Rotnitzky A, Robins J. Analysis of semi-parametric regression models with non-ignorable non-
response. Stat Med 1997;16:81-102. 
 (25)  Little RJ, Wang Y. Pattern-mixture models for multivariate incomplete data with covariates. 
Biometrics 1996;52:98-111. 
 (26)  Shen C, Weissfeld L. Application of pattern-mixture models to outcomes that are potentially 
missing not at random using pseudo maximum likelihood estimation. Biostatistics 2005;6:333-
347. 
 
 
 
 
 

 
 
26 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 1:  ProACT Informed Consent Form Template 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
 
Title: Procalcitonin Antibiotic Consensus Trial (ProACT) 
 
PRINCIPAL INVESTIGATOR:  
 
 
Sub-Investigator:  
 
 
 
 
Study Sponsor:  
 
 
National Institutes of Health 
 
 
INTRODUCTION 
You are being asked to consider participating in this research study because you have been 
diagnosed with a lung infection. 
 
There are two main types of germs that cause infections: bacteria and viruses. Most lung 
infections are caused by viruses. Antibiotics kill bacteria, but not viruses. Taking antibiotics for 
virus infections is harmful; patients can experience side effects, and unnecessary antibiotics 
make bacteria harder to kill in the long run. 
 
A new FDA (Food and Drug Administration) approved blood test called “procalcitonin” can help 
determine if your lung infection is caused by a bacteria or a virus. Procalcitonin levels are 
typically high with bacterial infection, and low with viral infection. 
 
In this consent form, “you” always refers to the subject.  If you are a Legally Authorized 
Representative (LAR), please remember that “you” refers to the study subject. 
 
PURPOSE OF THE STUDY 
This research study will test if a guideline using this new blood test can help doctors make 
better antibiotic decisions. The guideline recommends taking antibiotics if your procalcitonin 
level is high and no antibiotics if your procalcitonin level is low. Because this is just a 
guideline, the final decision on antibiotic use is entirely up to your treating doctors.  
 
 
DESCRIPTION OF THE RESEARCH 
A total of 1674 men and women 18 years old and older will be enrolled at approximately 14 
different study sites across the US. You will be expected to participate in the study for 30 days.  
At SITE, 150 subjects will be enrolled in this research study. 
 
STUDY PROCEDURES 
If you decide to take part in this study, the following will occur in addition to your standard 
medical care: 
 
▪ 
You will be assigned by 50:50 chance (like a coin flip) to the “procalcitonin” group or the 
“usual care” group.  
 

 
 
27 
ProACT protocol 
Version 1.4;  March 8, 2017 
For the procalcitonin group – to check your procalcitonin level, you will have 1 
teaspoon (5mL) of blood drawn, and this lab result and the procalcitonin 
guideline will be provided to your doctors, who will take into account this 
information when deciding your plan of care. Your procalcitonin level will be 
checked once in the Emergency Department (ED), and if you are hospitalized, 
we will withdraw 1 additional teaspoon of blood at 4 timepoints (6-24 hours later, 
on Days 3, 5 and 7) to check procalcitonin level again during your hospital stay.  
Additionally, we will collect and store a 20mL blood sample (4 teaspoons) in the 
Emergency Department for storage and future analysis. 
Upon discharge from the ED or hospital, you will receive a ProACT information 
packet, which includes a letter to your primary care physician explaining your 
participation in this research study, a study instructional letter for your reference 
and a 30 day antibiotic use calendar.  The completion of this calendar is not 
mandatory, but will assist you in tracking your antibiotic use.   
 
For the usual care group – doctors will treat you according to their standard 
treatment plan and without any influence from the study team. We will collect 
and store a 20mL blood sample (4 teaspoons) in the Emergency Department for 
storage and future analysis. Upon discharge from the ED or hospital, you will 
receive a ProACT information packet, which includes a study instructional letter 
for your reference and a 30 day antibiotic use calendar.  The completion of this 
calendar is not mandatory, but will assist you in tracking your antibiotic use.  
 
▪ 
In both groups, the blood sample obtained in ED for future analysis (20 mL) will be stored in 
the CRISMA Molecular Core Lab at the University of Pittsburgh for potential inclusion in 
future research studies. As part of the study, your blood sample will be stored indefinitely. 
The sample may be tested for molecules related to procalcitonin, infection and outcome, 
differences in genes, and/or other types of research purposes.  Personal identifiers such as 
name, address, Medical Record Number, etc. will be removed before they are sent to be 
stored. 
 
▪ 
In both groups, we will check your progress by reviewing your hospital records until you are 
discharged from the hospital or hospital day 30, whichever comes first.  We will also obtain 
your hospital records for any re-hospitalization you may have during the first 30 days after 
enrolling in this study; this includes obtaining hospital records from a hospitalization not 
occurring at SITE.   
 
▪ 
In both groups, we will contact you approximately 2 and 4 weeks from now for a brief 
interview (5-10 minutes) to find out about your antibiotic use, medical care you have 
received since your ED visit, and ask you questions specific to your current respiratory 
status. If you are hospitalized at either time point, the telephone interview will not occur. The 
telephone interview will not occur if you are still in the hospital. Contact information will also 
be collected for you and 2 family members and/or friends (name, address and telephone 
number). We will reach your contact member in case we are unable to locate you after your 
discharge from hospital for the telephone interview.  We may also send you a letter with a 
toll free number that you can use to call us to complete your interviews. 
 
▪ 
Your direct participation in the study is complete after the interview at 4 weeks, but after that 
we will collect survival status information at Day 90 and 1 year post study enrollment on you 
through the NCHC/NDI (National Center for Health Statistics/National Death Index).  

 
 
28 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
POTENTIAL RISKS AND DISCOMFORTS 
 
Procalcitonin Guideline: The risks are minimal. Your doctors may be influenced by the 
guideline, but they are not required to follow it. Your doctors will use their best clinical judgment 
in determining your care, just as they would without the guideline.  
 
Blood Sampling: You may experience some temporary discomfort, bruising and pain at the 
blood draw site. These risks will be reduced by making every attempt to use blood that has 
already been drawn, or to collect this sample when you are having other blood drawn. 
 
Breach of Confidentiality: It is possible that someone could find out you were in this study and 
could find out information about you. Every effort will be made to prevent this from happening. 
To protect your confidentiality, we will remove your name and other personal identifiers from the 
samples and from the medical record information we obtain.  This information will be identified 
by a code and sent to a research laboratory at the University of Pittsburgh, where it will be 
stored indefinitely.   
 
Genetic information from your stored blood samples may be used for research in the 
future.  Any information gathered will be stripped of personal identifiers (such as name, address, 
Medical Record Number, etc.).  It is possible that someone could figure out who you are from 
this information, even without the personal identifiers.  This re-identified genetic information 
could potentially be used against you, your family, or other groups.  We will safeguard this 
information using multiple widely accepted standard practices.  You may withdraw consent for 
research use of genetic information at any time without penalty or loss of benefit.  However, 
please be advised that any information already distributed for research use will not be retrieved  
 
 
ANTICIPATED BENEFITS TO SUBJECTS 
You may receive no direct benefit from taking part in this research study. If you are in the 
procalcitonin group, your doctors may use your procalcitonin results to avoid prescribing an 
antibiotic when your lung infection is likely caused by a virus. It is also possible that study 
findings will help future patients with lung infections.  
 
COSTS AND PAYMENTS  
After both interviews are completed (at 2 weeks and 4 weeks), you will be sent a $50 debit card 
to compensate you for your time. 
 
You and your insurer will not be billed for research-related services; services related solely to 
the research will be paid for by the sponsor. You or your insurer will be billed for all other usual 
care services and/or services not connected with the study, just as you would if not in the study.  
 
If you decide to not participate in this study, your doctors will continue to treat you according to 
their usual treatment plan.  
 
USE AND DISCLOSURE OF PROTECTED HEALTH INFORMATION 
As part of this study, we are also requesting your authorization or permission to review your 
medical records to obtain past, current, and future medical information from hospital and other 

 
 
29 
ProACT protocol 
Version 1.4;  March 8, 2017 
medical facilities. We will obtain information concerning your diagnosis, age, past medical history, 
diagnostic procedures, and results of any blood tests, including results of genetic tests that were 
already done as part of your standard medical or psychiatric evaluations a SITE.  
 
This identifiable information will be made available to members of the research team for an 
indefinite period of time. That medical information, as well as information obtained during this 
research study, may be shared with other groups, possibly including authorized officials from the 
Food and Drug Administration and from the National Institutes of Health (the agency that is paying 
for this study) and the SITE Research Conduct and Compliance Office, for the purpose of 
monitoring the study.  You should also be aware that as part of this research study, some 
information that we obtain from you may be placed into your medical records held at SITE, 
including the results of medical tests.  Any information that is entered into your medical records 
will be available to you, in accordance with SITE Privacy Practices. A description of this clinical 
trial will be available on www.clinicaltrials.gov, as required by US law. This website will not include 
information that can identify you. At most, the website will include a summary of the results from 
this study, but not your individual results. You can search this website at any time. 
 
MEDICAL CARE FOR RESEARCH RELATED INJURY 
If you think that injury or illness has happened to you from being in the study, contact the Principal 
Investigator listed on the first page of this consent. Emergency medical treatment for injuries 
solely and directly related to your participation in this research study will be provided to you by 
the hospitals of SITE. Your insurance provider may be billed for the costs of this emergency 
treatment, but none of those costs will be charged directly to you. If your research-related injury 
requires medical care beyond this emergency treatment, you will be responsible for the costs of 
this follow-up care. At this time, there is no plan for any additional financial compensation. 
 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Participation is completely voluntary and a decision to participate, or to later withdraw from the 
study, will not affect either your current or future medical care at SITE. If you decide you no 
longer wish to continue to participate after you have signed the consent form, contact the 
principal investigator listed on the first page of this consent document. You have the right to 
request that all information and/or blood samples be destroyed.  
 
 
VOLUNTARY CONSENT 
The study has been described to me and all of my questions have been answered.  Any 
additional questions or concerns about any aspect of this study will be answered by the 
researchers if questions, concerns or complaints arise.  Questions I might have about my rights 
as a research participant will be answered by the Human Subject Protection Advocate at 1-
XXX-XXX-XXXX. By signing this form I consent to participate in this research study and provide 
my authorization to share my medical records with the research team.  A copy of this consent 
form will be given to me. 
 
___________________ 
____________________________ _______________ 
Participant’s Signature 
Printed Name of Participant  
Date and Time 
 
 
SURROGATE CONSENT 
 
______________________ is unable to provide direct consent for study participation    
Participant’s Name (Print) 

 
 
30 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
because:____________________________________________________________ 
 
 
Therefore, by signing this form, I give my consent for his/her participation in this research study. 
 
_________________________ 
 
______________________ 
Representative’s Name (Print)  
 
Relationship to Participant 
  
____________________________  
_______________________ 
Representative’s Signature  
 
Date and Time 
INVESTIGATOR’S CERTIFICATION 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
participation in this research study have been explained to the subject or his/her authorized 
representative and any questions about this information have been answered. 
 
 
__________________________________  
_______________________________ 
Printed Name of Person Obtaining Consent  
Role in Research Study 
 
 
 
__________________________________  
_______________________________ 
Signature of Person Obtaining Consent 
 
Date and Time 
 
CONSENT FOR CONTINUED RESEARCH PARTICIPATION 
 
I understand I am currently participating in a research study. Permission for my participation in 
this study was obtained initially from my authorized representative (proxy) because of my 
inability to provide consent when initial permission was requested.  
 
I have now recovered to the point where I feel that I can provide direct consent for continued 
participation in this research study. 
 
The study has been described to me and all of my questions have been answered. I understand 
that I have the right to request that all information collected to date and/or my blood samples be 
destroyed. 
 
Any additional questions or concerns about any aspect of this study will be answered by the 
researchers. Questions I might have about my rights as a research participant will be answered 
by the Human Subject Protection Advocate at 1-XXX-XXX-XXXX. 
 
By signing below, I agree to continue my participation in this research study. A copy of this 
consent form will be given to me. 
 
__________________________________  
 
________________ 
Participant’s Signature 
 
 
 
 
Date and Time 
 
  
 

 
 
31 
ProACT protocol 
Version 1.4;  March 8, 2017 
INVESTIGATOR’S CERTIFICATION 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
continued participation in this research study have been explained to the subject or his/her 
authorized representative and any questions about this information have been answered. 
 
__________________________________  
_______________________________ 
Printed Name of Person Obtaining Consent  
Role in Research Study 
 
 
__________________________________  
_______________________________ 
Signature of Person Obtaining Consent 
 
Date and Time 

 
 
33 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 3:  Participant Timeline 
 
Pre- 
randomization 
Randomization 
/Allocation 
 
 
In ED/Hospital 
 
 
Post 
Discharge1 
Post-Randomization 
(within 1 hour) 
6-24h 
after 1st 
PCT 
draw 
Days 3, 5 & 7 while 
in ED/Hospital 
Days while in 
ED/Hospital2 
D/C from the 
ED/Hospital 
Day 
153 
Day 
30 4 
ENROLLMENT 
 
 
 
 
 
 
 
 
 
Eligibility screen  
X 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
LRTI Source Document   
X 
 
 
 
 
 
 
 
 
Allocation/Randomization 
 
X 
 
 
 
 
 
 
 
INTERVENTIONS 
 
 
 
 
 
 
 
 
 
Procalcitonin test 
 
 
X5 
X6 
X7 
 
 
 
 
Reporting of Procalcitonin 
 
 
X8 
X8 
X8 
 
 
 
 
Biobank samples 
 
 
X9 
 
 
 
 
 
 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
PHI  
 
 
X 
 
 
 
 
 
 
Sociodemographic information 
 
 
X 
 
 
 
 
 
 
Baseline variables & medical history 
 
 
X 
 
 
 
 
 
 
Diagnostics/Therapeutics/Microbiology/labs 
 
 
X 
 
 
X 
 
 
 
Safety outcomes 
 
 
 
 
 
X 
 
 
 
Antibiotic use  
 
 
X 
 
 
X 
 
 
 
Outcome/Disposition 
 
 
 
 
 
 
X 
 
 
D/C packet 
 
 
 
 
 
 
X10 
 
 
TELEPHONE VISITS 
 
 
 
 
 
 
 
 
 
AQ-20 Questionnaire11 
 
 
 
 
 
 
 
x 
x 
Antibiotic Use 
 
 
 
 
 
 
 
x 
x 
Post D/C information 
 
 
 
 
 
 
 
x 
x 
Debit card sent to patient 
 
 
 
 
 
 
 
 
x 
                                                          
1 A telephone call will be conducted by the ProACT Coordinating Center Long-term Follow-Up Core for Days 15 & 30.  If the participant is still in the hospital for this visit or has been re-admitted to the same hospital, the SC will be responsible for collecting 
medical record data only. 
2 Day 1 is defined as time of enrollment through 11:59p of the same day.  Data collected at this timepoint also includes any rehospitalizations. 
3; Day 15 will be defined as Day 15 (+/- 5 days)   
4 Day 30 will be defined as Day 30 (+7 days) 
5 Participants randomized to the PCT arm only 
6 PCT arm only; attempt to draw 2nd PCT 6-24 hours after initial ED draw 
7 While in hospital for PCT arm only; if on  antibiotics and/or at treating physician’s discretion (days 3, 5 & 7) 
8 In the ED, the clinician will be given the PCT result within < 1 hour (goal) – for PCT arm only 
9 All participants will have samples sent to CRISMA at the University of Pittsburgh for research purposes 
10 The discharge packet will consist of an instructional letter and a 30 day antibiotic use calendar. 
11 The AQ-20 questionnaire is not completed if participant still hospitalized at Day15 or Day 30. 

 
 
34 
ProACT protocol 
Version 1.4;  March 8, 2017 
 

 
 
35 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 4:  ProACT Telephone Interview Script 
 
 
 
ProACT Telephone Interview Script 
 
 
Interviewer: Please complete before start of the interview.  Enter ID number on top of every page.  
Date of ED/Hospital Discharge  
 
 
 
 
2 
0 
 
 
 
Date of last Interview (if applicable) 
 
 
 
 
2 
0 
 
 
 
Date of current interview (MMDDYYYY)  
 
 
 
 
2 
0 
 
  
 
Time Point   Day 15                   Day 30 
 
 
Start time:  _____   _____   :   _____   _____ 
 
Interviewer (After you have filled the information in the box above and have the proper consent in 
hand, start timing and begin.): 
My name is …from the University of Pittsburgh. I want to thank you for agreeing to participate in this 
interview as a part of the ProACT Study. As a reminder, you were enrolled into this study when you went to 
the Emergency Department   at [ENROLLING SITE NAME]. This study is being done to learn if a new lab 
test can help doctors make better decisions about prescribing antibiotics. 
 
The interview will take about 10 minutes to complete and is only for research purposes, does not affect 
your medical care and will not go into your medical record.  When you were discharged you were given a 
ProACT Study folder containing an Antibiotic Biotic Use Calendar.  If you have used the calendar it may be 
helpful for you to refer to it during this interview.  First, I would like to know how you would like to be 
addressed and verify your contact information.   
 
 
 
Respondent  
 Subject                            
 Proxy                                 
  Specify Relationship to Subject _________________                       
Reason for proxy response:  
Subject too sick/physically unable to speak on phone   
Subject has died  
Date of Death(mm/dd/yy):____________ 
Other ______________________________________ 
                                                                                   
 
Subject Study ID Number 
 
 
- 
 
 
 
 
- 
 

 
 
36 
ProACT protocol 
Version 1.4;  March 8, 2017 
Confirm current subject contact information 
Is the following information up to date?  
Refer to Contact Form to confirm street address, email address, and phone numbers. 
 NO CHANGE  
 
Street Address: 
(Only If Changed)  
 
 
City: 
 
State: 
 
 
Zip code: 
 
 
 
 
 
 
 
 
Telephone number 
(Only if Changed)  
 
 
 
-- 
 
 
 
-- 
 
 
 
 
Other number 
(If given another #) 
 
 
 
-- 
 
 
 
-- 
 
 
 
 
Email address 
(Only if Changed) 
 
 
 
 

 
 
37 
ProACT protocol 
Version 1.4;  March 8, 2017 
 SECTION 1: Antibiotic Use 
Interviewer:  I am now going to ask you some questions about your use of antibiotic medications since leaving 
the Emergency Department/ hospital/our last interview on _________________ [date]. Please refer to the 
antibiotic use calendar you were given when you left the hospital if you have been using it to keep track of the 
days you have used antibiotics since leaving the hospital.  As with everything else in the study, all of the 
information is confidential.  
 
 
1.  Since being discharged from the Emergency Department/Hospital/our last interview on [DATE] 
have you taken or are you taking any ANTIBIOTIC Medications? 
  
Yes 
  
  
No 
  
  
Unknown 
  
  
Refused 
  
 
Interviewer: If “no” or “unknown” skip to Section 2 
2. 
Since being discharged from the Emergency Department/Hospital/our last interview on [DATE] 
how many total days have you taken ANY antibiotic medication? 
 
Number 
________ 
 
Unknown   
 
Refused   
 
3. 
[If antibiotics have been used] What is/are the name(s) of the antibiotic medications you have 
taken? 
Name of Medication  
 
 
 
                                   
 
1. ______________________________________________ 
 
 
2. ______________________________________________ 
 
 
3. ______________________________________________ 
 
 
4. ______________________________________________ 
 
 
5. ______________________________________________ 
 
SECTION 2: Post-Discharge Resource Use 
  
4. 
Since being discharged from the Emergency Department/Hospital/our last interview on [DATE] have 
you had any return visits to any Emergency Department or Urgent Care Center? 
  
Yes 
  
  
Type of Return Visit:  
 
  
Emergency Department 
  
  
Urgent Care Center Visit 
  
 
No 
 
 
Unknown 
  
 
Refused  
 

 
 
38 
ProACT protocol 
Version 1.4;  March 8, 2017 
5. 
Since being discharged from the Emergency Department/Hospital/our last interview on  [DATE] 
have you been admitted to any hospital overnight (do not include overnight stays in the ED) 
 
Yes 
  
 
No 
  
 
Unknown 
  
 
Refused 
  
6. 
[If Yes to question 6]: What is the name of the hospital to which you were readmitted? 
 
Enrollment Hospital  
 
 
Name of Hospital if other: ___________________________________________ 
 
 
Date of Readmission (mm/dd/yy) :_________________________________ 
 
 
SECTION 3: AQ-20 Questionnaire 
Interviewer: The following are some questions about how any breathing or chest issues have been affecting 
you since leaving the Emergency Department/hospital/since our last Interview 
1. 
Do you suffer from coughing attacks during the day? 
Yes   
No   
Not Applicable  
 
2. 
Because of your chest trouble do you often feel restless? 
Yes   
No   
Not Applicable  
 
3. 
Because of your chest trouble do you feel breathless maintaining 
the garden? 
Yes   
No   
Not Applicable   
 
4. 
Do you worry when going to a friend’s house that there might be 
something there that will set off an attack of chest trouble? 
 
Yes   
No   
Not Applicable  
 
5. 
Do you suffer from chest symptoms as a result of exposure to 
strong smells, cigarette smoke or perfume? 
 
Yes   
No   
Not Applicable  
 
6. 
Is your partner bothered by your chest trouble? 
Yes   
No   
Not Applicable  
 
7. 
Do you feel breathless while trying to sleep? 
Yes   
No   
Not Applicable  
 
 

 
 
39 
ProACT protocol 
Version 1.4;  March 8, 2017 
8. 
Do you worry about the long term effects on your health of the 
drugs that you have to take because of your chest trouble? 
Yes   
No   
Not Applicable  
 
9. 
Does getting emotionally upset make your chest trouble worse? 
Yes   
No   
Not Applicable  
10. Because of your chest trouble are there times when you have 
difficulty getting around the house? 
Yes   
No   
Not Applicable   
 
11. Because of your chest trouble do you suffer from breathlessness 
carrying out activities at work? 
Yes   
No   
Not Applicable   
 
12. Do you feel breathless walking upstairs because of your chest 
trouble? 
Yes   
No   
Not Applicable  
 
 
13. 
 
Because of your chest trouble do you suffer from breathlessness 
doing housework? 
 
Yes   
No   
Not Applicable  
 
14. Because of your chest trouble do you go home sooner than others 
after a night out? 
Yes   
No   
Not Applicable  
Unknown   
Refused   
 
15. Because of your chest trouble do you suffer from breathlessness 
when you laugh? 
Yes   
No   
Not Applicable  
 
16. Because of your chest trouble do you often feel impatient? 
Yes   
No   
Not Applicable  
  
 
17. Because of your chest trouble do you feel that you cannot enjoy a 
full life? 
Yes   
No   
Not Applicable  
 
18. Do you feel drained after a cold because of your chest trouble? 
Yes   
No   
Not Applicable  
 
19. Do you have a feeling of chest heaviness? 
Yes   
No   
Not Applicable  
 
20. Do you bother much about your chest trouble? 
Yes   

 
 
40 
ProACT protocol 
Version 1.4;  March 8, 2017 
No   
Not Applicable  
 
Section 4: Interview Burden 
I have one final question for you.  We would like to know whether this interview was difficult, inconvenient, or 
was a problem for people to complete. 
 
1. BURDEN OF INTERVIEW.  Would you say that this interview was…? 
  
No problem 
 1 
  
A small problem 
 2 
  
A moderate problem 
 3 
 
 
A major problem 
 4 
 
INTERVIEWER: [For subjects who will have a subsequent Interview]: That completes the interview for today. 
In order to complete this study, we would like to speak with you one more time and repeat the same questions 
as were asked today.  We would like to schedule this interview with you in approximately 2 weeks, any day  
 
After [DAY 30 date].  What day and time would you like to set up our next phone appointment to complete this 
interview? [Interviewer: Attempt to schedule M-F 8:00 am to 4:00 pm Eastern time]. As a reminder, you will 
receive $50 as compensation for your time after the second interview is completed.  
 
Next Interview Date/Time; ______________________________ 
Thank you very much for your participation today and I look forward to speaking with you again on [next 
interview date/time]. If you have any questions or would like to change your interview time, please call me toll-
free at 888-238-0365. 
[If second interview completed]Thank you very much for your participation today. To compensate you for your 
time, we’d like to send you out a MasterCard brand debit card loaded with the amount of $50. [.  In order to 
activate the card, I just need to collect some information from you. [Interviewer: fill out WePay Information 
Form]. Thank you again for your participation, and please feel free to give me a call if you have any questions.  
My toll-free phone number is 1-888-238-0365.   
 
INTERVIEWER (do this AFTER THE END of the interview; this is not part of the script): Please 
describe your impressions of the attitude and cooperation of the respondent as well as any unusual 
circumstances that might have occurred during the interview.  
 
 
 
 
 
END TIME:  
 
 
 
 
 
 

 
 
41 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 5:  Sample Discharge Letter to PCP 
 
Primary care physician letter for ProACT participants randomized to the intervention arm 
 
Dear Site Coordinators, 
 
Please complete the yellow highlighted areas and provide this text on your site’s letterhead to the patient when 
discharged. 
 
____________________________________________________________________________ 
 
(Print on Site hospital / university letterhead) 
 
 
 
Insert Date 
  
Dear Colleague, 
  
Your patient, _______________, agreed to become a participant in a NIH funded randomized trial designed to 
determine the effectiveness and safety of implementing a procalcitonin-guided guideline on antibiotic use in 
lower respiratory tract infection (ProACT – Procalcitonin Antibiotic Consensus Trial). 
  
Your patient was enrolled in the intervention arm, which allowed the hospital clinicians to know serum 
procalcitonin results and view recommendations encapsulated in the below guideline. The treating clinicians 
could choose any treatment they saw fit after receiving this information. 
  
 
 
 
 
 
 
 
 
 
1. Initial antibiotics can be considered for critical illness, Legionella pneumophilia. Procalcitonin should be evaluated in 
context with all findings and the total clinical status; clinical judgment always necessary. 
 
2. For outpatients, antibiotic duration based on level (> 0.25-0.5 ug/L:3 days; > 0.5-1.0 ug/L:5 days; >1.0 ug/L:7 days). 
Physician follow-up is recommended. 
  
Your patient’s last procalcitonin result, on ____DATE_____, was ______ ug/mL. 
  
Sincerely, 
  
INSERT SITE PI NAME + CONTACT INFO 
Procalcitonin level 
(g/L) 
Bacterial etiology 
Recommendation 
< 0.1 
Very unlikely 
Antibiotics strongly discouraged1 
0.1 - 0.25 
Unlikely 
Antibiotics discouraged1 
> 0.25 - 0.5 
Likely 
Antibiotics recommended2 
> 0.5 
Very likely 
Antibiotics strongly recommended2 

 
 
42 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 6: Discharge Letter to Participant 
 
  
 
 
ProACT Team 
Principal Investigator  
David T. Huang, MD, MPH 
Associate Professor, Critical Care 
Medicine, Emergency Medicine, 
Clinical and Translational Science 
Director, Multidisciplinary Acute 
Care Research Organization 
(MACRO) 
University of Pittsburgh School of 
Medicine 
606B Scaife Hall 
3550 Terrace Street 
University of Pittsburgh 
Pittsburgh, PA 15261, USA 
Tel: 412 647-6818 (office) 
 
Project Manager  
Elizabeth Gimbel, B.S.  
CRISMA Center   
University of Pittsburgh 
Department of Critical Care 
Medicine  
605 Scaife Hall 
3550 Terrace St. 
Pittsburgh, PA 15261 
Tel: 412-647-7776 
Email: gimbele@upmc.edu  
 
Project Manager  
Ashley Ryman, BS, BA 
CRISMA Center 
University of Pittsburgh 
Department of Critical Care 
Medicine 
605 Scaife Hall 
3550 Terrace Street 
Pittsburgh, PA  15261 
Tel: 412-864-5507 
 
Dear Study Participant,  
Thank you for giving your consent to take part in this research study for the University 
of Pittsburgh.  The title of this study is ProACT-Procalcitonin Antibiotic Consensus 
Trial.  The goal of the study is to examine the decisions that doctors are making 
regarding prescribing antibiotics.  A member of the follow up team will be calling you 
up to two times within 30 days of your visit to the hospital.  During these phone calls 
we will be asking you about your antibiotic use and your health.  The calendar that we 
have included in your discharge folder will be a helpful tool for you to keep track of the 
days you took an antibiotic. After you have completed both of your follow up phone 
calls we will be sending you a debit MasterCard in the amount of $50.00 to compensate 
you for your participation.  Please feel free to contact me should you have any 
questions.  
Sincerely, 
Kourtney Wofford  
Project Coordinator 
(412) 647-2584 
 
 
 
 
 
Procalcitonin Antibiotic Consensus Trial  

 
 
43 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
Email: rymanam@upmc.edu  
 
 
 
Project Coordinator 
Kourtney Wofford 
CRISMA Center  
University of Pittsburgh  
Department of Critical Care 
Medicine  
609 Scaife Hall  
3550 Terrace St. 
Pittsburgh, PA 15261 
Tel: 412-647-2584  
Email: woffordka@upmc.edu  
 
 
 
 
 

 
 
44 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 7:  30 Day Antibiotic Use Calendar 
 
 
 
ProACT Study Antibiotic Use Tracker 
Instructions: For each day on your Antibiotic Use Tracker, please record if you have taken any antibiotics on this day by marking “yes” or “no”.  You will be asked about the 
number of days you have taken antibiotics since leaving the hospital at the time of your scheduled telephone interview appointment.  Begin marking your antibiotic use on the 
day that you leave the hospital. 
Date/Study Day 
 ________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/___ 
Date/Study Day 
_________/___ 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  ___no 
Date/Study Day 
________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/___ 
Date/Study Day 
_________/___ 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  ___no 
Date/Study Day 
________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/___ 
Date/Study Day 
_________/___ 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes ___no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  ___no 
Date/Study Day 
________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/____ 
Date/Study Day 
_________/___ 
Date/Study Day 
_________/___ 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes  __no 
Any Antibiotics? 
___yes ___no 
Any Antibiotics? 
___yes  ___no 
Date/Study Day 
________/____ 
Date/Study Day 
_________/____ 
Any Antibiotics? 
___yes  ___no 
Any Antibiotics? 
___yes  ___no 
ProACT Telephone Interview Appointment date: Mm/dd/yyyy 
Preferred time of day: Morning/Afternoon (circle one) 
Preferred Contact Phone Number: Home/Cell/Work (circle one) 

 
 
45 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 8:  Airway questionnaire 20 (AQ-20) 
 
 

 
 
46 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 9:  Honest Broker Standard Operating Procedures 
 
University of Pittsburgh 
Department of Critical Care 
Medicine 
 
CRISMA Center 
Data Management Core 
Standard Operating Procedures 
 
Honest Broker Services 
 
 
 
 
 
 

 
 
47 
ProACT protocol 
Version 1.4;  March 8, 2017 
Purpose 
This document describes the CRISMA Center’s policies for Honest Broker 
services for ensuring compliance with the Health Insurance Portability and 
Accountability Act (HIPAA) and US Department of Health and Human 
Services Office for Human Research Protections (OHRP) regulations 
regarding human subject data. 
 
Scope 
This document applies to all personnel employed by or using any computer 
owned and operated by CRISMA; all computers owned or operated by 
CRISMA; and all human subject data managed by CRISMA and determined 
by regulatory agencies to require Honest Broker services. 
 
Definitions 
Protected Health Information (PHI). Any information about health status, 
provision of health care or payment of health care that can be linked to a 
specific individual. 
 
HIPAA Privacy Rule. The portion of the Health Insurance Portability and 
Accountability Act of 1996 that governs use and disclosure of PHI. Under 
the privacy rule, PHI can be used for research purposes with either patient 
approval or waiver by an authorized regulatory agency. 
 
Common Rule. US Federal regulations for protection of human subjects in 
research, described by the Department of Health and Human Services in the 
Code of Federal Regulations Title 45 Part 46. 
 
Unique identifiers. Variables defined by HIPAA as uniquely identifying 
individuals, including names; geographical subdivisions smaller than a state 
except the initial three digits of a ZIP code as long as that ZIP code contains 
more than 20,000 people; all elements of dates except year and all ages 
over 89; phone numbers; fax numbers; e-mail address; social security 
numbers; medical record numbers; health plan numbers; account numbers; 
certificate/license numbers; vehicle numbers; web URLs; IP addresses; 
biometric identifiers; full face photos; and any other unique identifying 
numbers. 
 
De-identified data. Health data that does not contain unique identifiers as 
defined by HIPAA. 
 
Limited data set. A de-identified data set that contains either (a) geographic 
subdivisions not smaller than a town, city, state and ZIP code; (b) dates, or 
(c) ages over 89 
 
Safe harbor data set. A de-identified data set that does not contain any of 
the unique identifiers as defined by HIPAA. 
 
Researcher. As defined by the Common Rule, any individual conducting or a 
assisting in the conduct of a systematic investigation designed to develop or 
contribute generalizable knowledge. 
 

 
 
48 
ProACT protocol 
Version 1.4;  March 8, 2017 
Honest Broker. An individual serving as a disinterested intermediary 
between the researcher and PHI, ensuring that the researcher does not 
have access to identifiable information. 
 
Responsibilities 
Research team responsibilities 
Regulatory approval. All CRIMSA research projects involving PHI must be 
reviewed and approved by the University of Pittsburgh Institutional Review 
Board (IRB). CRISMA researchers are responsible for adhering to IRB-
approved data storage and analysis policies at all times, including seeking 
the services of an Honest Broker when required. 
 
Data security. CRISMA researchers or agents working with CRISMA data 
must maintain appropriate electronic and physical data security procedures 
at all times. Electronic security procedures include developing secure 
passwords, disabling automatic logons, locking computers when 
unattended, and reporting all suspicious electronic events. Physical security 
procedures include keeping all hard-copy PHI in locked filing cabinets in 
locked offices, shredding all paper records when finished, and securely 
delivering all hard-copy PHI to an Honest Broker as required by IRB policies. 
 
Honest Broker responsibilities 
Honest Broker agreement. The Honest Broker must execute and maintain 
an up-to-date Business Associate Agreement with UPMC and/or the 
University of Pittsburgh, the terms of which will specify the continuing 
confidentiality requirements, duties and other expectations of an Honest 
Broker service. 
 
Data security. The Honest Broker must maintain all data containing PHI 
according to the data security procedures set out in the CRISMA Standard 
Operating Procedures for Data Management. 
 
Confirmation of IRB approval. The Honest Broker must ensure IRB approval 
for the research study for which Honest Broker services are requested. 
 
Adherence to IRB terms. The Honest Broker must adhere to all of the terms 
and conditions specified by the IRB of record for any research study for 
which Honest Broker services are requested, including the type of data 
requested (Limited Data Set or Safe Harbor Data Set) and the identity of the 
researchers granted access to the data. 
 
Ensure proper de-identification. The Honest Broker will produce the 
requested dataset (either Limited Data Set or Safe Harbor Data Set) from 
the PHI as required by the investigator and approved by the IRB.  
 
Maintain documentation. The Honest Broker will maintain documentation 
of the processes and/or systems used to develop de-identified datasets 
from PHI. 
 

 
 
49 
ProACT protocol 
Version 1.4;  March 8, 2017 
 
 
 
 
Procedures 
Receipt of data 
• 
When the Honest Broker receives PHI, the Honest Broker will 
upload it onto a secure data storage system as described in the 
CRISMA Data Management Standard Operating Procedure. Access 
to the PHI shall be restricted to only the Honest Broker. 
• 
If the PHI is received via e-mail or network, the Honest Broker will 
ensure that the original and all copies of the file are deleted after 
uploading. 
• 
If the PHI is received via paper or electronic media, the Honest 
Broker will lock the media in a secure file cabinet in a secure office 
after uploading it the appropriate secure data storage system. 
 
De-identification of data 
• 
The Honest Broker will confirm IRB approval for the individual 
requesting data and the type of dataset requested. 
• 
If a limited data set is requested, the Honest Broker will create a 
new data set containing all the data present in the original data set 
except for the appropriate unique identifiers. The Honest Broker 
will create a new study identifier and retain a crosswalk between 
this identifier and unique identifiers in the PHI, storing this 
crosswalk in a secure location. 
• 
If a safe-harbor data set is requested, the Honest Broker will create 
a dataset containing all the data present in the original data except 
for any unique identifiers. 
 
Re-identification 
• 
If re-identification of data is necessary for research and approved by 
the IRB, the Honest Broker will use study identifiers in the retained 
crosswalk to link datasets to PHI. This process will be performed in a 
secure computing environment as described in the CRISMA Data 
Management SOPs. 
 
Documentation 
• 
The Honest Broker will keep a record of each data transaction, 
including the transaction date and time; the identity of the 
researcher; the name of the study; the nature of the data set; the 
name and location of the crosswalk file; and the corresponding IRB 
approval numbers. This record will kept in a secure data file as 
described in the CRISMA Data Management SOPs. 
 
Approval 
This CRISMA Standard Operating Procedure was approved by the CRISMA 
Executive Committee on 3.4.2013. 
 

 
 
50 
ProACT protocol 
Version 1.4;  March 8, 2017 
Appendix 10:  ProACT Medical Records Release Form         
 
 
Authorization to Release Protected Health Information for Research 
 
 
Participant Name __________________________        Date of Birth ____________ 
 
Social Security/Medical Record Number:  __________________________ 
 
I authorize _________________________________ to release information from the record ________________________________  
                         Hospital/Provider                                                                
                      Participant Name 
to the ProACT study team located within the Department of Critical Care Medicine at the University of Pittsburgh.  The reason for this 
request is that I am a participant in this research study. These records are for research purposes only, and are not being used for 
patient care.  I authorize a photocopy or facsimile of this authorization to be acceptable and valid.  I understand that I may revoke this 
authorization in writing at any time by providing a request to the study investigators.  I understand that once this information is 
disclosed, it may be re-disclosed by the recipient and the information may not be protected by federal privacy laws or regulations. My 
request to release these records will have no impact on the releasing facility’s provision of care to me. 
 
The records to be released are for the treatment dates:  __ __/__ __/__ __to __ __/__ __/__ __ for a diagnosis of  
 
________________________________. 
 
_X_ Face Sheet/Attestation with ICD codes  
_X_ Discharge/Death Summary 
 
_X_ Admitting History & Physical Exam 
 
 
 
 
 
_X_ Medication Administration Records 
 
 
 
 
_X_ Radiology Reports 
 
 
 
 
 
_______________________________________ 
_________________________________ 
Participant/ Representative Signature 
Date 
Witness  
 
 
Date 
 
 
________________________________________________ 
Relationship to participant, if representative 
 
Health Information Department:  
Records may be faxed to Jonathan Holton, Honest Broker, at 412.864.5901. Please call Elizabeth Gimbel at 412-647-7776 
or Ashley Ryman at 412-864-5507 with any questions about this request.