A Pilot Study of the Effect of Prophylactic Antibiotics on Hospitalized Patients With Advanced Cirrhosis
Phase: PHASE4
Conditions: Cirrhosis, Liver
Sponsor: Beth Israel Deaconess Medical Center

NCT Number:  
NCT04218695 
Official Title: 
A Pilot Study of the Effect of Prophylactic Antibiotics on Hospitalized 
Patients With Advanced Cirrhosis 
Document Type: 
Protocol with SAP 
Document Date: 
2/24/2021 

(CCI) Committee on Clinical Investigations 
Page 1 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
PART B 
STUDY DESCRIPTION 
 
TITLE OF PROTOCOL 
A pilot study of the effect of prophylactic antibiotics on 
hospitalized patients with advanced cirrhosis   
Principal Investigator 
Zachary Fricker, MD  
 
B1. 
PURPOSE OF PROTOCOL 
 
In this pilot study, we aim to assess feasibility of subject identification and data 
collection, including specimen processing, as well as the rate of enrollment for a future, larger 
randomized, placebo controlled trial of the effect of prophylactic antibiotics for all patients 
with advanced cirrhosis admitted to the hospital without an existing indication for new 
antibiotic use. Specifically, we will assess the incidence of infection after the time of 
enrollment and associated outcomes. 
 
 
B2. 
SIGNIFICANCE AND BACKGROUND FOR THE STUDY 
Advanced chronic liver disease/cirrhosis creates a state of relative immune-
compromise, and, indeed, infections are a key precipitant of clinical decline in patients with 
cirrhosis. Specifically, infections of any kind are a common cause of acute on chronic liver 
failure (ACLF) and complicate 20-40% of hospital admissions of patients with cirrhosis. 
Although other pathogens are also important, the vast majority of infections in patients with 
cirrhosis are of bacterial origin. In other high-risk hospitalized patient populations, early 
initiation of antibiotics has been shown to reduce the need for intensive care unit (ICU) 
admission and short-term mortality. Unfortunately, the presentation of infection in patients 
with cirrhosis is protean and may be subtle. Diagnosis may be delayed by the absence of 
classic signs of infection such as fever and absolute leukocytosis. Vital diagnostic studies, 
such as paracentesis or other culture (blood, urine, or sputum) may be delayed or may not 
yield results until days after presentation. Delaying antibiotics until such studies result is 
inadvisable in patients with infection; however, empiric administration of antibiotics to all 
patients with cirrhosis admitted to the hospital would result in waste and increased risk of 
antibiotic resistance, Clostridium difficile infection, and other adverse effects. Sub-groups of 
patients with cirrhosis are already known to benefit from empiric/prophylactic antibiotics 
including those with acute upper gastrointestinal hemorrhage and those with increased risk of 
spontaneous bacterial peritonitis. The risk of infection increases with more advanced 
cirrhosis, as marked by higher Model for End-stage Liver Disease – Sodium (MELD-Na).  
There are also biomarkers of systemic infection that, although not specific, may be 
used to identify patients more likely to have an active infection and thus allow more targeted 
use of empiric antibiotics. Specifically, increase in serum C-reactive protein (CRP, >25 mg/L) 
and Procalcitonin (>0.5 ng/mL) are associated with acute bacterial infection.  
These factors may permit identification of patients who would benefit from 
prophylactic/empiric antibiotics. There has not, however, been investigation of the effect of 
prophylactic antibiotics on hospitalized patients with advanced cirrhosis beyond the sub-
populations described above.  
 

(CCI) Committee on Clinical Investigations 
Page 2 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
 
B3. 
DESCRIPTION OF RESEARCH PROTOCOL 
A. 
Study Design – Overview, Methods, Procedures 
 
This is a blinded, randomized, placebo-controlled pilot trial to determine feasibility of 
subject identification, rate of enrollment, and data collection, including specimen processing, 
for a future, larger randomized trial of the effect of empiric antibiotics for all patients with 
advanced cirrhosis admitted to the hospital without an existing indication for new antibiotic 
use. Specifically, we will assess the incidence of infection after the time of enrollment and 
associated outcomes. Patients will be randomized to receive either ceftriaxone or placebo 
(normal saline). Study drug will be delivered in masked vials for daily IV administration. 
Case finding and Screening: Eligible patients will be identified in the emergency 
department or by admitting physicians upon their initial medical assessment or by study 
personnel via daily review of the inpatient hepatology ward and consultative service census. 
Study personnel will screen each potential subject by review of medical record for potential 
eligibility.  
Consent: If a patient meets basic eligibility criteria, a study investigator will meet with 
the potential subject/LAR to review the study protocol and obtain informed consent. 
Screening measures will be completed following consent and the balance of the baseline 
measures will be completed.   
Extended Screening/Baseline: Evaluation for undiagnosed infection will be 
completed following consent and prior to randomization including: chest x-ray, venous blood 
culture, urine culture- all, if not already performed via routine care. These studies may be 
deferred if they have been done within 7 days of enrollment and there has been no change in 
clinical status. Subjects with infection identified upon enrollment will be excluded from further 
participation and have further treatment directed by their standard clinical providers.  
Each subject’s medical record will be reviewed to determine the presence or absence 
of diuretic-resistant ascites (defined by history of TIPS, large volume paracentesis within the 
past 3 months despite diuretics, or intolerance of diuretics).  
Each subject’s medical record will be reviewed to determine the calculated baseline 
CLIF-C ACLF score (Chronic Liver Failure Consortium (CLIF-C) Acute on Chronic Liver 
Failure). This will be computed using data (laboratory and physical examination) collected as 
part of standard of care. These data points include: 
 bilirubin,  
 creatinine,  
 INR,  
 West Haven grade of encephalopathy,  
 mean arterial pressure, and  
 peripheral oxygen saturation (SpO2).  
A peripheral or central venous blood sample will be taken after consent is obtained. 
Approximately thirty milliliters (2 tablespoons) of whole blood will be collected.  We will 
measure serum procalcitonin and C-reactive protein for the research study and store 
remaining specimen for potential future testing.   

(CCI) Committee on Clinical Investigations 
Page 3 of 11 
 
Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
Patients will be excluded if there is a clinical indication for new treatment with antibiotics, e.g. 
upper gastrointestinal hemorrhage or apparent infection, Standard of care treatment will 
never be delayed.  
Randomization: Each subject will be randomized to receive antibiotic treatment 
(ceftriaxone) or placebo (normal saline).  Randomization will be blinded to patients, study 
investigators, and study staff. Only the BIDMC Research pharmacist will know treatment 
assignment. Randomization will be stratified by the presence of either serum creatinine >= 
2.0 mg/dL and/or diuretic-refractory ascites.  
Study Intervention: The research pharmacy staff will provide antibiotic or placebo in 
the form of masked vials of intravenous solution. This will consist of either 1 gr ceftriaxone or 
an equal volume of normal saline (approximately 100 mL). This administration will begin as 
soon as possible after enrollment and will be repeated once daily. If a subject is prescribed 
an equivalent intravenous antibiotic during the hospitalization (i.e., ceftriaxone, 
piperacillin/tazobactam, or a carbapenem), the study-treatment (ceftriaxone/placebo) will be 
withheld on those days. If the clinically prescribed antibiotic is subsequently discontinued 
prior to discharge, the study-treatment/placebo may be resumed. Study treatment will be 
discontinued on study treatment day 7, or at the time of discharge or liver transplantation, if 
such events occur earlier than treatment day 7.  
Monitoring during Study Intervention:  Monitoring during study treatment will utilize 
routine vital sign monitoring and standard care labs conducted as indicated (typically daily) 
during the patient’s in patient stay. Standard care monitoring may also include radiographic 
or microbiology studies (e.g. culture) or special procedures such as therapeutic or diagnostic 
paracentesis at the discretion of the inpatient care team. No additional monitoring will be 
required per the study protocol. Standard care monitoring/labs that will be of interests include 
vital signs (e.g. blood pressure, mean arterial pressure, and oxygen saturation), CBC with 
WBC differential, bilirubin, INR, serum creatinine, sodium, albumin.  
 
Incidental Findings:  In the event that a clinically significant incidental finding is 
discovered during a research procedure, findings will be immediately reported to the 
attending on service for treatment or referral; results will be in OMR.  These would be also be 
available to the in-patients care team via OMR.  Examples of incidental findings include 
previously un-identified lung findings on chest x-ray, such as infection, pulmonary nodule, 
fracture, etc.   
 
Safety Monitoring: The PI is ultimately responsible for protecting the rights, safety, 
and welfare of subjects enrolled into the trial. Study intervention will last for 7 days during the 
patient’s inpatient stay for conditions related to the diagnosis of advanced cirrhosis/end stage 
liver disease.  Safety monitoring will be conducted daily during the intervention phase; post-
intervention procedures will continue daily during the patient’s admission and on day 30 post 
end of intervention.  The PI and/or a co-physician investigator will review all safety 
parameters including clinical safety laboratory assessments.  Clinical laboratory values that 
fall outside of the pre-specified safety ranges will be brought to the PIs attention the day the 
reports are final to assess clinical significance.   
 
Patients in the trial will be under the care of the in-patient liver service and these medical 
staff will be responsible for care of the patient throughout the admission.  
 
The study PI will review data of all non-serious adverse events after randomization of 
the first 5 subjects, and every additional 10 subjects thereafter until the study is complete. 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
 
Monitoring for AE: Subjects will be monitored for the occurrence of adverse events 
during their participation in the study. Reporting procedures will comply with BIDMC IRB 
policies; US Federal Regulations (21CFR 312), and ICH Guideline E-6: Guidelines for Good 
Clinical Practice. 
 
Adverse events will be coded and graded according to the NIH/NCI Common 
Terminology Criteria for Adverse Events version 4.03 (June 2010).  All adverse events will be 
classified on seriousness (mild, moderate, serious), expectedness (expected, non-expected), 
and relatedness to trial (not related, possibly related, related).   
 
End of treatment: The study intervention will continue for 7 consecutive days (unless 
interrupted by equivalent antibiotic treatment for a new clinical indication). If the study 
intervention is interrupted the study intervention may be restarted following completion of the 
open label antibiotic treatment to complete the 7 days of study intervention.  
Follow-up Procedures:  Monitoring will continue until 30 days post-intervention.  
End of study: Subject data will be recorded for up to 30 days post-intervention. 
 
Data/Tissue Repository:  A data and bio-specimen repository will be created to 
permit future research on this topic. De-identified data for each subject will be stored in a 
restricted access, password-protected folder on the BIDMC network drive. This access will 
be limited to study personnel.  A master-code which links patient medical record number to 
the coded study subject ID will be stored in a separate location and available only to the PI 
and study personnel, as required for data entry. A blood specimen will also be collected from 
each subject upon enrollment for storage such that additional testing may be completed if 
preliminary results or subsequent knowledge suggest that another biomarker might have 
added prognostic significance. These specimens will be stored in a locked unit in the Liver 
Research Center (LMOB4) and coded with study ID only. Further testing on these specimens 
will not become part of the medical record.  
 
B. 
Statistical Considerations 
 
Sample Size Justification:  We estimate there will be a small prevalence of occult 
infection among patients who are believed to be eligible after initial screening is completed. 
Patients with identified infection at the time of enrollment will not be randomized and instead be 
treated as per standard of care at the discretion of the medical staff. We estimate there may be 
5-10 such patients who are thus enrolled but not randomized.    
 
We aim to randomize a total of 40 subjects, assigned to active intervention vs. placebo; 
hence as many as 50 may be screened / consented to determine eligibility. This is a pilot study 
intended to assess feasibility of patient identification, administration of required testing and 
enrollment processing, and the rate thereof. The magnitude of observed effect will permit 
sample size estimation for a larger, more definitive study which we hope to complete 
subsequently. It is unknown how many subjects will need to be screened to complete this 
planned enrollment. We will also obtain information on the dropout rate and/or rate of use of 
therapeutic antibiotics which may alter enrollment goals for a future study.  
 
Data Analysis:  As stated elsewhere, the proposed study is a pilot study, not intended to 
provide definitive results. However, there are multiple outcomes of interest that will be recorded 
in order to permit planning of a future study.  
 
The primary outcome is incident bacterial infection identified after randomization 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
screening (as defined below). 
 
Secondary outcomes include: 
1. In-hospital mortality;  
2. 30-day mortality; 
3. Incident acute on chronic liver failure (ACLF) defined as two or more of:  
 Grade 3-4 hepatic encephalopathy, 
 Need for renal replacement therapy, 
 Need for mechanical ventilation, 
 Need for vasopressors, or mean arterial pressure (MAP) <60 mmHg, or decrement of 
>40 mmHg in systolic blood pressure after volume resuscitation. 
4. Change in calculated CLIF-C ACLF score; 
5. Length of stay (LOS) after randomization; 
6. Intensive Care Unit (ICU) transfer after randomization; 
7. C difficile infection (positive stool polymerase chain reaction (PCR) or toxin-assay in the 
setting of diarrhea); 
8. Increment in MELD-Na >= 3 points between randomization and discharge; 
9. Acute kidney injury (increase in creatinine >= 0.3 mg/dL in 48 hr or >50% from baseline 
(within previous 3 months) occurring after randomization; 
10. Variceal hemorrhage. 
 
Covariates recorded/measured 
 Procalcitonin at enrollment 
 C-reactive protein at enrollment 
 Other antibiotic use in-hospital (type and duration) 
 Fungal infections (by positive culture) or use of systemic anti-fungal medications. 
 
We will monitor daily for the incidence of the outcomes above via review of the 
medical record and discussions with the inpatient providers (when necessary). For any 
subject with a positive culture result, the site, organism, and antibiotic susceptibility will be 
recorded when available.  
 
Infection definitions  
 Bacteremia (positive blood culture not felt to be a skin flora contaminate)  
 Spontaneous bacterial peritonitis (ascites PMN count >250/ L or positive ascites culture 
in the setting of new abdominal pain, or unexplained leukocytosis, fever, hypotension, 
fever, acute kidney injury, or exacerbation of hepatic encephalopathy, i.e., increase in 
West Have grade)  
 Pneumonia: Pulmonary infiltrate on chest x-ray (CXR) or computed tomography (CT) in 
the presence of A) respiratory symptom(s) (cough, pleuritic pain, or dyspnea) or B) 
auscultation findings, abnormal body temperature (>38C or< 36C), or newly abnormal 
leukocyte count >10,000/microL or < 4,000/microL (if baseline leukocyte count > 
4,500/microL).    
 Skin or Soft Tissue Infection (SSTI): Superficial erythema, warmth, or fluctuance in the 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
skin/soft tissues felt to be secondary to infection by the inpatient team, excluding mild 
superficial thrombophlebitis from IV catheter insertion 
 UTI: Urine leukocytes > 10/hpf, bacteruria, positive urine culture, urinary leukocyte 
esterase or nitrite in the presence of symptoms/signs of infection (dysuria, unexplained 
increased urinary frequency, fever, or leukocytosis) 
 Other infections as identified by the primary medical team 
 
 
For purposes of analysis, deidentified subject clinical data documenting the metrics 
above will be stored in a password protected file within the BIDMC network. Analysis will be 
conducted at BIDMC using R-studio software. There are no additional statistical consultants 
currently affiliated with this study. Descriptive statistics will include the incidence of the primary 
and secondary categorical outcomes in each arm with comparison via Chi-square test or 
Fisher’s exact test for rare events. As noted elsewhere, we do not anticipate this study will 
provide sufficient statistical power to demonstrate statistically significant differences between 
groups, but we will need to have an idea of the magnitude of effect prior to planning such a 
study and hope to obtain this information here.  
 
C. 
Subject Selection 
Potential subjects will be identified by attending hepatologists on the ward/consultation 
service during the course of clinical care and/or by study personnel via daily review of these 
patient lists in OMR. Patients meeting eligibility criteria below will be reviewed and 
approached to discuss the study, if appropriate.  
Inclusion Criteria:  
 Age >= 18  
 Cirrhosis, as defined by liver biopsy (completed as standard care) or a composite 
assessment of available results from imaging or elastography, prior records, and 
laboratory studies 
 MELD-Na >= 18 (Model for End Stage Liver Disease-Sodium, incorporating 
components of serum sodium, bilirubin, International Normalized Ratio (INR), and 
creatinine  
Exclusion Criteria:  
 Inability to obtain consent from subject or next of kin/legal authorized representative 
(LAR) 
 Allergy to cephalosporins 
 Pregnancy (due to limited prospective data regarding safety of ceftriaxone) 
 Presence of ascites amenable to paracentesis without paracentesis performed as 
SOC for exclusion of infection 
 Existing indication for new antibiotics, e.g. upper gastrointestinal hemorrhage or 
apparent infection  
 Use of major immunosuppressive medications (e.g. prednisone 20 mg/day or greater, 
immunosuppression for solid organ transplant)  
 History of recurrent C.difficile infection within the past year (>2 episodes) or requiring 
prior fecal microbiota transplant (FMT) 
 Enrollment in the study protocol during a previous admission 
 
 
There are no specific limitations regarding gender or racial distribution of the planned 
population studied and as such, our intended sample will reflect a subset of these patients 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
without selection based on either parameter. The only exception to this is pregnant women will 
be excluded due to theoretical risk of adverse effect of ceftriaxone exposure (Pregnancy 
category B). Please note that is exceptionally rare to encounter a pregnant patient with this 
degree of chronic liver illness. 
 
There are no specific requirements for contraception during this short study conducted with 
patients admitted to the hospital.  
 
B4. 
POSSIBLE BENEFITS 
Subjects may receive benefit via reduction in the risk or severity of infection during the 
admission. There may also be reduction in length of hospital stay or other complications such 
as indirect benefits such as rate of ICU transfer, variceal hemorrhage, or death. These will be 
identified in comparison to similar outcomes among subjects receiving placebo, noting, as 
above, that this is a pilot study, not intended to confirm such a benefit.  
The benefit to society would be validating the design of a larger trial which could confirm 
such benefits and thus improve medical care and metrics important to patients, such as length 
of stay and mortality.  
 
B5. 
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO 
 
Risks of participation in the study include reaction to the antibiotic used in the trial: 
Ceftriaxone is commonly used to treat patients with end stage liver disease, and subjects may 
be prescribed ceftriaxone as routine care even if they do not participate in this trial.   
 
Regardless of which treatment the subject is assigned, the study medication will be 
administered intravenously (IV), peripherally or via central venous catheter if one is already in 
place for routine care.    
 
 
Side effects rarely observed in patients receiving any type of fluid intravenously 
include fever, infection at the site of IV insertion, blood clot in the vein, or inflammation of the 
vein extending from the site of injection, IV fluid leakage into the tissue around the IV 
insertion, and fluid overload.  
 
Subjects randomized to receive ceftriaxone, may experience side effects that have 
been observed in prior clinical trials.     
 The most common side effects (>10%) observed in clinical trials of ceftriaxone include 
skin tightness, thickening of the skin, and a warm sensation around the site of the 
injection when ceftriaxone was administered as an intermuscular injection.   
 Less common side effects ( <10%) included pain and tenderness at the injection site 
when the drug is given as an intermuscular injection; skin rash, diarrhea, eosinophilia 
(excess of inflammatory/allergic blood cells), thrombocytopenia (excess of 
platelets/blood clotting-cells), leukopenia (low level of white/infection-fighting blood 
cells), increased serum transaminases (liver blood tests which may suggest liver 
injury) and increased blood urea nitrogen (a marker of kidney function).  
 Allergic reaction to the study drug which can vary in severity from asymptomatic rash, to 
pruritic (itchy) rash, to hives, to anaphylaxis (a life threatening allergic reaction). 
 Indirect adverse effect of the study drug: development of antibiotic resistance, 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
opportunistic infection- C difficile colitis or fungal infection. Diagnostic uncertainty related 
to treatment of subsequent infections. 
 
Subjects randomized to receive placebo, will receive approximately 100 mL (less than 
7 tablespoons) of normal saline. There are no additional side effects expected beyond those 
listed above. 
 
Blood draw and receiving medication intravenously:  The risks and discomforts of 
drawing blood from a vein include the possibility of pain or bruising at the site of the blood 
draw, occasional feeling of lightheadedness, and rarely, infection or blood clotting at the site 
of the blood draw. 
 
Some participants may need one or all of the following tests for the study:  
 
Chest X-Ray/Radiation Risk:   
 
Some patients may get a chest x-ray to rule out infection at screening if one has not 
been completed as standard care. Radiation exposure from a single chest x-ray will deliver 
approximately 0.2 milliSieverts, a measure of radiation exposure. For comparison, the 
average person in the United States receives a radiation exposure of 3.2 milliSieverts per 
year from natural background and exposures we encounter in our everyday life. One possible 
effect from this additional radiation exposure is an increase in the risk of cancer. The 
estimated increase in the cancer risk due to this radiation exposure is 0.002%. 
 
 
Other Tests, Imaging Studies, and Procedures: Based on the severity of your 
condition or if your disease worsens, you may be asked to undergo other diagnostic tests, 
imaging studies (e.g., ultrasound), and procedures as a standard of care for your condition.  
There may be risks associated with these tests, imaging studies, and procedures.  Your 
doctor will explain the risks associated with each test/study/procedure and you may be asked 
to sign a separate informed consent form depending on the test/study/procedure being 
performed. 
 
Loss of confidentiality: There is the potential for loss of confidentiality by 
participating in this study.  Every effort will be made to protect the confidentiality of your 
identifiable information.   
 
We feel that the potential benefit to this patient population of this type of treatment 
outweighs these risks. We have attempted to minimize risk by exclusion of subjects deemed to 
be at greater risk of adverse reaction (e.g. history of allergy to cephalosporins or recurrent 
clostridium difficile infection), permitted non-study clinical teams to provide treatment without 
limitation, and minimized the number of subjects exposed to the intervention. The potential 
benefit to future patients could include reduced admission length or mortality rate.  
 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
B6. 
RECRUITMENT AND CONSENT PROCEDURES 
 
Recruitment: Study participants will be identified from among the ranks of patients 
admitted to the BIDMC (Emergency Department and/or Liver Service) with end stage liver 
disease and advanced cirrhosis. 
 
The PI and physician co-Investigators will identify patients admitted to their Service 
(Liver / Transplant Services) who meet preliminary eligibility criteria.  Thereafter, a physician 
investigator will meet with the potential participant to introduce the study.  If the patient does 
not have capacity to consent, the Investigator will identify the patient’s Health Care Proxy / 
Legally Authorized Representative (LAR) to introduce the study.   
           Due to the COVID-19 global pandemic and hospital wide visitor restriction policies, 
informed consent will be conducted remotely via telephone with the patient’s LAR when 
necessary.  
 
Once the potential participant/LAR indicates willingness to consider enrollment, the 
physician investigator will explain the study in clear, easy-to-understand language; review study 
purpose and goals, study treatment, procedures (including randomization), burdens and 
benefits, and schedules.  Any questions from a potential participant/LAR regarding the study will 
be answered by the study investigator. 
 
Consent: Consent procedures will be completed for patients in a private setting beyond 
the ear shot of others. The physician investigator will review all study procedures, and risks 
and benefits will be discussed.  The patient/LAR will be given ample time to ask questions and 
all questions will be answered. If the patient/LAR wishes to discuss participation with others, 
arrangements will be made to facilitate/expedite these discussions as time from subject 
identification to treatment is of importance.     
 
Patients/LAR willing to consent to participation will be required to sign and date the 
BIDMC CCI approved consent; the Investigator completing consent procedures will also sign 
and date the consent document. The original consent will be maintained in the subject’s 
research record, a copy will be placed in the subject’s medical record, and a copy of the signed 
consent will be given to the subject.  
           When conducting consent remotely, a consent document will be emailed to the patient’s 
LAR. Once the investigator and LAR both have a hard copy of the consent document in front of 
them, the consent document will be reviewed according to the same standards as outline 
above. If the LAR is willing to consent to study participation, they will sign the consent 
document and email or fax return a picture of the consent document signature page to study 
staff. The signature page signed by the LAR will be filed in the patient’s research record 
alongside the consent document signed by the Investigator. A copy of both signed documents 
will be emailed to the LAR for their records.  
 
If informed consent is obtained from a LAR, capacity for consent will be documented in 
the medical record. Once the subject’s condition improves such that s/he regains capacity, 
informed consent for continued study participation will be obtained from the subject at that 
time. A separate ICF will be used to complete this consent. 
Subject Protection:  We do not 
believe potential participants are vulnerable to coercion or undue influence. Patients admitted 
to the hospital with advanced chronic liver disease frequently present with hepatic 
encephalopathy.  To exclude these patients would exclude a substantial group for whom the 
study is specifically intended to help.  When investigators encounter a patient who does not 
have capacity to consent, the LAR will be identified and approached to obtain consent on 

(CCI) Committee on Clinical Investigations 
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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
behalf of the potential subject. At such time as the patient regains capacity, the investigator will 
complete consent procedures directly with the subject. 
 
We will not enroll prisoners into the study.  
 
B7. 
STUDY LOCATION 
 
Privacy: Consent procedures will be completed in a private hospital setting, beyond 
earshot of others by study investigators during the patient’s hospital admission, e.g. private 
exam room, in-patient hospital room, etc.   
 
Study procedures will be completed in various hospital settings, outpatient clinic or on 
the telephone. Patient privacy will be maintained in accordance with hospital policy and 
procedures. Medical record reviews will be completed by study staff at workstations in 
BIDMC research and clinical staff offices. Information collected will be limited to the minimum 
amount of data necessary to accomplish the research purposes.  
 
All investigators and study staff are trained in HIPAA guidelines and requirements as 
well as Human Subjects Protections best practices. Only the investigators and study staff 
have access to data that identifies subjects by name. Subjects are assigned a unique study 
identifier and all subject records will be void of subject identifiers.   
 
Only investigators listed will be able to connect individual subject information with 
research data. Data will be kept on a password protected database on a firewall-protected, 
BIDMC password protected computer in a restricted access location. 
 
Physical Setting: Study investigators will interact with potential subjects during a 
hospitalization and following outpatient clinic visits in the Liver Center or Transplant Center. 
Subjects may be contact by phone in the event they do not return to the Center for a follow 
up visits prior to Day 30 post study treatment.  
 

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Study Description – Part B 
CCI Form:  9-2015 
 
PI Revision Date:  2/24/2021  
 
B8. 
DATA SECURITY 
 
Study staff is trained in human subject protections regulation including hospital 
mandated CITI and HIPAA standards.  Access to clinical medical records used for the trial is 
strictly limited in accordance with hospital policies.  Data abstracted from medical records will 
be managed in compliance with clinical research best practices; both hard copy and 
electronic data collected for the investigation will be stored in restricted access files in the 
Division’s Clinical Research Offices and in electronic files and folders behind hospital 
firewalls. Data included in analytic files will be de-identified and the key linking data to patient 
identity will be maintained by the investigators in a separated restricted access location. 
 
B9 
Multi-Site Studies 
 
Is the BIDMC the coordinating site?       
 Yes    
 No Not applicable 
Is the BIDMC PI the lead investigator of the multi-site study?     
 Yes    
 No Not applicable 
 
B10 
Dissemination of Research Results 
 
In this pilot study to determine feasibility of case finding, rate of enrollment, data 
capture, and specimen collection and processing for a future, larger study of the effect of 
empiric antibiotics for all patients with advanced cirrhosis admitted to the hospital without an 
existing indication for new antibiotic use. There will be no subject specific outcomes to 
present to participants. 
 
The results of this study may be published and/or presented at scientific meetings in 
accordance with customary academic, editorial, and ethical practices and requirements.