Statin Therapy in Acute Influenza
Phase: PHASE2
Conditions: Influenza
Sponsor: Beth Israel Deaconess Medical Center

(CCI) Committee on Clinical Investigations 
Page 1 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
Statin Therapy in Acute Influenza 
Principal Investigator 
Maureen Chase MD, MPH 
 
 
 
 
B1. 
PURPOSE OF PROTOCOL 
Influenza is a large-scale public health issue for which considerable focus has been placed on 
vaccination programs and on the development of antiviral therapies.  However, these strategies are 
confronted with the challenges of rapidly emerging influenza strains and increasing resistance to 
existing antiviral agents. In addition, these strategies do not address the contribution of the host 
inflammatory response in influenza pathogenicity as an overwhelming host cytokine response can 
lead to increased severity of the clinical illness, organ damage, and death. 
 
The objective of this study is to determine the potential effect of statin therapy for the treatment of 
acute influenza infection.  In addition, we will evaluate the mechanism by which statin therapy 
attenuates the host inflammatory response and the effect on clinical outcomes as follows: 
 
Specific Aim #1: To determine if the administration of statin therapy to patients with acute influenza 
will attenuate the inflammatory cascade. 
 
Specific Aim #2: To determine if the administration of statin drugs attenuates disease severity and 
improves time to clinical resolution of symptoms in patients with confirmed influenza. 
 
Specific Aim #3: To determine the effect of influenza on host metabolic response to disease. 
 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Influenza is associated with a high level of morbidity and mortality worldwide: The World Health 
Organization still estimates 3 to 5 million severe cases of influenza illness worldwide and attributes 
250,000-500,000 deaths to seasonal influenza outbreaks each year.1 While a reported 90% of 
influenza-associated deaths occur among adults aged ≥65 years, the morbidity associated with 2009 
swine-origin influenza A (H1N1) resulted in a shift in the ages and baseline health of patients who 
became ill and died.2-5 One epidemiologic study found that two-thirds of hospitalized patients and 
40%of those who died had no pre-existing medical conditions.6, 7 In addition, mortality rates in other 
major diseases also peak when influenza is circulating.8, 9  
 
No universal influenza vaccine exists: The best means of controlling influenza outbreaks is the 
development of protective vaccines. Because it takes months to generate, produce and distribute a 
strain-specific vaccine, populations with no prior immunity may be left vulnerable in the event of 
pandemic-associated vaccine shortages.  
 
Antivirals are currently the only primary defense: In the setting of inadequate vaccine supplies, the 
only line of treatment will be existing antiviral agents. There are challenges to using these agents 
including cost, utility late in disease, limited supplies and, perhaps most concerning with regard to 
using antivirals as a singular defense in influenza infection is emerging resistance.  
 
The host inflammatory response is a key component of influenza pathogenicity: A severe 
inflammatory response elicited by the influenza virus is thought to contribute significantly to the 
infection-associated morbidity and mortality.10-12  Kaiser and colleagues observed a positive 

(CCI) Committee on Clinical Investigations 
Page 2 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
correlation between plasma IL-6 levels and influenza symptom scores and temperatures in 16 adult 
patients with influenza; there was no significant difference in viral replication or cytokine levels 
between patients treated with placebo and those treated with oseltamivir.13  Paquette et al found that 
Il-6 levels were strongly associated with requirement for ICU level care and predicted fatal outcome in 
H1N1 infection.14 These studies highlight the fact that anti-influenza strategies should target both viral 
proliferation and the cytokine host response.  
 
For each of these reasons, it is essential to research alternative short-term adjunctive therapies in 
acute influenza treatment and pro-inflammatory mediators represent key therapeutic targets. The 
class 
of 
medications 
referred 
to 
as 
“statins” 
have 
pleiotropic 
anti-inflammatory 
and 
immunomodulatory effects including mitigation of the host pro-inflammatory cytokine response and 
protective effects on the vascular endothelium.  
 
We hypothesize that the administration of a statin medication will attenuate the inflammatory 
response in patients with acute influenza, resulting in 1.) decreased levels of circulating cytokines (IL-
6, VegF and TNF alpha) and 2.) a reduction in the severity of illness and time to clinical resolution of 
influenza symptoms. In order to test our hypotheses we will perform a prospective, randomized, 
double-blind study in which patients with acute influenza will be receive either statin therapy 
(atorvastatin 40mg) or placebo. We further hypothesize that influenza infection will cause a range of 
metabolic derangements in the host which will allow for elucidation of an influenza metabolomic 
profile and the potential identification of other anti-influenza therapeutic targets. 
 
Statins are inexpensive and widely available; if effective, statins may have a profound effect on the 
morbidity, mortality and economic burden associated with influenza worldwide. Thus, our 
investigation could lead to a practice-changing therapeutic intervention that complements the current 
strategies of prevention (vaccination) and direct antiviral therapy. 
 
 
 

(CCI) Committee on Clinical Investigations 
Page 3 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
Study Design: Prospective, double-blind, randomized clinical trial. 
Our primary hypothesis is that statin therapy will attenuate the inflammatory response in patients with 
influenza and lead to improved clinical outcomes.   
 
Randomization: We will create a master randomization list of 174 randomized assignments, with 87 
for the treatment group, and 87 for the control group. The master list will be maintained in the 
pharmacy area and the pharmacy staff will assign treatment allocation to ensure both study subject 
and investigational staff remains blinded.  
 
Sources of Materials  
Following written, informed consent trained research assistants will review and extract pertinent data 
and information from the patient's medical record including but not limited to patient demographics 
(including race), co-morbidities, initial and worst vital signs and laboratory tests (basic chemistry, 
complete blood counts, liver function tests and creatinine kinase). We will draw a small amount of 
blood (approximately 30mL) to assess baseline inflammatory biomarkers, CoQ10 levels and for 
metabolomic profiling.    
 
Patients who are enrolled in the trial and remain in the hospital will have data collected at the 
following time points 0, 12, 36, 48 and daily until hospital discharge. Safety lab testing (ALT, AST, 
CPK) will be performed at 24hrs and 72hrs. Any patient who is discharged from the hospital prior to 
the 72hr point will have a follow-up appointment at the GCRC for safety labs and follow-up 
measurements. Patients who are discharged without in-patient hospitalization will have all baseline 
measurements performed at enrollment and will be required to attend the 72-hour GCRC follow-up 
appointment for blood sample collection for inflammatory biomarker profiling and safety monitoring.  
If a subject has nasopharyngeal samples obtained as part of their routine medical care, we will obtain 
discarded samples from the laboratory and freeze them.  These samples will subsequently be used to 
evaluate the virus type and correlate with other disease parameters. 
 
Screening Protocol: 
 
 
Prior to presenting the written informed consent form for the main study to the subject or LAR, 
subjects will be verbally asked  to  undergo a bedside Rapid Antigen Test for influenza 
confirmation (Influenza A and B). Alternatively, another methodology for testing influenza, 
performed in a clinical lab setting for respiratory secretions may be used in place of the RAT 
test performed at bedside and interpreted by study staff.A urine or serum pregnancy test 
(females of childbearing potential only) will be performed if one is not already done as part of 
standard of care.   
 
A negative pregnancy test result should be confirmed prior to the first dose. 
 
Treatment Protocol: 
 
Patients will be administered study medication (either atrovastatin 40 mg or placebo) orally 
once daily for 5 days or  or for a maximum of 7 days for those remain hospitalized: 
           -Patients seen in the ED will receive a 5 day supply of the study medication. 
          - Patients who are hospitalized will receive a minimum of 5 day supply (7 days maximum for  
             those who remain hospitalized after 5 days) 
 
We will ask patients to provide an email address and telephone number for follow-up. 
 
For patients who are in hospital  study staff will go over the online diary at the bedside each 
day of the interventional period.  

(CCI) Committee on Clinical Investigations 
Page 4 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
 
For patients who are not admitted to the hospital or discharged before Day10, they will receive 
email or telephone reminders daily up to Day 10 to complete the diary online. If internet 
access is not available, study stuff will fill out the diary with patients over the phone. 
 
A 14-day telephone follow up interview will be conducted and patients will be asked about 
relapse, recurrence of symptoms or re-hospitalization.     
 
Female patients of child bearing potential and males capable of fathering children will be 
asked to provide a method of contraception and advised to continue for 2 weeks after finishing 
the study drug. 
 
Laboratory Analysis:  
 
Blood draws will occur at enrollment and every 24 hours for admitted patients (up to 7 days) 
and at 72 ±12 hours for discharged patients (at GCRC). For patients who remain in the 
hospital with ongoing influenza-related symptoms after day 7, blood draws will occur every 
other day while hospitalized to hospital day 14 maximum.  
 
 
Specific Aim 1: To determine if the acute administration of statin drugs to patients with confirmed 
influenza will attenuate the inflammatory cascade.  
 
The primary endpoint for this study is change in inflammatory biomarker IL-6 from the time of 
enrollment to 72 hours.  
 
Secondary endpoints will include change on additional markers of inflammation including 
VegF and TNFa.   
 
 
Specific Aim 2:  To determine if the administration of statin drugs attenuates disease severity and 
improves time to clinical resolution of symptoms in patients with confirmed influenza.  
 
The primary endpoint in this aim will be the time to clinical resolution based on a daily 
composite score of recorded major influenza symptoms. Study subjects will record a diary of 
symptom severity, temperature, ability to perform normal activities, and use of relief 
medication twice daily for 10 days. The diary will be used to create a composite score for each 
of 5 major symptoms (fever, cough, sore throat, headache, myalgia) ranked from 0 to 3 (none, 
mild, moderate, severe) for a score ranging from 0 to 15.80Clinical resolution of symptoms will 
be defined as time to alleviation in major symptoms recorded as no more than mild x 24 
hours.   
 
Secondary endpoints will be: 
1.) Change in severity of illness (APACHE II) from enrollment to 24-hour follow-up  
2.) Hospital and ICU lengths of stay  
3.) Rates of progression to vasopressor-dependent shock  
4.) In-hospital mortality  
 
Specific Aim 3(Exploratory): To determine the effect of influenza on host metabolic response to 
disease.  
 
The first exploratory endpoint (3a) will be to determine if influenza host response consists of 
a unique metabolic fingerprint for diagnostic or prognostic purposes. We will obtain a 
“metabolomic” fingerprint of all patients at baseline which will consist of over 250 metabolites. 
We will evaluate the association of the metabolic profiles to outcome measures including need 
for hospital or ICU admission and mortality. We will then evaluate the metabolomic profile as a 
prognostic indicator in comparison to other biomarker indices and severity of illness scoring.  
 
The second exploratory endpoint (3b) will be to identify metabolic derangements and 
deficiencies that can serve as adjunctive therapies. Specifically, we will examine whether 
CoQ10 and other metabolic derangements may lead to adjunctive interventional therapies in 
influenza infection.  

(CCI) Committee on Clinical Investigations 
Page 5 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
 
B. 
Statistical Considerations 
 
We will create a master randomization list of 174 randomized assignments, with 87 for the treatment 
group, and 87 for the control group. However, our total enrollment target for the study will be 1200 
subjects to account for RAT screen-out subjects. In the first year of the study, 139 subjects were RAT 
tested for study eligibility; 15 of the 31 subjects who tested positive for influenza were enrolled into 
the main study. With the total enrollment target at 1200 subjects, this number will allow us to RAT test 
approximately 240 patients each year over the course of five years in order to reach target enrollment 
of 174 patients over 5 years. 
 
Sample Size and Power Calculation, Aim #1: Sample size calculation is based on IL-6 data from our 
septic shock population. At the 72-hour time point, we found a change in IL-6 levels of (-964.3 ± 
1501.2) in the statin group and (-471.9 ± 620.0) in the placebo group.  Based on these numbers, we 
need 87 patients in each group to detect a change in biomarker levels between the statin and placebo 
groups at alpha 0.05 and 80% power.  
Data Analysis, Aim #1: We will first summarize data and examine the distribution of demographics 
and potential clinical confounding variables to ensure that the randomization scheme works. We will 
use 2-sample t-test or the Wilcoxon Rank Sum test to evaluate for the difference between groups for 
continuous variables and the chi-square or Fisher’s exact test for categorical variables. Next, IL-6, 
TNF alpha and VegF levels will be compared between the two groups at multiple time points using a 
two-sample t-test or Wilcoxon Rank sum test. Initially, we will use a univariate test to see if there is a 
difference between the mean (median) values between the two groups at each time point. We will 
then use a linear mixed-effects model with several covariance structures to account for the correlation 
from the within-subject measurements. In this model we will include an interaction factor between 
time and group and also control for any potential confounders. We will obtain the estimated mean 
difference and standard error for the effect of the treatment for each of the biomarkers. We will also 
report 95% confidence intervals around important parameter estimates. 
  
Sample Size and Power, Aim #2: 
Time to clinical resolution: Based on pooled analyses of past influenza antiviral efficacy studies, 
patients with laboratory confirmed influenza had a 1.5 day reduction in time to alleviation of symptoms 
as compared to control; the sample size (87 per group) obtained in Aim 1 will achieve 90% power at 
5% level of significance 
Data Analysis, Time to Clinical Resolution: If there are no censored observations and the data 
indicate normality (with or without transformations) then t-test will be used in the univariate setting 
and linear regression to adjust for covariates and their possible interactions. For censored 
observations, we will use Kaplan-Meir method in the univariate analysis. To adjust for the possible 
effect of covariates we will use Cox regression. 
 
Severity of Illness Score: We recorded APACHE II scores for patients with confirmed influenza and 
found that non-statin users had a score of 7.3±3.5. Clinically, we consider a 25% reduction in 
APACHE II significant; using an absolute score reduction of 1.8 points, assuming the same standard 
deviation and a 75% admission rate, we will have 90% power to detect a difference between groups 
with a one-sided Type 1 error of 0.05.   
Data Analysis, Severity of Illness Score: Similar to Aim 1, we will make use of all data points and fit a 
linear mixed-effects model where the within-subject correlation of the APACHE II score is 
incorporated into the model via an error term which allows for missing APACHE II data.  
 
Additional Endpoints: Fisher’s exact or chi-square test will be used to assess for differences between 
the statin and placebo groups with regard to development of shock and mortality; for lengths of stay, 

(CCI) Committee on Clinical Investigations 
Page 6 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
we will compare groups using Wilcoxon Rank Sum test. 
 
Sample size and Power, Aim #3:  
We will perform CoQ10 and metabolomic assessments on the first 50 patients enrolled in the trial. We 
will compare these results to those of controls in our data repository. A sample size of 50 patients per 
group will allow us to detect an effect size of 0.5 with 80% power (two-sided alpha 0.1). 
Data Analysis, Aim #3: Computational analysis will be performed for the metabolomic analysis and 
descriptive statistics will be employed for metabolomic profiles and CoQ10 levels. 
 
 
C. 
Subject Selection 
Inclusion Criteria (all must be present): 
1) Adult patient (age > 18 years) 
2) Positive influenza DFA/RAT test result 
3) <12 hours from positive influenza test result 
 
Exclusion Criteria: 
1) Prior statin medication use (within 30 days of positive influenza test result) 
2) Comfort measures only designation or anticipated withdrawal of life-support 
3) Atorvastatin specific exclusions:  
a. Documented liver cirrhosis or liver dysfunction (AST or ALT greater than 240) 
b. Known allergy or intolerance to statins 
c.   Rhabdomyolysis (CPK elevation > 6x normal) 
d. Patients taking the following medications:  cyclosporine, HIV protease inhibitors, hepatitis C 
protease inhibitor telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals 
(itraconazole, ketoconazole) clarithromycin and colchicine 
4) Patients unable to take oral or nasogastric medications or plan for no oral intake as part of 
medical course (eg. emergent surgical intervention) 
5) Known pregnancy or active breastfeeding 
6) Inability to provide written informed consent for any reason 
 
Justification of Inclusion/Exclusion Criteria: We have chosen to include adult patients with confirmed 
influenza.  We will enroll patients immediately after notification of a positive influenza test result and 
will attempt to capture patients early in their hospital course, as early intervention will likely provide 
the greatest benefit with respect to modulation of the inflammatory response and clinical resolution. 
The two potential (though unlikely with short term use) side effects of statin therapy include liver injury 
and rhabdomyolysis. Therefore, we will exclude patients with liver inflammation (defined by ALT or 
AST > 6x normal) or muscle inflammation (CPK > 3x normal) at baseline.  Moreover, we will exclude 
patients on medications known to potentiate the effect of statin therapy and therefore potentially 
increase the chance of adverse effects. We have chosen to exclude patients with recent prior statin 
use as this would likely confound the interpretation of the results of this investigation.  
 
  
 
 

(CCI) Committee on Clinical Investigations 
Page 7 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
B4. 
POSSIBLE BENEFITS 
Potential Benefits of the Proposed Research to Human Subjects and Others 
It is not known whether statin therapy will benefit patients with acute influenza.  Previous reports 
suggest that statins may attenuate the inflammatory cascade in patients with influenza. However, 
these reports have been mostly observational in nature and a causal relationship has yet to be 
established. Our primary hypothesis is that statin therapy will attenuate the inflammatory response in 
patients with influenza and lead to improved clinical outcomes. We are therefore conducting a 
randomized placebo controlled clinical trial of atorvastatin versus placebo for adult patients with 
confirmed influenza. If our hypothesis is correct, patients who receive the statin medication will have 
an improved clinical course compared to the placebo arm of the study which may include shorter time 
to hospital discharge and improvement in severity of illness.   
 
Importance of the Knowledge to be Gained  
Statin medications are very common for treatment of hyperlipidemia.  Our investigation will determine 
the effects of atorvastatin on the inflammatory cascade and clinical manifestations of the influenza 
virus.  If statins demonstrate a positive result in comparison to placebo we could potentially use 
statins as an early therapeutic agent for patients with positive influenza.  This has significant public 
health implications as statins are relatively safe in a majority of the population and could potentially 
impact large numbers of patients who are afflicted with influenza each year in the United States. 
 
 
 
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
Statin risks: 
The two potential (though unlikely with short term use) side effects of statin therapy include liver injury 
and rhabdomyolysis. In general, statins have an excellent safety profile as a  recent study of 129,288 
patients started on a statin and followed for 4.4 years found a rate of any diagnosed muscle problem 
to be 4.1/ 10,000 in the first year and no cases in >500,000 person years of observation in 
rhabdomyolysis.  
 
Blood draw risk 
In addition, we will collect blood samples from study participants which the risk of pain during needle 
insertion, and hematoma at the site of needle insertion. We will minimize the highly unlikely side 
effects of a blood draw by conforming with standard phlebotomy techniques including drawing blood 
while patients are supine or sitting, the site of the blood draw will be cleansed prior to the draw, and 
direct pressure will be held post-blood draw.  All research assistants performing phlebotomy will have 
formalized training and oversight.  Infection, excess bleeding, and fainting are also possible, although 
unlikely.  .   
 
Rapid Antigen Test and Viral Swabs collection 
The currently known mild effects that have been seen with the rapid antigen test procedure and viral 
swab collection are listed below. 
  
Swab Collection: Generally, the side effects have been mild.  The most common side effects have 
been as follows: 
 
Sneezing 
 
Runny nose 
 
Watery eyes 
 
Soreness where the nose is swabbed 
 
There are not known risks associated with the viral swab collection. 
 

(CCI) Committee on Clinical Investigations 
Page 8 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
Pregnancy and Breastfeeding Risks: 
The risks to the unborn baby include birth defects, premature delivery or death. Atorvastatin may 
pass through the breast milk and harm the baby. All women of child bearing potential will be given a 
pregnancy test to confirm they are not pregnant prior to the first dose of study medication.  
 
We do not anticipate any psychological risks of participating in the study.  There will be no financial 
risks associated with study participation 
 
We have carefully evaluated the risk: benefit ratio and feel that the potential benefits of a positive trial 
significantly outweigh the potential risks for participation in the investigation.  As described above, the 
potential risks to subjects are minimal and we have carefully considered a plan to ensure that risks 
are minimized throughout the interventional period.   
 
Adverse Events 
An Adverse Event (AE) is defined by any symptom, illness or disease that commences or worsens 
during the 5 day study duration and is confirmed to be the result of study intervention.  We have an 
advantage in studying a drug with well documented safety profile. Though rare, the known side-
effects of atorvastatin include the potential for liver toxicity and skeletal muscle effects (myopathy and 
rhabdomyolysis).  For all patients enrolled in this trial liver function tests (LFTs) including AST and 
ALT as well as creatine kinase (CPK) will be measured at the time of enrollment and at the 72-hour 
follow-up.  Of note, we will exclude patients from this investigation if at the time of enrollment they 
have LFTs or CPK above 6x the normal range as described in the Inclusion/Exclusion section above. 
  
Safety Monitoring Plan 
The study will undergo regular data safety monitoring to ensure the safety of the intervention in this 
patient population.  We will include a Data Safety Monitoring Board (DSMB) comprised of an 
emergency physician, a specialist in influenza research investigations and a biostatistician.  The 
DSMB will meet at regular intervals as follows: the DSMB will convene initially when 30 subjects are 
enrolled into the trial to ensure no obvious safety concerns for the investigational protocol. 
 Subsequent to the initial meeting, the DSMB will convene when the trial reaches 1/3 and 2/3 
enrollments and those subjects have completed the intervention. 
 
 

(CCI) Committee on Clinical Investigations 
Page 9 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
Recruitment 
Screening: Our research team provides in-house coverage 24 hours a day. We have successfully 
developed and utilized an electronic screening mechanism through the ED patient registry system 
that allows for nearly 100% capture of all potentially eligible patients. Primary screening for eligible 
patients with acute influenza will occur in the emergency department as our data show that over 92% 
of patients admitted with influenza present through the ED. In addition, any positive influenza test in 
the hospital laboratory generates an automatic email alert to the investigative team enabling for 
further identification of hospitalized, non-ED patients.  
 
Consent 
 
Verbal RAT consent for Influenza A and B confirmation: Patients will first be approached to undergo 
the Rapid Antigen Screening for influenza confirmation before they are presented with the main 
written informed consent form. The research assistant will provide the patient information regarding 
the background and significance of the RAT test, eligibility criteria, and a brief description of the main 
protocol. Verbal consent will be obtained from the study subject or legal authorized representative 
prior to undergoing the RAT test. IF the subject is flu positive, the subject will be presented with the 
main written informed consent form.  
 
Main Consent and Enrollment: Patients who meet all inclusion criteria and none of the exclusion 
criteria will be approached for written informed consent. The research assistant will provide to the 
patient information regarding the background and significance of the study, eligibility criteria, and a 
description of the protocol. Written informed consent will be obtained from the study subject or legal 
authorized representative prior to performing any procedures solely for the purpose of research. 
 
For the verbal RAT consent, research staff will document that subject gave permission. The subject will 
be provided with an information sheet. 
 
For the Main ICF, if the patient / LAR agrees to participate, he / she will sign and date (and a witness if 
applicable) the inform consent form. The name of the study investigator obtaining consent will be 
clearly documented, and this person will sign the informed consent document and provide the date of 
their signature and time. Signed copies of the consent form will be given to the participant/LAR, and 
the original consent document will be stored in the secure study file.  A copy of the consent form will 
also be placed in the subject’s medical record. 
 
 
In the event that a physician Investigator is not physically present in the hospital to perform 
the consent process, a research assistant will introduce the study and obtain preliminary 
consent from the patient or LAR. We anticipate that this will occur predominantly on weekends 
and/ or nights.  
 
The research assistant will then coordinate a video or phone conference with  physician 
investigator or co-investigator such that any additional questions can be addressed by the 
physician investigator who will confirm consent directly with the patient or LAR.   
 
The research assistant will sign the consent, in addition to the patient or LAR, and that signed 
copy will be included in the patient’s medical record and as well as be provided to the study 
subject.   
 
The research assistant will place a note to file documenting the physician investigator’s role in 
the consent (via phone or video conference).   
 
Remote recruitment and consent from proxy: 
Patients who qualify for this study may be intubated or confused due to the disease process that impairs 
their ability to provide informed consent. In our experience, the patient’s proxy is sometimes not 
present in the ICU or the ED when the patient is intubated to provide written consent. The enrollment 

(CCI) Committee on Clinical Investigations 
Page 10 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
criteria for this study create a short time window when the patients can be enrolled (12 hours from a 
positive influenza test result).. In such a circumstance, the study staff will send the informed consent 
document to the subject’s surrogate electronically (email, facsimile, etc.) and a licensed physician 
investigator, or a co-investigator will conduct the consent discussion by video or telephone. Once the 
surrogate has had time to review the consent form, if he/she agrees to participation he/she will sign the 
consent and return the signed document to the investigator electronically (email, facsimile, etc.).  
 
All email correspondence will occur in accordance with BIDMC guidelines. Once the signed consent form 
has been received by the investigator, he/she will then sign, date, and time the form. No study 
procedures will occur before the consent form has been signed by both the surrogate and the 
investigator. The surrogate will be instructed to return the original signed consent form to BIDMC which 
will be kept in the subject’s research record with the electronically transmitted copy and a detailed note to 
file. 
 
 
The research assistant will record demographic data (including age, sex, race, and ethnicity), vital 
signs and laboratory data and perform venipuncture to collect approximately 30mL of blood at the 
time of enrollment. During this process, confidentiality will be strictly maintained.  
 
Subject Protection 
There will be no undue influences on the potential study subjects to participate. 
 
There is a DSMB comprised of an independent group sponsored by the NIGMS who will make 
recommendations in general about the efficacy of study intervention, the benefit/risk ratio of 
procedures and participant burden, selection, recruitment and retention of participants, 
amendments, safety and referral for abnormal findings.  
 
Dr. Chase will also periodically review the data to evaluate subjects’ safety and data integrity. 
The purpose is to determine whether study subjects are exposed to unreasonable risk 
because of study participation, and to monitor study progress and integrity. Dr. Chase will 
review all adverse events to the CCI according to the adverse event reporting policy of the 
CCI. 
 
All biological material will be stored in a locked refrigerator within a locked facility, which is 
under hospital security surveillance at all times.  All electronic records will be maintained on 
BIDMC IS compliant computers. 
 
 
 
B7. 
STUDY LOCATION 
 Privacy  
Standard clinical protocols regarding protecting patient confidentiality will be followed during the 
course of this study.  Consideration is given to their privacy when discussing their condition. In order 
to maintain privacy, the investigators will discuss the study and consent the subjects in a private area.  
Once consent is obtained, blood samples and patient information is obtained at the bedside.  For the 
14 day follow up phone call, the phone calls will be made through a secure hospital land line.  
 
Physical Setting 
Patients (or their legally authorized representatives) will be approached, recruited and enrolled in the 
Beth Israel Deaconess Medical Center’s Emergency Department, inpatient floor and intensive care 
units.  
 

(CCI) Committee on Clinical Investigations 
Page 11 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:02/01/2017 
 
The follow-up phone calls will take place in the Emergency Department research offices. 
 
No patient information will be provided to the sponsor. Additionally, no one other than the research 
team, the patient’s physicians and family will be apprised of the patient’s participation in the study.  
 
 
B8. 
DATA SECURITY 
Data will be stored in electronic form on computer hard drive.   The computer will be password 
protected behind the BIDMC firewall, making the data available only to study personnel. Only the 
principal investigator, co-investigators and research staff will have access to the database. Patient 
data will be accessible only to study personnel. All efforts to protect patient confidentiality will be 
strictly enforced.  
 
Data Management: Clinical, laboratory and safety data for this trial will be stored in the REDCap 
electronic data management system. The online database ensures confidentiality through the use of 
a patient ID number. In order to ensure accuracy and protection of the data, we will maintain an 
electronic and hard copy of the master list with identifiers. The computer list will be maintained on the 
hard-drive of two separate computers in password-protected files kept in a locked research office 
used only by study investigators. The online database has the capacity for generating periodic 
reports for the Data Safety and Monitoring Board (DSMB). 
 
Frozen blood specimens will have only the study ID as the identifying information. 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No  
 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No  
 
B10 
Dissemination of Research Results 
 
We will plan to disseminate the results after completion of data analysis through a peer-reviewed 
scientific publication as appropriate and through oral presentations at seminars and scientific 
conferences. 
 
A description of the study will be available on clinicaltrials.gov as required by U.S. law. The website 
will not include information that can identify the participant. The website will include a summary of the 
results. The participant can search this website at any time.