Randomized Clinical Trial of Multi-respiratory Pathogen Testing Versus Usual Care in Emergency Department (ED) Patients With Upper Respiratory Symptoms
Phase: NA
Conditions: Respiratory Tract Infections, Influenza, Human, Common Cold
Sponsor: University of California, Davis

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
Page 1 of 7 
 
Revised: April 28, 2016 
1) Protocol Title:  
Pilot randomized clinical trial of multi-respiratory pathogen testing versus usual care in 
emergency department (ED) patients with upper respiratory symptoms 
Version Date: February 23, 2018 
 
2) 
Objectives 
 
To prospectively evaluate the effect of rapid, multi-respiratory pathogen molecular testing vs. 
usual care among patients being evaluated for influenza like illness (fever or cough and sore 
throat; ILI) and/or upper respiratory infection (nonspecific upper respiratory symptoms without 
fever; URI) in the emergency department (ED) setting. Specifically, we will evaluate the impact 
of having the rapid, multi-respiratory pathogen molecular test results on the frequency of 
respiratory pathogen detection, clinical treatment and outcomes among patients. To do so, we 
plan to conduct a prospective, patient-oriented, pilot randomized clinical trial of the BioFire 
FilmArray Respiratory Panel (FilmArray RP) from clinical nasopharyngeal swab viral transport 
media versus usual care (which may include but is not limited to no testing or targeted influenza 
molecular testing Alere I Influenza A & B). 
 
Our study has two hypotheses: 
1) Rapid, FilmArray RP testing will increase the proportion of ED patients with a specific 
respiratory virus detected and decrease the proportion of ED patients receiving 
unnecessary antibiotics for viral infection, relative to patients receiving usual care. 
 
2) Rapid, FilmArray RP testing will increase the frequency of a confirmed influenza 
diagnosis and improve overall anti-influenza medication use (composite rate of anti-
influenza treatment in positive patients and non-use of anti-influenza treatment in 
negative patients) in ED patients, relative to usual care.  
 
3) 
Background 
 
ILI and URI are a frequent cause of ED visits but most patients of have a viral infection, which 
resolves without treatment and does not need specific treatment or antibiotics. Influenza and 
Respiratory syncytial virus (RSV) are the most common cause of ILI and URI during the winter 
respiratory season; Rhinovirus/Enterovirus infections predominate during summer and fall. Other 
viruses such as human Parainfluenza viruses, Adenovirus and human Metapneumovirus (hMPV) 
are less common but account for a sizable proportion of patients in aggregate. Most symptoms of 
ILI (cough or sore throat and fever) and URI (cough, sore throat, runny nose, and sneezing 
without fever) are non-specific. The current standard of care for ILI and URI does not typically 
include microbiologic testing and test results are often not available until after the patient has left 
the ED, when they are obtained. Thus, patients are often treated presumptively with antibiotics or 
hospitalized unnecessarily due to physician uncertainty and lack of rapid and comprehensive 
microbiologic tests. This leads to antibiotic overuse, excess healthcare costs, and antibiotic 
resistance among other things.  
 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
Page 2 of 7 
 
Revised: April 28, 2016 
Recent improvements in molecular diagnostic tests and the development of rapid, multi-
respiratory pathogen tests provide an opportunity to identify viruses and viral infections like ILI 
and URI during the ED visit and potentially improve patient management. The FDA-cleared 
FilmArray RP provides results for 20 different respiratory pathogens in approximately 1 hour 
with 85-100% sensitivity and 90-100% specificity. However, the clinical utility and impact of 
rapid, multi-pathogen testing on patient management, physician decision-making and patient and 
system-level outcomes has not been rigorously evaluated, especially in the ED setting. This 
creates challenges for physicians, laboratories, and hospitals in justifying the cost of instruments 
and tests and lack of guidance regarding optimal use. Hence, this study will evaluate whether 
rapid, multi-pathogen detection can have a significant impact on outcomes in the ED setting that 
might make tests like this become standard of care. This study will provide important 
preliminary data to guide larger pragmatic outcomes-oriented clinical trials. 
 
4) 
Inclusion and Exclusion Criteria 
 
All UC Davis ED patients who are being evaluated for ILI or URI by an ED physician and who 
agree to having a nasopharyngeal swab sample collected for the study will be eligible for 
recruitment. Since this procedure poses minimal risk to individuals and no risks to an embryo or 
fetus should the patient be or become pregnant, we will not exclude pregnant women from this 
study. 
 
Our study will also include children (individuals below 18 years old) since the collection of the 
nasopharyngeal swab sample poses minimal risk to them. Informed consent will be obtained 
from the children’s parents, legally authorized representative or guardian before the child is 
enrolled. In addition, should an adult be incapable of giving informed consent, consent will be 
obtained from the individual’s legally authorized representative. 
 
Spanish speaking patients will also be included. We plan to translate our informed consent 
documents into Spanish after IRB approval and a translator will be present in the ED to allow 
proper communication between the patient and ED research coordinators, ED nurse, or physician 
throughout the study. Other non-English speaking patients will be excluded.   
 
We will also exclude those patients who are prisoners or are currently taking antibiotic or 
antiviral medications.  
 
5) 
Study Timelines 
 
The study will begin upon IRB approval and continue until December 2017. Eligible patients 
will be identified by ED research coordinators or EMRAP students and will be approached by 
ED Research Coordinators and asked for consent to enroll. The patient will continue to be a part 
of the study throughout their time in the ED. Additional follow up data collection and analysis of 
results will be performed for 1-5 years after completion of the active enrollment phase. 
  
6) 
Study Endpoints 
 
Patients may be recruited until the end of December 2018 while primary data analysis will be 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
Page 3 of 7 
 
Revised: April 28, 2016 
completed within one year after patient recruitment ends. 
 
7) 
Procedures Involved 
 
All UC Davis ED patients who are being evaluated for ILI or URI by an ED physician during the 
study period will be eligible for recruitment. Once the ED research coordinator or EMRAP 
students identify an eligible patient, the patient will be approached by the ED Research 
Coordinator and asked for consent to enroll. After obtaining informed consent, patients will be 
randomized to one of two arms: multi-respiratory pathogen testing together with usual care or 
clinician directed standard of care (which may include but is not limited to no testing or targeted 
influenza molecular testing Alere I Influenza A & B) using a simple randomization scheme. In 
this study, the randomization scheme we are planning to use is individual randomization. To 
ensure that the study population includes patients treated as outpatients vs. admitted, patients will 
be recruited from the ‘up front care’ treatment area (urgent care unit for ED patients expected to 
be treated as outpatients), in addition to our main emergency department area. 
 
A brief demographic and symptom questionnaire will be administered to all subjects (see 
attachment). If patients are assigned into the control group, they will receive clinician directed 
standard of care (which may include but is not limited to no testing, point-of-care influenza 
molecular testing Alere I Influenza A & B, or multi-pathogen respiratory viral panel testing at 
off-site laboratory performed 3-4 times weekly in scheduled batches). Conversely, patients 
randomized to receive the rapid FilmArray RP, will receive usual care plus have a 
nasopharyngeal swab collected by an ED nurse or ED physician for FilmArray RP testing. The 
nasopharyngeal swab will be transported to the CLIA-certified clinical laboratory located one-
floor above the ED where a licensed Clinical Laboratory Scientist (CLS) will perform the 
FilmArray RP test in real-time. Once the test is completed, FilmArray RP results will be reported 
in EMR via standard procedures and be available to ED physicians for use in patient 
management. ED physicians are free to decide how the test results will impact their treatment 
decisions and whether they would like to share these results with their patients. To ensure that 
results are available before ED physicians make treatment decision, we will encourage the ED 
triage physician to order the test before patients are put into ED rooms and ensure that FilmArray 
RP results are reported within 2 hours of sample collection. 
 
In order to evaluate the impact of having rapid FilmArray RP results on clinical treatment, 
outcomes, and costs among ED patients, we will collect additional clinical and administrative 
data from EMR, laboratory, and UCDHS administrative databases. These data may include but 
are not limited to demographic characteristics, ICD10, CPT, and DRG diagnosis, procedure, and 
billing codes, charge and cost data, admission source, discharge disposition, clinical signs and 
symptoms of respiratory or other illness, relevant laboratory and radiology results, medications, 
antibiotics, antiviral and other respiratory treatments (e.g., oxygen, nebulizers and inhaled 
treatment) 30 days before, during, and after the ED episode of care, length of ED encounter, and 
data for any hospitalization, ED, or outpatient clinic visits within 30 days. These additional data 
collection and analysis of results will be performed for 1-5 years after completion of the active 
enrollment period (December 2017). 
 
8) 
Data and/or Specimen Management and Confidentiality 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
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Revised: April 28, 2016 
 
Power Analysis - Based on existing literature and baseline data, we anticipate approximately 
50% of patients with the diagnosis of ILI or viral URI in the control group will receive 
antibiotics, whereas 10% with confirmed influenza will receive antivirals. Based on the effect 
sizes, anticipating significant improvement in detection rates for influenza and other viral 
pathogens, and hypothesizing a 15 percentage point decrease in antibiotic use for patients with 
ILI or URI from 40 to 25% in the multi-respiratory pathogen test group, we plan to enroll 
approximately 304 – 325 patients over 12-18 months (June 2016 – December 2017). A sample 
size of at least 152 enrolled patients in each of the control and intervention arms will provide > 
80% power to detect any true 15 percentage point difference between the multi-respiratory 
pathogen test and usual care arms. 
 
Data for this study will be collected from the patient questionnaire, electronically in bulk from 
EMR, administrative and laboratory databases, and from individual patient charts in EMR. Entry 
into individual patients charts (EMR) will be used primarily to clarify responses to the patient 
questionnaire, evaluate physician awareness of and utilization of FilmArray RP results and 
decision-making (e.g. to determine how the results from the rapid, multi-respiratory pathogen 
testing influences physicians’ decision to prescribe antibiotics, to obtain respiratory radiology 
results), and clarify gaps in the bulk electronic data. 
 
All data will be maintained for 5 years after completion of this project. All data will be 
maintained in password-protected spreadsheets/databases located on a secure UCDHS server. 
Patients’ PHI will be removed and data assigned a unique study identifier as soon as possible 
after extraction and electronic matching. Access to databases with identifiable electronic data 
will be limited to authorized investigators, study personnel, research coordinators and analysts 
directly involved in the study. All signed HIPAA Authorization forms granting research 
personnel permission to use PHI for research will be kept in a locked cabinet in the office of the 
principal investigator or in a lockbox in the ED for 5 years. Any unauthorized entry into 
individual EMR patient records (e.g. to identify potential subjects and before the HIPAA 
Authorization form is signed) will be documented and reported to the UCDHS compliance office 
via Break the Glass on EMR. 
 
9) 
Data and/or Specimen Banking 
 
Samples – Remnant nasopharyngeal swab samples in viral transport media will be labeled with a 
non-PHI containing code number and kept in an access-controlled UC Davis laboratory freezer 
for 5 years after the active study period for potential repeat, confirmatory, or additional 
respiratory pathogen testing. Access to the laboratory freezer will be limited to authorized 
investigators and research personnel. Only authorized investigators will be allowed to request 
further testing on these samples.  
 
Data – All subjects’ questionnaires and signed consent forms will be kept in locked cabinets in 
the office of the principal investigator or in a lockbox in the ED. Patient test results (which 
includes both the clinician directed standard of care and the rapid, FilmArray RP testing) will be 
documented in the laboratory LIS and EMR as per routine procedures. All extracted and 
collected data will be maintained in password-protected spreadsheets/databases located on a 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
Page 5 of 7 
 
Revised: April 28, 2016 
secure UCDHS server and will be coded (e.g. stripped of PHI and assigned a unique study 
identifier) as soon as possible after extraction and electronic matching. Data will only be 
accessible to trained project personnel. Coded data will be maintained for 5 years after the study 
is closed. 
 
10) Withdrawal of Subject 
 
The investigator can decide to withdraw subjects from the study at any time due to reasons such 
as missing information, collection of a sample inadequate for testing or because the entire study 
is terminated. Subjects are also free to withdraw from the study whenever they want. 
 
If a patient withdraws from the study, research personnel will discard the patient’s remnant 
nasopharyngeal swab sample and no longer obtain new clinical and administrative data about the 
patient from EMR, laboratory and UCDHS administrative databases. However, already collected 
data relating to any subject who chooses to withdraw will be retained and analyzed to maintain 
the integrity or reliability of the research.  
 
11) Risks to Subjects 
 
This study poses minimal risk of harm or discomfort to subjects. For patients assigned to receive 
the rapid FilmArray RP test, it is possible that the collection of the nasopharyngeal swab sample 
may make some of them feel uncomfortable. However, there is little or no risk of injury as the 
swab will be administered by trained ED personnel and there should be no lasting physical or 
emotional harm associated with the procedure. This procedure also has no risks to an embryo or 
fetus should the patient be or become pregnant. 
 
There will be no risk to patients placed in the usual care control group since they will receive the 
clinician directed standard of care (which may include but is not limited to no testing, point-of-
care influenza molecular testing Alere I Influenza A & B, or multi-pathogen respiratory viral 
panel testing at off-site laboratory performed 3-4 times weekly in scheduled batches); patients 
will receive similar treatment should they decide not to be enrolled in this study. 
 
12) Potential Benefits to Subjects 
 
Patients who are assigned to receive the rapid FilmArray RP test may or may not benefit directly 
from participating in the study. There are no guidelines on how physicians should utilize the 
results; instead, physicians are free to decide how the results will impact their decision-making. 
Depending on how physicians use the results, a possible benefit these patients may have is not 
receiving unnecessary antibiotics for viral infection. 
 
Patients placed in the usual care control group will receive no direct benefit from this study. 
However, we expect general benefits to the public as our study results may have the impact to 
change the clinical paradigm and testing/treatment strategy when diagnosing IRI or URI in ED 
patients.  
 
13) Community-Based Participatory Research 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
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Revised: April 28, 2016 
This study is limited to UCD Emergency Department patients; there will be no community 
participation. 
 
14) Sharing of Results with Subjects 
 
The rapid FilmArray RP test results will be released by CLS and reported to physicians through 
EMR. Physicians may decide if they would like to share these results with subjects. 
 
Results from clinician directed standard of care test results will also be released to physicians 
through EMR as per standard hospital protocol.  
 
15) Prior Approvals 
 
This clinical trial is sponsored by BioFire Diagnostics and thus the contract between BioFire and 
UC Davis Health Systems must be approved before this study is conducted. 
 
16) Provisions to Protect the Privacy Interests of Subjects 
 
An ED research coordinator will be present to educate and clarify any questions or uncertainties 
the patients might have about the study before they sign the informed consent form. The ED 
research coordinator will also emphasize that none of the patient’s identifiable information will 
be released and that all responses and results will be kept confidential and used for research 
purposes only. All patient enrollment, completion of the questionnaire and collection of the 
nasopharyngeal swab sample will be done in a private room in the ED. 
 
17) Economic Burden to Subjects 
 
As part of the agreement with BioFire Diagnostics, the UC Davis ED will be provided two 
FilmArray instruments and approximately 900 FilmArray respiratory panel reagent pouches. 
Hence, subjects who are assigned to the rapid, multi-respiratory pathogen testing will not incur 
any additional costs.  
 
18) Consent Process 
 
Once an eligible patient is identified, the patient will be approached by an ED Research 
Coordinator and asked for consent to enroll. Consent will occur after recruitment, but prior to 
any research activities. Consent will also occur face to face in a private room in the ED. Prior to 
obtaining consent, ED research coordinators will describe the study protocol and the possible 
risks and benefits and also address any questions or concerns the subject may have about the 
study. Patients will be provided with the IRB approved informed consent document to read given 
ample time to read the document and decide if they want to participate. After this point, eligible 
patients will sign the consent form. The signed consent form will be copied and the copy of the 
signed consent form will be given to the patient for personal records while the original will be 
kept by the ED Research Coordinator for the research record. After all research activities are 
completed, all data collected will be entered into a database. Hard copies of the consent forms 
and questionnaire will be stored in a lock box in a secure location in the ED. Contents of the lock 

PROTOCOL TITLE: Pilot randomized clinical trial of multi-respiratory pathogen testing versus 
usual care in emergency department (ED) patients with upper respiratory symptoms 
Page 7 of 7 
 
Revised: April 28, 2016 
box will be collected by study personnel when necessary and transferred to a locked cabinet in 
the principal investigator’s office. 
 
For patients who are children (individuals below 18 years old), informed consent will be 
obtained from one of the child’s parents, legally authorized representative or guardian before the 
child is enrolled. In addition, should an adult be incapable of giving informed consent, consent 
will be obtained from the individual’s legally authorized representative. 
 
19) Drugs or Devices 
 
√ I confirm that all investigational devices will be labeled in accordance with FDA 
regulations and stored and dispensed in such a manner that they will be used only on 
subjects and be used only by authorized investigators. 
 
The BioFire FilmArray RP test and instruments are FDA-cleared/approved for diagnostic use. 
The device will be labelled in accordance with FDA regulations and will be stored in a clinical 
laboratory located one-floor above the ED where only laboratory personnel and authorized 
investigators are allowed to enter. The device will be used only on enrolled subject samples and 
used only by trained CLS and authorized investigators. The FilmArray instrument and 
respiratory panel reagent pouches will be maintained and stored as instructed in the instrument’s 
manual.